Full text data of MAPK1
MAPK1
(ERK2, PRKM1, PRKM2)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Mitogen-activated protein kinase 1; MAP kinase 1; MAPK 1; 2.7.11.24 (ERT1; Extracellular signal-regulated kinase 2; ERK-2; MAP kinase isoform p42; p42-MAPK; Mitogen-activated protein kinase 2; MAP kinase 2; MAPK 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Mitogen-activated protein kinase 1; MAP kinase 1; MAPK 1; 2.7.11.24 (ERT1; Extracellular signal-regulated kinase 2; ERK-2; MAP kinase isoform p42; p42-MAPK; Mitogen-activated protein kinase 2; MAP kinase 2; MAPK 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P28482
ID MK01_HUMAN Reviewed; 360 AA.
AC P28482; A8CZ64;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Mitogen-activated protein kinase 1;
DE Short=MAP kinase 1;
DE Short=MAPK 1;
DE EC=2.7.11.24;
DE AltName: Full=ERT1;
DE AltName: Full=Extracellular signal-regulated kinase 2;
DE Short=ERK-2;
DE AltName: Full=MAP kinase isoform p42;
DE Short=p42-MAPK;
DE AltName: Full=Mitogen-activated protein kinase 2;
DE Short=MAP kinase 2;
DE Short=MAPK 2;
GN Name=MAPK1; Synonyms=ERK2, PRKM1, PRKM2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1540184; DOI=10.1016/0006-291X(92)91891-S;
RA Owaki H., Makar R., Boulton T.G., Cobb M.H., Geppert T.D.;
RT "Extracellular signal-regulated kinases in T cells: characterization
RT of human ERK1 and ERK2 cDNAs.";
RL Biochem. Biophys. Res. Commun. 182:1416-1422(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1319925; DOI=10.1016/0014-5793(92)80612-K;
RA Gonzalez F.A., Raden D.L., Rigby M.R., Davis R.J.;
RT "Heterogeneous expression of four MAP kinase isoforms in human
RT tissues.";
RL FEBS Lett. 304:170-178(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING.
RA Cheng H., Ren S., Qiu R., Wang M., Feng Y.H.;
RT "Identification of dominant negative Erk1/2 variants in cancer
RT cells.";
RL Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 2-15, AND ACETYLATION AT ALA-2.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [7]
RP FUNCTION IN PHOSPHORYLATION OF ERF.
RX PubMed=7588608;
RA Sgouras D.N., Athanasiou M.A., Beal G.J. Jr., Fisher R.J., Blair D.G.,
RA Mavrothalassitis G.J.;
RT "ERF: an ETS domain protein with strong transcriptional repressor
RT activity, can suppress ets-associated tumorigenesis and is regulated
RT by phosphorylation during cell cycle and mitogenic stimulation.";
RL EMBO J. 14:4781-4793(1995).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF MAPKAPK3.
RX PubMed=8622688;
RA Sithanandam G., Latif F., Duh F.-M., Bernal R., Smola U., Li H.,
RA Kuzmin I., Wixler V., Geil L., Shrestha S., Lloyd P.A., Bader S.,
RA Sekido Y., Tartof K.D., Kashuba V.I., Zabarovsky E.R., Dean M.,
RA Klein G., Lerman M.I., Minna J.D., Rapp U.R., Allikmets R.;
RT "3pK, a new mitogen-activated protein kinase-activated protein kinase
RT located in the small cell lung cancer tumor suppressor gene region.";
RL Mol. Cell. Biol. 16:868-876(1996).
RN [9]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=8794306;
RA Greenway A.L., Azad A., Mills J., McPhee D.A.;
RT "Human immunodeficiency virus type 1 Nef binds directly to LCK and
RT mitogen-activated protein kinase, inhibiting kinase activity.";
RL J. Virol. 70:6701-6708(1996).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF MAPKAPK5.
RX PubMed=9480836; DOI=10.1006/bbrc.1998.8135;
RA Ni H., Wang X.S., Diener K., Yao Z.;
RT "MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated
RT protein kinase, is a substrate of the extracellular-regulated kinase
RT (ERK) and p38 kinase.";
RL Biochem. Biophys. Res. Commun. 243:492-496(1998).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF RPS6KA5/MSK1.
RX PubMed=9687510; DOI=10.1093/emboj/17.15.4426;
RA Deak M., Clifton A.D., Lucocq J.M., Alessi D.R.;
RT "Mitogen- and stress-activated protein kinase-1 (MSK1) is directly
RT activated by MAPK and SAPK2/p38, and may mediate activation of CREB.";
RL EMBO J. 17:4426-4441(1998).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF BCL6.
RX PubMed=9649500;
RA Niu H., Ye B.H., Dalla-Favera R.;
RT "Antigen receptor signaling induces MAP kinase-mediated
RT phosphorylation and degradation of the BCL-6 transcription factor.";
RL Genes Dev. 12:1953-1961(1998).
RN [13]
RP INTERACTION WITH DUSP6, AND FUNCTION.
RX PubMed=9596579; DOI=10.1126/science.280.5367.1262;
RA Camps M., Nichols A., Gillieron C., Antonsson B., Muda M., Chabert C.,
RA Boschert U., Arkinstall S.;
RT "Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-
RT activated protein kinase.";
RL Science 280:1262-1265(1998).
RN [14]
RP DEPHOSPHORYLATION BY DUSP3.
RX PubMed=10224087; DOI=10.1074/jbc.274.19.13271;
RA Todd J.L., Tanner K.G., Denu J.M.;
RT "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic
RT substrates for the dual-specificity protein-tyrosine phosphatase VHR.
RT A novel role in down-regulating the ERK pathway.";
RL J. Biol. Chem. 274:13271-13280(1999).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF ELK1.
RX PubMed=10637505; DOI=10.1038/sj.onc.1203362;
RA Cruzalegui F.H., Cano E., Treisman R.;
RT "ERK activation induces phosphorylation of Elk-1 at multiple S/T-P
RT motifs to high stoichiometry.";
RL Oncogene 18:7948-7957(1999).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF DUSP1.
RX PubMed=10617468; DOI=10.1126/science.286.5449.2514;
RA Brondello J.M., Pouyssegur J., McKenzie F.R.;
RT "Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-
RT dependent phosphorylation.";
RL Science 286:2514-2517(1999).
RN [17]
RP FUNCTION AS MKNK2 KINASE.
RX PubMed=11154262; DOI=10.1128/MCB.21.3.743-754.2001;
RA Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.;
RT "The mitogen-activated protein kinase signal-integrating kinase Mnk2
RT is a eukaryotic initiation factor 4E kinase with high levels of basal
RT activity in mammalian cells.";
RL Mol. Cell. Biol. 21:743-754(2001).
RN [18]
RP FUNCTION IN PHOSPHORYLATION OF ATF2.
RX PubMed=12110590; DOI=10.1093/emboj/cdf361;
RA Ouwens D.M., de Ruiter N.D., van der Zon G.C., Carter A.P.,
RA Schouten J., van der Burgt C., Kooistra K., Bos J.L., Maassen J.A.,
RA van Dam H.;
RT "Growth factors can activate ATF2 via a two-step mechanism:
RT phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69
RT through RalGDS-Src-p38.";
RL EMBO J. 21:3782-3793(2002).
RN [19]
RP FUNCTION IN PHOSPHORYLATION OF IER3, INTERACTION WITH IER3, AND ENZYME
RP REGULATION.
RX PubMed=12356731; DOI=10.1093/emboj/cdf488;
RA Garcia J., Ye Y., Arranz V., Letourneux C., Pezeron G., Porteu F.;
RT "IEX-1: a new ERK substrate involved in both ERK survival activity and
RT ERK activation.";
RL EMBO J. 21:5151-5163(2002).
RN [20]
RP INTERACTION WITH NISCH.
RX PubMed=11912194; DOI=10.1074/jbc.M111838200;
RA Sano H., Liu S.C.H., Lane W.S., Piletz J.E., Lienhard G.E.;
RT "Insulin receptor substrate 4 associates with the protein IRAS.";
RL J. Biol. Chem. 277:19439-19447(2002).
RN [21]
RP FUNCTION IN PHOSPHORYLATION OF FRS2.
RX PubMed=12974390; DOI=10.1515/BC.2003.134;
RA Wu Y., Chen Z., Ullrich A.;
RT "EGFR and FGFR signaling through FRS2 is subject to negative feedback
RT control by ERK1/2.";
RL Biol. Chem. 384:1215-1226(2003).
RN [22]
RP FUNCTION IN PHOSPHORYLATION OF DUSP16.
RX PubMed=12794087; DOI=10.1074/jbc.M213254200;
RA Masuda K., Shima H., Katagiri C., Kikuchi K.;
RT "Activation of ERK induces phosphorylation of MAPK phosphatase-7, a
RT JNK specific phosphatase, at Ser-446.";
RL J. Biol. Chem. 278:32448-32456(2003).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF CASP9.
RX PubMed=12792650; DOI=10.1038/ncb1005;
RA Allan L.A., Morrice N., Brady S., Magee G., Pathak S., Clarke P.R.;
RT "Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK
RT MAPK.";
RL Nat. Cell Biol. 5:647-654(2003).
RN [24]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH NEK2.
RX PubMed=15358203; DOI=10.1016/j.bbrc.2004.06.171;
RA Lou Y., Xie W., Zhang D.F., Yao J.H., Luo Z.F., Wang Y.Z., Shi Y.Y.,
RA Yao X.B.;
RT "Nek2A specifies the centrosomal localization of Erk2.";
RL Biochem. Biophys. Res. Commun. 321:495-501(2004).
RN [25]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [26]
RP FUNCTION IN PHOSPHORYLATION OF SORBS3.
RX PubMed=15184391; DOI=10.1074/jbc.M402304200;
RA Mitsushima M., Suwa A., Amachi T., Ueda K., Kioka N.;
RT "Extracellular signal-regulated kinase activated by epidermal growth
RT factor and cell adhesion interacts with and phosphorylates vinexin.";
RL J. Biol. Chem. 279:34570-34577(2004).
RN [27]
RP FUNCTION IN PHOSPHORYLATION OF MCL1.
RX PubMed=15241487; DOI=10.1038/sj.onc.1207692;
RA Domina A.M., Vrana J.A., Gregory M.A., Hann S.R., Craig R.W.;
RT "MCL1 is phosphorylated in the PEST region and stabilized upon ERK
RT activation in viable cells, and at additional sites with cytotoxic
RT okadaic acid or taxol.";
RL Oncogene 23:5301-5315(2004).
RN [28]
RP FUNCTION IN PHOSPHORYLATION OF GRB10.
RX PubMed=15952796; DOI=10.1021/bi050413i;
RA Langlais P., Wang C., Dong L.Q., Carroll C.A., Weintraub S.T., Liu F.;
RT "Phosphorylation of Grb10 by mitogen-activated protein kinase:
RT identification of Ser150 and Ser476 of human Grb10zeta as major
RT phosphorylation sites.";
RL Biochemistry 44:8890-8897(2005).
RN [29]
RP FUNCTION IN PHOSPHORYLATION OF DAPK1, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH DAPK1.
RX PubMed=15616583; DOI=10.1038/sj.emboj.7600510;
RA Chen C.H., Wang W.J., Kuo J.C., Tsai H.C., Lin J.R., Chang Z.F.,
RA Chen R.H.;
RT "Bidirectional signals transduced by DAPK-ERK interaction promote the
RT apoptotic effect of DAPK.";
RL EMBO J. 24:294-304(2005).
RN [30]
RP FUNCTION IN PHOSPHORYLATION OF BTG2.
RX PubMed=15788397; DOI=10.1074/jbc.M500318200;
RA Hong J.W., Ryu M.S., Lim I.K.;
RT "Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces
RT Pin-1 binding in cytoplasm and cell death.";
RL J. Biol. Chem. 280:21256-21263(2005).
RN [31]
RP FUNCTION IN PHOSPHORYLATION OF RAF1.
RX PubMed=15664191; DOI=10.1016/j.molcel.2004.11.055;
RA Dougherty M.K., Muller J., Ritt D.A., Zhou M., Zhou X.Z.,
RA Copeland T.D., Conrads T.P., Veenstra T.D., Lu K.P., Morrison D.K.;
RT "Regulation of Raf-1 by direct feedback phosphorylation.";
RL Mol. Cell 17:215-224(2005).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [33]
RP INTERACTION WITH ARHGEF2.
RX PubMed=18211802; DOI=10.1016/j.bbrc.2008.01.066;
RA Fujishiro S.H., Tanimura S., Mure S., Kashimoto Y., Watanabe K.,
RA Kohno M.;
RT "ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide
RT exchange activity toward RhoA.";
RL Biochem. Biophys. Res. Commun. 368:162-167(2008).
RN [34]
RP FUNCTION, AND INTERACTION WITH HSF4.
RX PubMed=16581800; DOI=10.1128/MCB.26.8.3282-3294.2006;
RA Hu Y., Mivechi N.F.;
RT "Association and regulation of heat shock transcription factor 4b with
RT both extracellular signal-regulated kinase mitogen-activated protein
RT kinase and dual-specificity tyrosine phosphatase DUSP26.";
RL Mol. Cell. Biol. 26:3282-3294(2006).
RN [35]
RP PHOSPHORYLATION.
RX PubMed=17274988; DOI=10.1016/j.febslet.2007.01.039;
RA Degoutin J., Vigny M., Gouzi J.Y.;
RT "ALK activation induces Shc and FRS2 recruitment: Signaling and
RT phenotypic outcomes in PC12 cells differentiation.";
RL FEBS Lett. 581:727-734(2007).
RN [36]
RP INTERACTION WITH ARRB2.
RX PubMed=18435604; DOI=10.1042/BJ20080685;
RA Xu T.-R., Baillie G.S., Bhari N., Houslay T.M., Pitt A.M., Adams D.R.,
RA Kolch W., Houslay M.D., Milligan G.;
RT "Mutations of beta-arrestin 2 that limit self-association also
RT interfere with interactions with the beta2-adrenoceptor and the ERK1/2
RT MAPKs: implications for beta2-adrenoceptor signalling via the ERK1/2
RT MAPKs.";
RL Biochem. J. 413:51-60(2008).
RN [37]
RP INTERACTION WITH ADAM15.
RX PubMed=18296648; DOI=10.1158/1541-7786.MCR-07-2028;
RA Zhong J.L., Poghosyan Z., Pennington C.J., Scott X., Handsley M.M.,
RA Warn A., Gavrilovic J., Honert K., Kruger A., Span P.N., Sweep F.C.,
RA Edwards D.R.;
RT "Distinct functions of natural ADAM-15 cytoplasmic domain variants in
RT human mammary carcinoma.";
RL Mol. Cancer Res. 6:383-394(2008).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [39]
RP PHOSPHORYLATION AT SER-246 AND SER-248, INTERACTION WITH IPO7, AND
RP SUBCELLULAR LOCATION.
RX PubMed=18760948; DOI=10.1016/j.molcel.2008.08.007;
RA Chuderland D., Konson A., Seger R.;
RT "Identification and characterization of a general nuclear
RT translocation signal in signaling proteins.";
RL Mol. Cell 31:850-861(2008).
RN [40]
RP FUNCTION IN PHOSPHORYLATION OF TPR, INTERACTION WITH TPR, AND
RP MUTAGENESIS OF LYS-54; 176-PRO--ASP-179; THR-185; TYR-187; LEU-234;
RP ASP-318 AND ASP-321.
RX PubMed=18794356; DOI=10.1128/MCB.00925-08;
RA Vomastek T., Iwanicki M.P., Burack W.R., Tiwari D., Kumar D.,
RA Parsons J.T., Weber M.J., Nandicoori V.K.;
RT "Extracellular signal-regulated kinase 2 (ERK2) phosphorylation sites
RT and docking domain on the nuclear pore complex protein Tpr
RT cooperatively regulate ERK2-Tpr interaction.";
RL Mol. Cell. Biol. 28:6954-6966(2008).
RN [41]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-185 AND TYR-187, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [42]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [43]
RP FUNCTION AS A TRANSCRIPTIONAL REPRESSOR, AND DNA-BINDING.
RX PubMed=19879846; DOI=10.1016/j.cell.2009.08.037;
RA Hu S., Xie Z., Onishi A., Yu X., Jiang L., Lin J., Rho H.-S.,
RA Woodard C., Wang H., Jeong J.-S., Long S., He X., Wade H.,
RA Blackshaw S., Qian J., Zhu H.;
RT "Profiling the human protein-DNA interactome reveals ERK2 as a
RT transcriptional repressor of interferon signaling.";
RL Cell 139:610-622(2009).
RN [44]
RP FUNCTION IN KIT SIGNALING PATHWAY, AND PHOSPHORYLATION.
RX PubMed=19265199; DOI=10.1074/jbc.M808058200;
RA Sun J., Pedersen M., Ronnstrand L.;
RT "The D816V mutation of c-Kit circumvents a requirement for Src family
RT kinases in c-Kit signal transduction.";
RL J. Biol. Chem. 284:11039-11047(2009).
RN [45]
RP PHOSPHORYLATION AT TYR-187, DEPHOSPHORYLATION BY PTPRJ AT TYR-187, AND
RP MUTAGENESIS OF ASP-318.
RX PubMed=19494114; DOI=10.1074/jbc.M109.002758;
RA Sacco F., Tinti M., Palma A., Ferrari E., Nardozza A.P.,
RA Hooft van Huijsduijnen R., Takahashi T., Castagnoli L., Cesareni G.;
RT "Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the
RT RAS pathway by direct dephosphorylation of ERK1/2 kinases.";
RL J. Biol. Chem. 284:22048-22058(2009).
RN [46]
RP PHOSPHORYLATION AT SER-29 BY SGK1, AND INTERACTION WITH SGK1.
RX PubMed=19447520; DOI=10.1016/j.jhep.2009.02.027;
RA Won M., Park K.A., Byun H.S., Kim Y.R., Choi B.L., Hong J.H., Park J.,
RA Seok J.H., Lee Y.H., Cho C.H., Song I.S., Kim Y.K., Shen H.M.,
RA Hur G.M.;
RT "Protein kinase SGK1 enhances MEK/ERK complex formation through the
RT phosphorylation of ERK2: implication for the positive regulatory role
RT of SGK1 on the ERK function during liver regeneration.";
RL J. Hepatol. 51:67-76(2009).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-284, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [48]
RP AUTOPHOSPHORYLATION AT THR-190, ENZYME REGULATION, SUBUNIT, AND
RP SUBCELLULAR LOCATION.
RX PubMed=19060905; DOI=10.1038/nm.1893;
RA Lorenz K., Schmitt J.P., Schmitteckert E.M., Lohse M.J.;
RT "A new type of ERK1/2 autophosphorylation causes cardiac
RT hypertrophy.";
RL Nat. Med. 15:75-83(2009).
RN [49]
RP REVIEW ON FUNCTION.
RX PubMed=16393692; DOI=10.1080/02699050500284218;
RA Yoon S., Seger R.;
RT "The extracellular signal-regulated kinase: multiple substrates
RT regulate diverse cellular functions.";
RL Growth Factors 24:21-44(2006).
RN [50]
RP REVIEW ON FUNCTION, AND REVIEW ON SUBCELLULAR LOCATION.
RX PubMed=19565474; DOI=10.1002/biof.52;
RA Yao Z., Seger R.;
RT "The ERK signaling cascade--views from different subcellular
RT compartments.";
RL BioFactors 35:407-416(2009).
RN [51]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-185 AND TYR-187, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [52]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [53]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [54]
RP REVIEW ON ENZYME REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=21779493; DOI=10.1177/1947601911407328;
RA Wortzel I., Seger R.;
RT "The ERK cascade: distinct functions within various subcellular
RT organelles.";
RL Genes Cancer 2:195-209(2011).
RN [55]
RP FUNCTION, AND INTERACTION WITH PML.
RX PubMed=22033920; DOI=10.1074/jbc.M111.289512;
RA Lim J.H., Liu Y., Reineke E., Kao H.Y.;
RT "Mitogen-activated protein kinase extracellular signal-regulated
RT kinase 2 phosphorylates and promotes Pin1 protein-dependent
RT promyelocytic leukemia protein turnover.";
RL J. Biol. Chem. 286:44403-44411(2011).
RN [56]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-185 AND TYR-187, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [57]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [58]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=9827991;
RA Fox T., Coll J.T., Xie X., Ford P.J., Germann U.A., Porter M.D.,
RA Pazhanisamy S., Fleming M.A., Galullo V., Su M.S., Wilson K.P.;
RT "A single amino acid substitution makes ERK2 susceptible to pyridinyl
RT imidazole inhibitors of p38 MAP kinase.";
RL Protein Sci. 7:2249-2255(1998).
RN [59]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=16139248; DOI=10.1016/j.bbrc.2005.08.082;
RA Ohori M., Kinoshita T., Okubo M., Sato K., Yamazaki A., Arakawa H.,
RA Nishimura S., Inamura N., Nakajima H., Neya M., Miyake H., Fujii T.;
RT "Identification of a selective ERK inhibitor and structural
RT determination of the inhibitor-ERK2 complex.";
RL Biochem. Biophys. Res. Commun. 336:357-363(2005).
RN [60]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=16242327; DOI=10.1016/j.bmcl.2005.09.055;
RA Kinoshita T., Warizaya M., Ohori M., Sato K., Neya M., Fujii T.;
RT "Crystal structure of human ERK2 complexed with a pyrazolo[3,4-
RT c]pyridazine derivative.";
RL Bioorg. Med. Chem. Lett. 16:55-58(2006).
RN [61]
RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=17194451; DOI=10.1016/j.bbrc.2006.12.083;
RA Ohori M., Kinoshita T., Yoshimura S., Warizaya M., Nakajima H.,
RA Miyake H.;
RT "Role of a cysteine residue in the active site of ERK and the MAPKK
RT family.";
RL Biochem. Biophys. Res. Commun. 353:633-637(2007).
RN [62]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 2-359 IN COMPLEX WITH
RP INHIBITOR.
RX PubMed=17300186; DOI=10.1021/jm061381f;
RA Aronov A.M., Baker C., Bemis G.W., Cao J., Chen G., Ford P.J.,
RA Germann U.A., Green J., Hale M.R., Jacobs M., Janetka J.W.,
RA Maltais F., Martinez-Botella G., Namchuk M.N., Straub J., Tang Q.,
RA Xie X.;
RT "Flipped out: structure-guided design of selective pyrazolylpyrrole
RT ERK inhibitors.";
RL J. Med. Chem. 50:1280-1287(2007).
RN [63]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 186-191, AND PHOSPHORYLATION
RP AT TYR-187.
RX PubMed=19053285; DOI=10.1021/bi801724n;
RA Critton D.A., Tortajada A., Stetson G., Peti W., Page R.;
RT "Structural basis of substrate recognition by hematopoietic tyrosine
RT phosphatase.";
RL Biochemistry 47:13336-13345(2008).
RN [64]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=19827834; DOI=10.1021/jm900630q;
RA Aronov A.M., Tang Q., Martinez-Botella G., Bemis G.W., Cao J.,
RA Chen G., Ewing N.P., Ford P.J., Germann U.A., Green J., Hale M.R.,
RA Jacobs M., Janetka J.W., Maltais F., Markland W., Namchuk M.N.,
RA Nanthakumar S., Poondru S., Straub J., ter Haar E., Xie X.;
RT "Structure-guided design of potent and selective pyrimidylpyrrole
RT inhibitors of extracellular signal-regulated kinase (ERK) using
RT conformational control.";
RL J. Med. Chem. 52:6362-6368(2009).
CC -!- FUNCTION: Serine/threonine kinase which acts as an essential
CC component of the MAP kinase signal transduction pathway.
CC MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important
CC role in the MAPK/ERK cascade. They participate also in a signaling
CC cascade initiated by activated KIT and KITLG/SCF. Depending on the
CC cellular context, the MAPK/ERK cascade mediates diverse biological
CC functions such as cell growth, adhesion, survival and
CC differentiation through the regulation of transcription,
CC translation, cytoskeletal rearrangements. The MAPK/ERK cascade
CC plays also a role in initiation and regulation of meiosis,
CC mitosis, and postmitotic functions in differentiated cells by
CC phosphorylating a number of transcription factors. About 160
CC substrates have already been discovered for ERKs. Many of these
CC substrates are localized in the nucleus, and seem to participate
CC in the regulation of transcription upon stimulation. However,
CC other substrates are found in the cytosol as well as in other
CC cellular organelles, and those are responsible for processes such
CC as translation, mitosis and apoptosis. Moreover, the MAPK/ERK
CC cascade is also involved in the regulation of the endosomal
CC dynamics, including lysosome processing and endosome cycling
CC through the perinuclear recycling compartment (PNRC); as well as
CC in the fragmentation of the Golgi apparatus during mitosis. The
CC substrates include transcription factors (such as ATF2, BCL6,
CC ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as
CC CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of
CC apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG),
CC regulators of translation (such as EIF4EBP1) and a variety of
CC other signaling-related molecules (like ARHGEF2, DCC, FRS2 or
CC GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2,
CC RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2,
CC RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases
CC (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which
CC enable the propagation the MAPK/ERK signal to additional cytosolic
CC and nuclear targets, thereby extending the specificity of the
CC cascade. Mediates phosphorylation of TPR in respons to EGF
CC stimulation. May play a role in the spindle assembly checkpoint.
CC Phosphorylates PML and promotes its interaction with PIN1, leading
CC to PML degradation.
CC -!- FUNCTION: Acts as a transcriptional repressor. Binds to a
CC [GC]AAA[GC] consensus sequence. Repress the expression of
CC interferon gamma-induced genes. Seems to bind to the promoter of
CC CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and
CC STAT1. Transcriptional activity is independent of kinase activity.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- ENZYME REGULATION: Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2
CC on Thr-185 and Tyr-187 in response to external stimuli like
CC insulin or NGF. Both phosphorylations are required for activity.
CC This phosphorylation causes dramatic conformational changes, which
CC enable full activation and interaction of MAPK1/ERK2 with its
CC substrates. Phosphorylation on Ser-29 by SGK1 results in its
CC activation by enhancing its interaction with MAP2K1/MEK1 and
CC MAP2K2/MEK2. Dephosphorylated and inactivated by DUSP3, DUSP6 and
CC DUSP9. Inactivated by pyrimidylpyrrole inhibitors.
CC -!- SUBUNIT: Binds both upstream activators and downstream substrates
CC in multimolecular complexes. Binds to HIV-1 Nef through its SH3
CC domain. This interaction inhibits its tyrosine-kinase activity.
CC Interacts with ADAM15, ARHGEF2, ARRB2, DAPK1 (via death domain),
CC HSF4, IER3, IPO7, DUSP6, NISCH, SGK1, and isoform 1 of NEK2.
CC Interacts (phosphorylated form) with CAV2 ('Tyr-19'-phosphorylated
CC form); the interaction, promoted by insulin, leads to nuclear
CC location and MAPK1 activation. Interacts with MORG1, PEA15 and
CC MKNK2 (By similarity). MKNK2 isoform 1 binding prevents from
CC dephosphorylation and inactivation (By similarity). Interacts with
CC DCC (By similarity). The phosphorylated form interacts with PML
CC (isoform PML-4).
CC -!- INTERACTION:
CC Q9U1H0:cic (xeno); NbExp=2; IntAct=EBI-959949, EBI-98330;
CC P28562:DUSP1; NbExp=6; IntAct=EBI-959949, EBI-975493;
CC Q05922:Dusp2 (xeno); NbExp=2; IntAct=EBI-959949, EBI-7898692;
CC Q16690:DUSP5; NbExp=4; IntAct=EBI-959949, EBI-7487376;
CC P14921:ETS1; NbExp=2; IntAct=EBI-959949, EBI-913209;
CC Q02750:MAP2K1; NbExp=2; IntAct=EBI-959949, EBI-492564;
CC Q16539-3:MAPK14; NbExp=5; IntAct=EBI-959949, EBI-6932370;
CC P27361:MAPK3; NbExp=3; IntAct=EBI-959949, EBI-73995;
CC P02687:MBP (xeno); NbExp=2; IntAct=EBI-959949, EBI-908215;
CC P35813:PPM1A; NbExp=19; IntAct=EBI-959949, EBI-989143;
CC P35236:PTPN7; NbExp=5; IntAct=EBI-959949, EBI-2265723;
CC Q12913:PTPRJ; NbExp=7; IntAct=EBI-959949, EBI-2264500;
CC Q69559:U24 (xeno); NbExp=2; IntAct=EBI-959949, EBI-8015758;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, spindle (By
CC similarity). Nucleus. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome. Cytoplasm. Note=Associated with the
CC spindle during prometaphase and metaphase (By similarity). PEA15-
CC binding and phosphorylated DAPK1 promote its cytoplasmic
CC retention. Phosphorylation at Ser- 246 and Ser-248 as well as
CC autophosphorylation at Thr-190 promote nuclear localization.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P28482-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P28482-2; Sequence=VSP_047815;
CC -!- DOMAIN: The TXY motif contains the threonine and tyrosine residues
CC whose phosphorylation activates the MAP kinases.
CC -!- PTM: Phosphorylated upon KIT and FLT3 signaling (By similarity).
CC Dually phosphorylated on Thr-185 and Tyr-187, which activates the
CC enzyme. Undergoes regulatory phosphorylation on additional
CC residues such as Ser-246 and Ser-248 in the kinase insert domain
CC (KID) These phosphorylations, which are probably mediated by more
CC than one kinase, are important for binding of MAPK1/ERK2 to
CC importin-7 (IPO7) and its nuclear translocation. In addition,
CC autophosphorylation of Thr-190 was shown to affect the subcellular
CC localization of MAPK1/ERK2 as well. Ligand-activated ALK induces
CC tyrosine phosphorylation. Dephosphorylated by PTPRJ at Tyr-187.
CC Phosphorylation on Ser-29 by SGK1 results in its activation by
CC enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. DUSP3
CC and DUSP6 dephosphorylate specifically MAPK1/ERK2 and MAPK3/ERK1
CC whereas DUSP9 dephosphorylates a broader range of MAPKs.
CC -!- PTM: ISGylated (By similarity).
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC
CC Ser/Thr protein kinase family. MAP kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA77753.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Extracellular signal-regulated
CC kinase entry;
CC URL="http://en.wikipedia.org/wiki/Extracellular_signal-regulated_kinase";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MAPK1ID41288ch22q11.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M84489; AAA58459.1; -; mRNA.
DR EMBL; Z11694; CAA77752.1; -; mRNA.
DR EMBL; Z11695; CAA77753.1; ALT_INIT; mRNA.
DR EMBL; DQ399292; ABD60303.1; -; mRNA.
DR EMBL; AP000553; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000554; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000555; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC017832; AAH17832.1; -; mRNA.
DR PIR; JQ1400; JQ1400.
DR RefSeq; NP_002736.3; NM_002745.4.
DR RefSeq; NP_620407.1; NM_138957.2.
DR UniGene; Hs.431850; -.
DR PDB; 1PME; X-ray; 2.00 A; A=1-360.
DR PDB; 1TVO; X-ray; 2.50 A; A=1-360.
DR PDB; 1WZY; X-ray; 2.50 A; A=1-360.
DR PDB; 2OJG; X-ray; 2.00 A; A=2-359.
DR PDB; 2OJI; X-ray; 2.60 A; A=2-359.
DR PDB; 2OJJ; X-ray; 2.40 A; A=2-359.
DR PDB; 2Y9Q; X-ray; 1.55 A; A=1-360.
DR PDB; 3D42; X-ray; 2.46 A; B=184-191.
DR PDB; 3D44; X-ray; 1.90 A; B=186-191.
DR PDB; 3I5Z; X-ray; 2.20 A; A=1-360.
DR PDB; 3I60; X-ray; 2.50 A; A=1-360.
DR PDB; 3SA0; X-ray; 1.59 A; A=1-360.
DR PDB; 3TEI; X-ray; 2.40 A; A=1-360.
DR PDB; 3W55; X-ray; 3.00 A; A=1-360.
DR PDB; 4FMQ; X-ray; 2.10 A; A=1-360.
DR PDB; 4FUX; X-ray; 2.20 A; A=1-360.
DR PDB; 4FUY; X-ray; 2.00 A; A=1-360.
DR PDB; 4FV0; X-ray; 2.10 A; A=1-360.
DR PDB; 4FV1; X-ray; 1.99 A; A=1-360.
DR PDB; 4FV2; X-ray; 2.00 A; A=1-360.
DR PDB; 4FV3; X-ray; 2.20 A; A=1-360.
DR PDB; 4FV4; X-ray; 2.50 A; A=1-360.
DR PDB; 4FV5; X-ray; 2.40 A; A=1-360.
DR PDB; 4FV6; X-ray; 2.50 A; A=1-360.
DR PDB; 4FV7; X-ray; 1.90 A; A=1-360.
DR PDB; 4FV8; X-ray; 2.00 A; A=1-360.
DR PDB; 4FV9; X-ray; 2.11 A; A=1-360.
DR PDB; 4G6N; X-ray; 2.00 A; A=1-360.
DR PDB; 4G6O; X-ray; 2.20 A; A=1-360.
DR PDB; 4H3P; X-ray; 2.30 A; A/D=1-360.
DR PDB; 4H3Q; X-ray; 2.20 A; A=1-360.
DR PDB; 4IZ5; X-ray; 3.19 A; A/B/C/D=8-360.
DR PDB; 4IZ7; X-ray; 1.80 A; A/C=8-360.
DR PDB; 4IZA; X-ray; 1.93 A; A/C=8-360.
DR PDBsum; 1PME; -.
DR PDBsum; 1TVO; -.
DR PDBsum; 1WZY; -.
DR PDBsum; 2OJG; -.
DR PDBsum; 2OJI; -.
DR PDBsum; 2OJJ; -.
DR PDBsum; 2Y9Q; -.
DR PDBsum; 3D42; -.
DR PDBsum; 3D44; -.
DR PDBsum; 3I5Z; -.
DR PDBsum; 3I60; -.
DR PDBsum; 3SA0; -.
DR PDBsum; 3TEI; -.
DR PDBsum; 3W55; -.
DR PDBsum; 4FMQ; -.
DR PDBsum; 4FUX; -.
DR PDBsum; 4FUY; -.
DR PDBsum; 4FV0; -.
DR PDBsum; 4FV1; -.
DR PDBsum; 4FV2; -.
DR PDBsum; 4FV3; -.
DR PDBsum; 4FV4; -.
DR PDBsum; 4FV5; -.
DR PDBsum; 4FV6; -.
DR PDBsum; 4FV7; -.
DR PDBsum; 4FV8; -.
DR PDBsum; 4FV9; -.
DR PDBsum; 4G6N; -.
DR PDBsum; 4G6O; -.
DR PDBsum; 4H3P; -.
DR PDBsum; 4H3Q; -.
DR PDBsum; 4IZ5; -.
DR PDBsum; 4IZ7; -.
DR PDBsum; 4IZA; -.
DR ProteinModelPortal; P28482; -.
DR SMR; P28482; 9-358.
DR DIP; DIP-519N; -.
DR IntAct; P28482; 66.
DR MINT; MINT-144006; -.
DR STRING; 9606.ENSP00000215832; -.
DR BindingDB; P28482; -.
DR ChEMBL; CHEMBL4040; -.
DR DrugBank; DB01169; Arsenic trioxide.
DR GuidetoPHARMACOLOGY; 1495; -.
DR PhosphoSite; P28482; -.
DR DMDM; 119554; -.
DR OGP; P28482; -.
DR PaxDb; P28482; -.
DR PeptideAtlas; P28482; -.
DR PRIDE; P28482; -.
DR DNASU; 5594; -.
DR Ensembl; ENST00000215832; ENSP00000215832; ENSG00000100030.
DR Ensembl; ENST00000398822; ENSP00000381803; ENSG00000100030.
DR Ensembl; ENST00000544786; ENSP00000440842; ENSG00000100030.
DR GeneID; 5594; -.
DR KEGG; hsa:5594; -.
DR UCSC; uc010gtk.1; human.
DR CTD; 5594; -.
DR GeneCards; GC22M022108; -.
DR HGNC; HGNC:6871; MAPK1.
DR HPA; CAB004229; -.
DR HPA; HPA003995; -.
DR HPA; HPA005700; -.
DR HPA; HPA030069; -.
DR MIM; 176948; gene.
DR neXtProt; NX_P28482; -.
DR Orphanet; 261330; Distal 22q11.2 microdeletion syndrome.
DR PharmGKB; PA30616; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233024; -.
DR HOVERGEN; HBG014652; -.
DR InParanoid; P28482; -.
DR KO; K04371; -.
DR OMA; VCSAYDR; -.
DR OrthoDB; EOG7M3J0K; -.
DR PhylomeDB; P28482; -.
DR BRENDA; 2.7.11.24; 2681.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P28482; -.
DR ChiTaRS; MAPK1; human.
DR EvolutionaryTrace; P28482; -.
DR GeneWiki; MAPK1; -.
DR GenomeRNAi; 5594; -.
DR NextBio; 21708; -.
DR PRO; PR:P28482; -.
DR ArrayExpress; P28482; -.
DR Bgee; P28482; -.
DR CleanEx; HS_MAPK1; -.
DR Genevestigator; P28482; -.
DR GO; GO:0005901; C:caveola; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
DR GO; GO:0032839; C:dendrite cytoplasm; IEA:Ensembl.
DR GO; GO:0005769; C:early endosome; TAS:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; TAS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; TAS:UniProtKB.
DR GO; GO:0005770; C:late endosome; TAS:UniProtKB.
DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:HPA.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; TAS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0031143; C:pseudopodium; IEA:Ensembl.
DR GO; GO:0005819; C:spindle; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0004707; F:MAP kinase activity; TAS:ProtInc.
DR GO; GO:0008353; F:RNA polymerase II carboxy-terminal domain kinase activity; ISS:UniProtKB.
DR GO; GO:0000187; P:activation of MAPK activity; TAS:Reactome.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0050853; P:B cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0072584; P:caveolin-mediated endocytosis; TAS:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:Ensembl.
DR GO; GO:0019858; P:cytosine metabolic process; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0060397; P:JAK-STAT cascade involved in growth hormone signaling pathway; TAS:Reactome.
DR GO; GO:0060716; P:labyrinthine layer blood vessel development; IEA:Ensembl.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0000189; P:MAPK import into nucleus; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045596; P:negative regulation of cell differentiation; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0009887; P:organ morphogenesis; IEA:Ensembl.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IEA:Ensembl.
DR GO; GO:0045727; P:positive regulation of translation; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:0051493; P:regulation of cytoskeleton organization; TAS:UniProtKB.
DR GO; GO:2000641; P:regulation of early endosome to late endosome transport; TAS:UniProtKB.
DR GO; GO:0090170; P:regulation of Golgi inheritance; TAS:UniProtKB.
DR GO; GO:0031647; P:regulation of protein stability; ISS:UniProtKB.
DR GO; GO:0051090; P:regulation of sequence-specific DNA binding transcription factor activity; TAS:Reactome.
DR GO; GO:0032872; P:regulation of stress-activated MAPK cascade; TAS:UniProtKB.
DR GO; GO:0070849; P:response to epidermal growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0043627; P:response to estrogen stimulus; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR003527; MAP_kinase_CS.
DR InterPro; IPR008349; MAPK_ERK1/2.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR PRINTS; PR01770; ERK1ERK2MAPK.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS01351; MAPK; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Apoptosis;
KW ATP-binding; Cell cycle; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; DNA-binding; Host-virus interaction;
KW Kinase; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Repressor; Serine/threonine-protein kinase;
KW Transcription; Transcription regulation; Transferase; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 360 Mitogen-activated protein kinase 1.
FT /FTId=PRO_0000186247.
FT DOMAIN 25 313 Protein kinase.
FT NP_BIND 31 39 ATP (By similarity).
FT DNA_BIND 259 277
FT REGION 105 108 Inhibitor-binding.
FT REGION 153 154 Inhibitor-binding.
FT MOTIF 185 187 TXY.
FT MOTIF 318 322 Cytoplasmic retention motif.
FT MOTIF 327 333 Nuclear translocation motif.
FT COMPBIAS 2 9 Poly-Ala.
FT ACT_SITE 149 149 Proton acceptor (By similarity).
FT BINDING 54 54 ATP (By similarity).
FT BINDING 54 54 Inhibitor.
FT BINDING 108 108 Inhibitor; via amide nitrogen and
FT carbonyl oxygen.
FT BINDING 114 114 Inhibitor.
FT BINDING 154 154 Inhibitor.
FT BINDING 166 166 Inhibitor.
FT BINDING 167 167 Inhibitor.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 29 29 Phosphoserine; by SGK1.
FT MOD_RES 185 185 Phosphothreonine; by MAP2K1 and MAP2K2.
FT MOD_RES 187 187 Phosphotyrosine; by MAP2K1 and MAP2K2.
FT MOD_RES 190 190 Phosphothreonine; by autocatalysis.
FT MOD_RES 246 246 Phosphoserine.
FT MOD_RES 248 248 Phosphoserine.
FT MOD_RES 284 284 Phosphoserine.
FT VAR_SEQ 242 285 Missing (in isoform 2).
FT /FTId=VSP_047815.
FT MUTAGEN 54 54 K->R: Does not inhibit interaction with
FT MAP2K1.
FT MUTAGEN 176 179 Missing: Inhibits homodimerization and
FT interaction with TPR.
FT MUTAGEN 185 185 T->A: Inhibits interaction with TPR; when
FT associated with A-187.
FT MUTAGEN 187 187 Y->A: Inhibits interaction with TPR; when
FT associated with A-185.
FT MUTAGEN 234 234 L->A: Inhibits interaction with TPR.
FT MUTAGEN 318 318 D->A: Loss of dephosphorylation by PTPRJ.
FT MUTAGEN 318 318 D->N: Inhibits interaction with MAP2K1
FT but not with TPR; when associated with N-
FT 321.
FT MUTAGEN 321 321 D->N: Inhibits interaction with MAP2K1
FT but not with TPR; when associated with N-
FT 318.
FT CONFLICT 91 91 R -> Q (in Ref. 2; CAA77752).
FT STRAND 12 19
FT TURN 22 24
FT STRAND 25 33
FT STRAND 38 44
FT TURN 45 48
FT STRAND 49 56
FT STRAND 59 61
FT HELIX 62 77
FT STRAND 88 90
FT TURN 95 97
FT STRAND 101 106
FT STRAND 109 111
FT HELIX 112 118
FT HELIX 123 142
FT HELIX 152 154
FT STRAND 155 157
FT TURN 159 161
FT STRAND 163 165
FT HELIX 168 170
FT HELIX 176 178
FT TURN 181 185
FT HELIX 191 193
FT HELIX 196 200
FT STRAND 202 205
FT HELIX 208 223
FT HELIX 233 244
FT HELIX 249 252
FT STRAND 253 255
FT HELIX 258 266
FT HELIX 275 278
FT STRAND 279 282
FT HELIX 284 293
FT HELIX 298 300
FT HELIX 304 308
FT HELIX 311 313
FT TURN 314 316
FT HELIX 319 321
FT TURN 335 337
FT HELIX 340 351
FT HELIX 352 354
FT TURN 356 358
SQ SEQUENCE 360 AA; 41390 MW; E85D0B2A5D2D724E CRC64;
MAAAAAAGAG PEMVRGQVFD VGPRYTNLSY IGEGAYGMVC SAYDNVNKVR VAIKKISPFE
HQTYCQRTLR EIKILLRFRH ENIIGINDII RAPTIEQMKD VYIVQDLMET DLYKLLKTQH
LSNDHICYFL YQILRGLKYI HSANVLHRDL KPSNLLLNTT CDLKICDFGL ARVADPDHDH
TGFLTEYVAT RWYRAPEIML NSKGYTKSID IWSVGCILAE MLSNRPIFPG KHYLDQLNHI
LGILGSPSQE DLNCIINLKA RNYLLSLPHK NKVPWNRLFP NADSKALDLL DKMLTFNPHK
RIEVEQALAH PYLEQYYDPS DEPIAEAPFK FDMELDDLPK EKLKELIFEE TARFQPGYRS
//
ID MK01_HUMAN Reviewed; 360 AA.
AC P28482; A8CZ64;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Mitogen-activated protein kinase 1;
DE Short=MAP kinase 1;
DE Short=MAPK 1;
DE EC=2.7.11.24;
DE AltName: Full=ERT1;
DE AltName: Full=Extracellular signal-regulated kinase 2;
DE Short=ERK-2;
DE AltName: Full=MAP kinase isoform p42;
DE Short=p42-MAPK;
DE AltName: Full=Mitogen-activated protein kinase 2;
DE Short=MAP kinase 2;
DE Short=MAPK 2;
GN Name=MAPK1; Synonyms=ERK2, PRKM1, PRKM2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1540184; DOI=10.1016/0006-291X(92)91891-S;
RA Owaki H., Makar R., Boulton T.G., Cobb M.H., Geppert T.D.;
RT "Extracellular signal-regulated kinases in T cells: characterization
RT of human ERK1 and ERK2 cDNAs.";
RL Biochem. Biophys. Res. Commun. 182:1416-1422(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1319925; DOI=10.1016/0014-5793(92)80612-K;
RA Gonzalez F.A., Raden D.L., Rigby M.R., Davis R.J.;
RT "Heterogeneous expression of four MAP kinase isoforms in human
RT tissues.";
RL FEBS Lett. 304:170-178(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND ALTERNATIVE SPLICING.
RA Cheng H., Ren S., Qiu R., Wang M., Feng Y.H.;
RT "Identification of dominant negative Erk1/2 variants in cancer
RT cells.";
RL Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M.,
RA Clamp M., Smink L.J., Ainscough R., Almeida J.P., Babbage A.K.,
RA Bagguley C., Bailey J., Barlow K.F., Bates K.N., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Buck D., Burgess J.,
RA Burrill W.D., Burton J., Carder C., Carter N.P., Chen Y., Clark G.,
RA Clegg S.M., Cobley V.E., Cole C.G., Collier R.E., Connor R.,
RA Conroy D., Corby N.R., Coville G.J., Cox A.V., Davis J., Dawson E.,
RA Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M., Ellington A.G.,
RA Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S.,
RA Hunt S.E., Jones M.C., Kershaw J., Kimberley A.M., King A.,
RA Laird G.K., Langford C.F., Leversha M.A., Lloyd C., Lloyd D.M.,
RA Martyn I.D., Mashreghi-Mohammadi M., Matthews L.H., Mccann O.T.,
RA Mcclay J., Mclaren S., McMurray A.A., Milne S.A., Mortimore B.J.,
RA Odell C.N., Pavitt R., Pearce A.V., Pearson D., Phillimore B.J.C.T.,
RA Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y., Rogers L., Ross M.T.,
RA Scott C.E., Sehra H.K., Skuce C.D., Smalley S., Smith M.L.,
RA Soderlund C., Spragon L., Steward C.A., Sulston J.E., Swann R.M.,
RA Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J.,
RA Shintani A., Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S.,
RA Roe B.A., Chen F., Chu L., Crabtree J., Deschamps S., Do A., Do T.,
RA Dorman A., Fang F., Fu Y., Hu P., Hua A., Kenton S., Lai H., Lao H.I.,
RA Lewis J., Lewis S., Lin S.-P., Loh P., Malaj E., Nguyen T., Pan H.,
RA Phan S., Qi S., Qian Y., Ray L., Ren Q., Shaull S., Sloan D., Song L.,
RA Wang Q., Wang Y., Wang Z., White J., Willingham D., Wu H., Yao Z.,
RA Zhan M., Zhang G., Chissoe S., Murray J., Miller N., Minx P.,
RA Fulton R., Johnson D., Bemis G., Bentley D., Bradshaw H., Bourne S.,
RA Cordes M., Du Z., Fulton L., Goela D., Graves T., Hawkins J.,
RA Hinds K., Kemp K., Latreille P., Layman D., Ozersky P., Rohlfing T.,
RA Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K., Nelson J.,
RA Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S.,
RA Budarf M.L., McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E.,
RA Edelmann L., Kim U.J., Shizuya H., Simon M.I., Dumanski J.P.,
RA Peyrard M., Kedra D., Seroussi E., Fransson I., Tapia I., Bruder C.E.,
RA O'Brien K.P., Wilkinson P., Bodenteich A., Hartman K., Hu X.,
RA Khan A.S., Lane L., Tilahun Y., Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEIN SEQUENCE OF 2-15, AND ACETYLATION AT ALA-2.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [7]
RP FUNCTION IN PHOSPHORYLATION OF ERF.
RX PubMed=7588608;
RA Sgouras D.N., Athanasiou M.A., Beal G.J. Jr., Fisher R.J., Blair D.G.,
RA Mavrothalassitis G.J.;
RT "ERF: an ETS domain protein with strong transcriptional repressor
RT activity, can suppress ets-associated tumorigenesis and is regulated
RT by phosphorylation during cell cycle and mitogenic stimulation.";
RL EMBO J. 14:4781-4793(1995).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF MAPKAPK3.
RX PubMed=8622688;
RA Sithanandam G., Latif F., Duh F.-M., Bernal R., Smola U., Li H.,
RA Kuzmin I., Wixler V., Geil L., Shrestha S., Lloyd P.A., Bader S.,
RA Sekido Y., Tartof K.D., Kashuba V.I., Zabarovsky E.R., Dean M.,
RA Klein G., Lerman M.I., Minna J.D., Rapp U.R., Allikmets R.;
RT "3pK, a new mitogen-activated protein kinase-activated protein kinase
RT located in the small cell lung cancer tumor suppressor gene region.";
RL Mol. Cell. Biol. 16:868-876(1996).
RN [9]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=8794306;
RA Greenway A.L., Azad A., Mills J., McPhee D.A.;
RT "Human immunodeficiency virus type 1 Nef binds directly to LCK and
RT mitogen-activated protein kinase, inhibiting kinase activity.";
RL J. Virol. 70:6701-6708(1996).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF MAPKAPK5.
RX PubMed=9480836; DOI=10.1006/bbrc.1998.8135;
RA Ni H., Wang X.S., Diener K., Yao Z.;
RT "MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated
RT protein kinase, is a substrate of the extracellular-regulated kinase
RT (ERK) and p38 kinase.";
RL Biochem. Biophys. Res. Commun. 243:492-496(1998).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF RPS6KA5/MSK1.
RX PubMed=9687510; DOI=10.1093/emboj/17.15.4426;
RA Deak M., Clifton A.D., Lucocq J.M., Alessi D.R.;
RT "Mitogen- and stress-activated protein kinase-1 (MSK1) is directly
RT activated by MAPK and SAPK2/p38, and may mediate activation of CREB.";
RL EMBO J. 17:4426-4441(1998).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF BCL6.
RX PubMed=9649500;
RA Niu H., Ye B.H., Dalla-Favera R.;
RT "Antigen receptor signaling induces MAP kinase-mediated
RT phosphorylation and degradation of the BCL-6 transcription factor.";
RL Genes Dev. 12:1953-1961(1998).
RN [13]
RP INTERACTION WITH DUSP6, AND FUNCTION.
RX PubMed=9596579; DOI=10.1126/science.280.5367.1262;
RA Camps M., Nichols A., Gillieron C., Antonsson B., Muda M., Chabert C.,
RA Boschert U., Arkinstall S.;
RT "Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-
RT activated protein kinase.";
RL Science 280:1262-1265(1998).
RN [14]
RP DEPHOSPHORYLATION BY DUSP3.
RX PubMed=10224087; DOI=10.1074/jbc.274.19.13271;
RA Todd J.L., Tanner K.G., Denu J.M.;
RT "Extracellular regulated kinases (ERK) 1 and ERK2 are authentic
RT substrates for the dual-specificity protein-tyrosine phosphatase VHR.
RT A novel role in down-regulating the ERK pathway.";
RL J. Biol. Chem. 274:13271-13280(1999).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF ELK1.
RX PubMed=10637505; DOI=10.1038/sj.onc.1203362;
RA Cruzalegui F.H., Cano E., Treisman R.;
RT "ERK activation induces phosphorylation of Elk-1 at multiple S/T-P
RT motifs to high stoichiometry.";
RL Oncogene 18:7948-7957(1999).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF DUSP1.
RX PubMed=10617468; DOI=10.1126/science.286.5449.2514;
RA Brondello J.M., Pouyssegur J., McKenzie F.R.;
RT "Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-
RT dependent phosphorylation.";
RL Science 286:2514-2517(1999).
RN [17]
RP FUNCTION AS MKNK2 KINASE.
RX PubMed=11154262; DOI=10.1128/MCB.21.3.743-754.2001;
RA Scheper G.C., Morrice N.A., Kleijn M., Proud C.G.;
RT "The mitogen-activated protein kinase signal-integrating kinase Mnk2
RT is a eukaryotic initiation factor 4E kinase with high levels of basal
RT activity in mammalian cells.";
RL Mol. Cell. Biol. 21:743-754(2001).
RN [18]
RP FUNCTION IN PHOSPHORYLATION OF ATF2.
RX PubMed=12110590; DOI=10.1093/emboj/cdf361;
RA Ouwens D.M., de Ruiter N.D., van der Zon G.C., Carter A.P.,
RA Schouten J., van der Burgt C., Kooistra K., Bos J.L., Maassen J.A.,
RA van Dam H.;
RT "Growth factors can activate ATF2 via a two-step mechanism:
RT phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69
RT through RalGDS-Src-p38.";
RL EMBO J. 21:3782-3793(2002).
RN [19]
RP FUNCTION IN PHOSPHORYLATION OF IER3, INTERACTION WITH IER3, AND ENZYME
RP REGULATION.
RX PubMed=12356731; DOI=10.1093/emboj/cdf488;
RA Garcia J., Ye Y., Arranz V., Letourneux C., Pezeron G., Porteu F.;
RT "IEX-1: a new ERK substrate involved in both ERK survival activity and
RT ERK activation.";
RL EMBO J. 21:5151-5163(2002).
RN [20]
RP INTERACTION WITH NISCH.
RX PubMed=11912194; DOI=10.1074/jbc.M111838200;
RA Sano H., Liu S.C.H., Lane W.S., Piletz J.E., Lienhard G.E.;
RT "Insulin receptor substrate 4 associates with the protein IRAS.";
RL J. Biol. Chem. 277:19439-19447(2002).
RN [21]
RP FUNCTION IN PHOSPHORYLATION OF FRS2.
RX PubMed=12974390; DOI=10.1515/BC.2003.134;
RA Wu Y., Chen Z., Ullrich A.;
RT "EGFR and FGFR signaling through FRS2 is subject to negative feedback
RT control by ERK1/2.";
RL Biol. Chem. 384:1215-1226(2003).
RN [22]
RP FUNCTION IN PHOSPHORYLATION OF DUSP16.
RX PubMed=12794087; DOI=10.1074/jbc.M213254200;
RA Masuda K., Shima H., Katagiri C., Kikuchi K.;
RT "Activation of ERK induces phosphorylation of MAPK phosphatase-7, a
RT JNK specific phosphatase, at Ser-446.";
RL J. Biol. Chem. 278:32448-32456(2003).
RN [23]
RP FUNCTION IN PHOSPHORYLATION OF CASP9.
RX PubMed=12792650; DOI=10.1038/ncb1005;
RA Allan L.A., Morrice N., Brady S., Magee G., Pathak S., Clarke P.R.;
RT "Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK
RT MAPK.";
RL Nat. Cell Biol. 5:647-654(2003).
RN [24]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH NEK2.
RX PubMed=15358203; DOI=10.1016/j.bbrc.2004.06.171;
RA Lou Y., Xie W., Zhang D.F., Yao J.H., Luo Z.F., Wang Y.Z., Shi Y.Y.,
RA Yao X.B.;
RT "Nek2A specifies the centrosomal localization of Erk2.";
RL Biochem. Biophys. Res. Commun. 321:495-501(2004).
RN [25]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [26]
RP FUNCTION IN PHOSPHORYLATION OF SORBS3.
RX PubMed=15184391; DOI=10.1074/jbc.M402304200;
RA Mitsushima M., Suwa A., Amachi T., Ueda K., Kioka N.;
RT "Extracellular signal-regulated kinase activated by epidermal growth
RT factor and cell adhesion interacts with and phosphorylates vinexin.";
RL J. Biol. Chem. 279:34570-34577(2004).
RN [27]
RP FUNCTION IN PHOSPHORYLATION OF MCL1.
RX PubMed=15241487; DOI=10.1038/sj.onc.1207692;
RA Domina A.M., Vrana J.A., Gregory M.A., Hann S.R., Craig R.W.;
RT "MCL1 is phosphorylated in the PEST region and stabilized upon ERK
RT activation in viable cells, and at additional sites with cytotoxic
RT okadaic acid or taxol.";
RL Oncogene 23:5301-5315(2004).
RN [28]
RP FUNCTION IN PHOSPHORYLATION OF GRB10.
RX PubMed=15952796; DOI=10.1021/bi050413i;
RA Langlais P., Wang C., Dong L.Q., Carroll C.A., Weintraub S.T., Liu F.;
RT "Phosphorylation of Grb10 by mitogen-activated protein kinase:
RT identification of Ser150 and Ser476 of human Grb10zeta as major
RT phosphorylation sites.";
RL Biochemistry 44:8890-8897(2005).
RN [29]
RP FUNCTION IN PHOSPHORYLATION OF DAPK1, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH DAPK1.
RX PubMed=15616583; DOI=10.1038/sj.emboj.7600510;
RA Chen C.H., Wang W.J., Kuo J.C., Tsai H.C., Lin J.R., Chang Z.F.,
RA Chen R.H.;
RT "Bidirectional signals transduced by DAPK-ERK interaction promote the
RT apoptotic effect of DAPK.";
RL EMBO J. 24:294-304(2005).
RN [30]
RP FUNCTION IN PHOSPHORYLATION OF BTG2.
RX PubMed=15788397; DOI=10.1074/jbc.M500318200;
RA Hong J.W., Ryu M.S., Lim I.K.;
RT "Phosphorylation of serine 147 of tis21/BTG2/pc3 by p-Erk1/2 induces
RT Pin-1 binding in cytoplasm and cell death.";
RL J. Biol. Chem. 280:21256-21263(2005).
RN [31]
RP FUNCTION IN PHOSPHORYLATION OF RAF1.
RX PubMed=15664191; DOI=10.1016/j.molcel.2004.11.055;
RA Dougherty M.K., Muller J., Ritt D.A., Zhou M., Zhou X.Z.,
RA Copeland T.D., Conrads T.P., Veenstra T.D., Lu K.P., Morrison D.K.;
RT "Regulation of Raf-1 by direct feedback phosphorylation.";
RL Mol. Cell 17:215-224(2005).
RN [32]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [33]
RP INTERACTION WITH ARHGEF2.
RX PubMed=18211802; DOI=10.1016/j.bbrc.2008.01.066;
RA Fujishiro S.H., Tanimura S., Mure S., Kashimoto Y., Watanabe K.,
RA Kohno M.;
RT "ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide
RT exchange activity toward RhoA.";
RL Biochem. Biophys. Res. Commun. 368:162-167(2008).
RN [34]
RP FUNCTION, AND INTERACTION WITH HSF4.
RX PubMed=16581800; DOI=10.1128/MCB.26.8.3282-3294.2006;
RA Hu Y., Mivechi N.F.;
RT "Association and regulation of heat shock transcription factor 4b with
RT both extracellular signal-regulated kinase mitogen-activated protein
RT kinase and dual-specificity tyrosine phosphatase DUSP26.";
RL Mol. Cell. Biol. 26:3282-3294(2006).
RN [35]
RP PHOSPHORYLATION.
RX PubMed=17274988; DOI=10.1016/j.febslet.2007.01.039;
RA Degoutin J., Vigny M., Gouzi J.Y.;
RT "ALK activation induces Shc and FRS2 recruitment: Signaling and
RT phenotypic outcomes in PC12 cells differentiation.";
RL FEBS Lett. 581:727-734(2007).
RN [36]
RP INTERACTION WITH ARRB2.
RX PubMed=18435604; DOI=10.1042/BJ20080685;
RA Xu T.-R., Baillie G.S., Bhari N., Houslay T.M., Pitt A.M., Adams D.R.,
RA Kolch W., Houslay M.D., Milligan G.;
RT "Mutations of beta-arrestin 2 that limit self-association also
RT interfere with interactions with the beta2-adrenoceptor and the ERK1/2
RT MAPKs: implications for beta2-adrenoceptor signalling via the ERK1/2
RT MAPKs.";
RL Biochem. J. 413:51-60(2008).
RN [37]
RP INTERACTION WITH ADAM15.
RX PubMed=18296648; DOI=10.1158/1541-7786.MCR-07-2028;
RA Zhong J.L., Poghosyan Z., Pennington C.J., Scott X., Handsley M.M.,
RA Warn A., Gavrilovic J., Honert K., Kruger A., Span P.N., Sweep F.C.,
RA Edwards D.R.;
RT "Distinct functions of natural ADAM-15 cytoplasmic domain variants in
RT human mammary carcinoma.";
RL Mol. Cancer Res. 6:383-394(2008).
RN [38]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [39]
RP PHOSPHORYLATION AT SER-246 AND SER-248, INTERACTION WITH IPO7, AND
RP SUBCELLULAR LOCATION.
RX PubMed=18760948; DOI=10.1016/j.molcel.2008.08.007;
RA Chuderland D., Konson A., Seger R.;
RT "Identification and characterization of a general nuclear
RT translocation signal in signaling proteins.";
RL Mol. Cell 31:850-861(2008).
RN [40]
RP FUNCTION IN PHOSPHORYLATION OF TPR, INTERACTION WITH TPR, AND
RP MUTAGENESIS OF LYS-54; 176-PRO--ASP-179; THR-185; TYR-187; LEU-234;
RP ASP-318 AND ASP-321.
RX PubMed=18794356; DOI=10.1128/MCB.00925-08;
RA Vomastek T., Iwanicki M.P., Burack W.R., Tiwari D., Kumar D.,
RA Parsons J.T., Weber M.J., Nandicoori V.K.;
RT "Extracellular signal-regulated kinase 2 (ERK2) phosphorylation sites
RT and docking domain on the nuclear pore complex protein Tpr
RT cooperatively regulate ERK2-Tpr interaction.";
RL Mol. Cell. Biol. 28:6954-6966(2008).
RN [41]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-185 AND TYR-187, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [42]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [43]
RP FUNCTION AS A TRANSCRIPTIONAL REPRESSOR, AND DNA-BINDING.
RX PubMed=19879846; DOI=10.1016/j.cell.2009.08.037;
RA Hu S., Xie Z., Onishi A., Yu X., Jiang L., Lin J., Rho H.-S.,
RA Woodard C., Wang H., Jeong J.-S., Long S., He X., Wade H.,
RA Blackshaw S., Qian J., Zhu H.;
RT "Profiling the human protein-DNA interactome reveals ERK2 as a
RT transcriptional repressor of interferon signaling.";
RL Cell 139:610-622(2009).
RN [44]
RP FUNCTION IN KIT SIGNALING PATHWAY, AND PHOSPHORYLATION.
RX PubMed=19265199; DOI=10.1074/jbc.M808058200;
RA Sun J., Pedersen M., Ronnstrand L.;
RT "The D816V mutation of c-Kit circumvents a requirement for Src family
RT kinases in c-Kit signal transduction.";
RL J. Biol. Chem. 284:11039-11047(2009).
RN [45]
RP PHOSPHORYLATION AT TYR-187, DEPHOSPHORYLATION BY PTPRJ AT TYR-187, AND
RP MUTAGENESIS OF ASP-318.
RX PubMed=19494114; DOI=10.1074/jbc.M109.002758;
RA Sacco F., Tinti M., Palma A., Ferrari E., Nardozza A.P.,
RA Hooft van Huijsduijnen R., Takahashi T., Castagnoli L., Cesareni G.;
RT "Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the
RT RAS pathway by direct dephosphorylation of ERK1/2 kinases.";
RL J. Biol. Chem. 284:22048-22058(2009).
RN [46]
RP PHOSPHORYLATION AT SER-29 BY SGK1, AND INTERACTION WITH SGK1.
RX PubMed=19447520; DOI=10.1016/j.jhep.2009.02.027;
RA Won M., Park K.A., Byun H.S., Kim Y.R., Choi B.L., Hong J.H., Park J.,
RA Seok J.H., Lee Y.H., Cho C.H., Song I.S., Kim Y.K., Shen H.M.,
RA Hur G.M.;
RT "Protein kinase SGK1 enhances MEK/ERK complex formation through the
RT phosphorylation of ERK2: implication for the positive regulatory role
RT of SGK1 on the ERK function during liver regeneration.";
RL J. Hepatol. 51:67-76(2009).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-284, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [48]
RP AUTOPHOSPHORYLATION AT THR-190, ENZYME REGULATION, SUBUNIT, AND
RP SUBCELLULAR LOCATION.
RX PubMed=19060905; DOI=10.1038/nm.1893;
RA Lorenz K., Schmitt J.P., Schmitteckert E.M., Lohse M.J.;
RT "A new type of ERK1/2 autophosphorylation causes cardiac
RT hypertrophy.";
RL Nat. Med. 15:75-83(2009).
RN [49]
RP REVIEW ON FUNCTION.
RX PubMed=16393692; DOI=10.1080/02699050500284218;
RA Yoon S., Seger R.;
RT "The extracellular signal-regulated kinase: multiple substrates
RT regulate diverse cellular functions.";
RL Growth Factors 24:21-44(2006).
RN [50]
RP REVIEW ON FUNCTION, AND REVIEW ON SUBCELLULAR LOCATION.
RX PubMed=19565474; DOI=10.1002/biof.52;
RA Yao Z., Seger R.;
RT "The ERK signaling cascade--views from different subcellular
RT compartments.";
RL BioFactors 35:407-416(2009).
RN [51]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-185 AND TYR-187, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [52]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [53]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [54]
RP REVIEW ON ENZYME REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=21779493; DOI=10.1177/1947601911407328;
RA Wortzel I., Seger R.;
RT "The ERK cascade: distinct functions within various subcellular
RT organelles.";
RL Genes Cancer 2:195-209(2011).
RN [55]
RP FUNCTION, AND INTERACTION WITH PML.
RX PubMed=22033920; DOI=10.1074/jbc.M111.289512;
RA Lim J.H., Liu Y., Reineke E., Kao H.Y.;
RT "Mitogen-activated protein kinase extracellular signal-regulated
RT kinase 2 phosphorylates and promotes Pin1 protein-dependent
RT promyelocytic leukemia protein turnover.";
RL J. Biol. Chem. 286:44403-44411(2011).
RN [56]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-185 AND TYR-187, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [57]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [58]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=9827991;
RA Fox T., Coll J.T., Xie X., Ford P.J., Germann U.A., Porter M.D.,
RA Pazhanisamy S., Fleming M.A., Galullo V., Su M.S., Wilson K.P.;
RT "A single amino acid substitution makes ERK2 susceptible to pyridinyl
RT imidazole inhibitors of p38 MAP kinase.";
RL Protein Sci. 7:2249-2255(1998).
RN [59]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=16139248; DOI=10.1016/j.bbrc.2005.08.082;
RA Ohori M., Kinoshita T., Okubo M., Sato K., Yamazaki A., Arakawa H.,
RA Nishimura S., Inamura N., Nakajima H., Neya M., Miyake H., Fujii T.;
RT "Identification of a selective ERK inhibitor and structural
RT determination of the inhibitor-ERK2 complex.";
RL Biochem. Biophys. Res. Commun. 336:357-363(2005).
RN [60]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=16242327; DOI=10.1016/j.bmcl.2005.09.055;
RA Kinoshita T., Warizaya M., Ohori M., Sato K., Neya M., Fujii T.;
RT "Crystal structure of human ERK2 complexed with a pyrazolo[3,4-
RT c]pyridazine derivative.";
RL Bioorg. Med. Chem. Lett. 16:55-58(2006).
RN [61]
RP X-RAY CRYSTALLOGRAPHY (3.00 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=17194451; DOI=10.1016/j.bbrc.2006.12.083;
RA Ohori M., Kinoshita T., Yoshimura S., Warizaya M., Nakajima H.,
RA Miyake H.;
RT "Role of a cysteine residue in the active site of ERK and the MAPKK
RT family.";
RL Biochem. Biophys. Res. Commun. 353:633-637(2007).
RN [62]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 2-359 IN COMPLEX WITH
RP INHIBITOR.
RX PubMed=17300186; DOI=10.1021/jm061381f;
RA Aronov A.M., Baker C., Bemis G.W., Cao J., Chen G., Ford P.J.,
RA Germann U.A., Green J., Hale M.R., Jacobs M., Janetka J.W.,
RA Maltais F., Martinez-Botella G., Namchuk M.N., Straub J., Tang Q.,
RA Xie X.;
RT "Flipped out: structure-guided design of selective pyrazolylpyrrole
RT ERK inhibitors.";
RL J. Med. Chem. 50:1280-1287(2007).
RN [63]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 186-191, AND PHOSPHORYLATION
RP AT TYR-187.
RX PubMed=19053285; DOI=10.1021/bi801724n;
RA Critton D.A., Tortajada A., Stetson G., Peti W., Page R.;
RT "Structural basis of substrate recognition by hematopoietic tyrosine
RT phosphatase.";
RL Biochemistry 47:13336-13345(2008).
RN [64]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
RX PubMed=19827834; DOI=10.1021/jm900630q;
RA Aronov A.M., Tang Q., Martinez-Botella G., Bemis G.W., Cao J.,
RA Chen G., Ewing N.P., Ford P.J., Germann U.A., Green J., Hale M.R.,
RA Jacobs M., Janetka J.W., Maltais F., Markland W., Namchuk M.N.,
RA Nanthakumar S., Poondru S., Straub J., ter Haar E., Xie X.;
RT "Structure-guided design of potent and selective pyrimidylpyrrole
RT inhibitors of extracellular signal-regulated kinase (ERK) using
RT conformational control.";
RL J. Med. Chem. 52:6362-6368(2009).
CC -!- FUNCTION: Serine/threonine kinase which acts as an essential
CC component of the MAP kinase signal transduction pathway.
CC MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important
CC role in the MAPK/ERK cascade. They participate also in a signaling
CC cascade initiated by activated KIT and KITLG/SCF. Depending on the
CC cellular context, the MAPK/ERK cascade mediates diverse biological
CC functions such as cell growth, adhesion, survival and
CC differentiation through the regulation of transcription,
CC translation, cytoskeletal rearrangements. The MAPK/ERK cascade
CC plays also a role in initiation and regulation of meiosis,
CC mitosis, and postmitotic functions in differentiated cells by
CC phosphorylating a number of transcription factors. About 160
CC substrates have already been discovered for ERKs. Many of these
CC substrates are localized in the nucleus, and seem to participate
CC in the regulation of transcription upon stimulation. However,
CC other substrates are found in the cytosol as well as in other
CC cellular organelles, and those are responsible for processes such
CC as translation, mitosis and apoptosis. Moreover, the MAPK/ERK
CC cascade is also involved in the regulation of the endosomal
CC dynamics, including lysosome processing and endosome cycling
CC through the perinuclear recycling compartment (PNRC); as well as
CC in the fragmentation of the Golgi apparatus during mitosis. The
CC substrates include transcription factors (such as ATF2, BCL6,
CC ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as
CC CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of
CC apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG),
CC regulators of translation (such as EIF4EBP1) and a variety of
CC other signaling-related molecules (like ARHGEF2, DCC, FRS2 or
CC GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2,
CC RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2,
CC RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases
CC (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which
CC enable the propagation the MAPK/ERK signal to additional cytosolic
CC and nuclear targets, thereby extending the specificity of the
CC cascade. Mediates phosphorylation of TPR in respons to EGF
CC stimulation. May play a role in the spindle assembly checkpoint.
CC Phosphorylates PML and promotes its interaction with PIN1, leading
CC to PML degradation.
CC -!- FUNCTION: Acts as a transcriptional repressor. Binds to a
CC [GC]AAA[GC] consensus sequence. Repress the expression of
CC interferon gamma-induced genes. Seems to bind to the promoter of
CC CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and
CC STAT1. Transcriptional activity is independent of kinase activity.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Magnesium (By similarity).
CC -!- ENZYME REGULATION: Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2
CC on Thr-185 and Tyr-187 in response to external stimuli like
CC insulin or NGF. Both phosphorylations are required for activity.
CC This phosphorylation causes dramatic conformational changes, which
CC enable full activation and interaction of MAPK1/ERK2 with its
CC substrates. Phosphorylation on Ser-29 by SGK1 results in its
CC activation by enhancing its interaction with MAP2K1/MEK1 and
CC MAP2K2/MEK2. Dephosphorylated and inactivated by DUSP3, DUSP6 and
CC DUSP9. Inactivated by pyrimidylpyrrole inhibitors.
CC -!- SUBUNIT: Binds both upstream activators and downstream substrates
CC in multimolecular complexes. Binds to HIV-1 Nef through its SH3
CC domain. This interaction inhibits its tyrosine-kinase activity.
CC Interacts with ADAM15, ARHGEF2, ARRB2, DAPK1 (via death domain),
CC HSF4, IER3, IPO7, DUSP6, NISCH, SGK1, and isoform 1 of NEK2.
CC Interacts (phosphorylated form) with CAV2 ('Tyr-19'-phosphorylated
CC form); the interaction, promoted by insulin, leads to nuclear
CC location and MAPK1 activation. Interacts with MORG1, PEA15 and
CC MKNK2 (By similarity). MKNK2 isoform 1 binding prevents from
CC dephosphorylation and inactivation (By similarity). Interacts with
CC DCC (By similarity). The phosphorylated form interacts with PML
CC (isoform PML-4).
CC -!- INTERACTION:
CC Q9U1H0:cic (xeno); NbExp=2; IntAct=EBI-959949, EBI-98330;
CC P28562:DUSP1; NbExp=6; IntAct=EBI-959949, EBI-975493;
CC Q05922:Dusp2 (xeno); NbExp=2; IntAct=EBI-959949, EBI-7898692;
CC Q16690:DUSP5; NbExp=4; IntAct=EBI-959949, EBI-7487376;
CC P14921:ETS1; NbExp=2; IntAct=EBI-959949, EBI-913209;
CC Q02750:MAP2K1; NbExp=2; IntAct=EBI-959949, EBI-492564;
CC Q16539-3:MAPK14; NbExp=5; IntAct=EBI-959949, EBI-6932370;
CC P27361:MAPK3; NbExp=3; IntAct=EBI-959949, EBI-73995;
CC P02687:MBP (xeno); NbExp=2; IntAct=EBI-959949, EBI-908215;
CC P35813:PPM1A; NbExp=19; IntAct=EBI-959949, EBI-989143;
CC P35236:PTPN7; NbExp=5; IntAct=EBI-959949, EBI-2265723;
CC Q12913:PTPRJ; NbExp=7; IntAct=EBI-959949, EBI-2264500;
CC Q69559:U24 (xeno); NbExp=2; IntAct=EBI-959949, EBI-8015758;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, spindle (By
CC similarity). Nucleus. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome. Cytoplasm. Note=Associated with the
CC spindle during prometaphase and metaphase (By similarity). PEA15-
CC binding and phosphorylated DAPK1 promote its cytoplasmic
CC retention. Phosphorylation at Ser- 246 and Ser-248 as well as
CC autophosphorylation at Thr-190 promote nuclear localization.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P28482-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P28482-2; Sequence=VSP_047815;
CC -!- DOMAIN: The TXY motif contains the threonine and tyrosine residues
CC whose phosphorylation activates the MAP kinases.
CC -!- PTM: Phosphorylated upon KIT and FLT3 signaling (By similarity).
CC Dually phosphorylated on Thr-185 and Tyr-187, which activates the
CC enzyme. Undergoes regulatory phosphorylation on additional
CC residues such as Ser-246 and Ser-248 in the kinase insert domain
CC (KID) These phosphorylations, which are probably mediated by more
CC than one kinase, are important for binding of MAPK1/ERK2 to
CC importin-7 (IPO7) and its nuclear translocation. In addition,
CC autophosphorylation of Thr-190 was shown to affect the subcellular
CC localization of MAPK1/ERK2 as well. Ligand-activated ALK induces
CC tyrosine phosphorylation. Dephosphorylated by PTPRJ at Tyr-187.
CC Phosphorylation on Ser-29 by SGK1 results in its activation by
CC enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. DUSP3
CC and DUSP6 dephosphorylate specifically MAPK1/ERK2 and MAPK3/ERK1
CC whereas DUSP9 dephosphorylates a broader range of MAPKs.
CC -!- PTM: ISGylated (By similarity).
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC
CC Ser/Thr protein kinase family. MAP kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA77753.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Extracellular signal-regulated
CC kinase entry;
CC URL="http://en.wikipedia.org/wiki/Extracellular_signal-regulated_kinase";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MAPK1ID41288ch22q11.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M84489; AAA58459.1; -; mRNA.
DR EMBL; Z11694; CAA77752.1; -; mRNA.
DR EMBL; Z11695; CAA77753.1; ALT_INIT; mRNA.
DR EMBL; DQ399292; ABD60303.1; -; mRNA.
DR EMBL; AP000553; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000554; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000555; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC017832; AAH17832.1; -; mRNA.
DR PIR; JQ1400; JQ1400.
DR RefSeq; NP_002736.3; NM_002745.4.
DR RefSeq; NP_620407.1; NM_138957.2.
DR UniGene; Hs.431850; -.
DR PDB; 1PME; X-ray; 2.00 A; A=1-360.
DR PDB; 1TVO; X-ray; 2.50 A; A=1-360.
DR PDB; 1WZY; X-ray; 2.50 A; A=1-360.
DR PDB; 2OJG; X-ray; 2.00 A; A=2-359.
DR PDB; 2OJI; X-ray; 2.60 A; A=2-359.
DR PDB; 2OJJ; X-ray; 2.40 A; A=2-359.
DR PDB; 2Y9Q; X-ray; 1.55 A; A=1-360.
DR PDB; 3D42; X-ray; 2.46 A; B=184-191.
DR PDB; 3D44; X-ray; 1.90 A; B=186-191.
DR PDB; 3I5Z; X-ray; 2.20 A; A=1-360.
DR PDB; 3I60; X-ray; 2.50 A; A=1-360.
DR PDB; 3SA0; X-ray; 1.59 A; A=1-360.
DR PDB; 3TEI; X-ray; 2.40 A; A=1-360.
DR PDB; 3W55; X-ray; 3.00 A; A=1-360.
DR PDB; 4FMQ; X-ray; 2.10 A; A=1-360.
DR PDB; 4FUX; X-ray; 2.20 A; A=1-360.
DR PDB; 4FUY; X-ray; 2.00 A; A=1-360.
DR PDB; 4FV0; X-ray; 2.10 A; A=1-360.
DR PDB; 4FV1; X-ray; 1.99 A; A=1-360.
DR PDB; 4FV2; X-ray; 2.00 A; A=1-360.
DR PDB; 4FV3; X-ray; 2.20 A; A=1-360.
DR PDB; 4FV4; X-ray; 2.50 A; A=1-360.
DR PDB; 4FV5; X-ray; 2.40 A; A=1-360.
DR PDB; 4FV6; X-ray; 2.50 A; A=1-360.
DR PDB; 4FV7; X-ray; 1.90 A; A=1-360.
DR PDB; 4FV8; X-ray; 2.00 A; A=1-360.
DR PDB; 4FV9; X-ray; 2.11 A; A=1-360.
DR PDB; 4G6N; X-ray; 2.00 A; A=1-360.
DR PDB; 4G6O; X-ray; 2.20 A; A=1-360.
DR PDB; 4H3P; X-ray; 2.30 A; A/D=1-360.
DR PDB; 4H3Q; X-ray; 2.20 A; A=1-360.
DR PDB; 4IZ5; X-ray; 3.19 A; A/B/C/D=8-360.
DR PDB; 4IZ7; X-ray; 1.80 A; A/C=8-360.
DR PDB; 4IZA; X-ray; 1.93 A; A/C=8-360.
DR PDBsum; 1PME; -.
DR PDBsum; 1TVO; -.
DR PDBsum; 1WZY; -.
DR PDBsum; 2OJG; -.
DR PDBsum; 2OJI; -.
DR PDBsum; 2OJJ; -.
DR PDBsum; 2Y9Q; -.
DR PDBsum; 3D42; -.
DR PDBsum; 3D44; -.
DR PDBsum; 3I5Z; -.
DR PDBsum; 3I60; -.
DR PDBsum; 3SA0; -.
DR PDBsum; 3TEI; -.
DR PDBsum; 3W55; -.
DR PDBsum; 4FMQ; -.
DR PDBsum; 4FUX; -.
DR PDBsum; 4FUY; -.
DR PDBsum; 4FV0; -.
DR PDBsum; 4FV1; -.
DR PDBsum; 4FV2; -.
DR PDBsum; 4FV3; -.
DR PDBsum; 4FV4; -.
DR PDBsum; 4FV5; -.
DR PDBsum; 4FV6; -.
DR PDBsum; 4FV7; -.
DR PDBsum; 4FV8; -.
DR PDBsum; 4FV9; -.
DR PDBsum; 4G6N; -.
DR PDBsum; 4G6O; -.
DR PDBsum; 4H3P; -.
DR PDBsum; 4H3Q; -.
DR PDBsum; 4IZ5; -.
DR PDBsum; 4IZ7; -.
DR PDBsum; 4IZA; -.
DR ProteinModelPortal; P28482; -.
DR SMR; P28482; 9-358.
DR DIP; DIP-519N; -.
DR IntAct; P28482; 66.
DR MINT; MINT-144006; -.
DR STRING; 9606.ENSP00000215832; -.
DR BindingDB; P28482; -.
DR ChEMBL; CHEMBL4040; -.
DR DrugBank; DB01169; Arsenic trioxide.
DR GuidetoPHARMACOLOGY; 1495; -.
DR PhosphoSite; P28482; -.
DR DMDM; 119554; -.
DR OGP; P28482; -.
DR PaxDb; P28482; -.
DR PeptideAtlas; P28482; -.
DR PRIDE; P28482; -.
DR DNASU; 5594; -.
DR Ensembl; ENST00000215832; ENSP00000215832; ENSG00000100030.
DR Ensembl; ENST00000398822; ENSP00000381803; ENSG00000100030.
DR Ensembl; ENST00000544786; ENSP00000440842; ENSG00000100030.
DR GeneID; 5594; -.
DR KEGG; hsa:5594; -.
DR UCSC; uc010gtk.1; human.
DR CTD; 5594; -.
DR GeneCards; GC22M022108; -.
DR HGNC; HGNC:6871; MAPK1.
DR HPA; CAB004229; -.
DR HPA; HPA003995; -.
DR HPA; HPA005700; -.
DR HPA; HPA030069; -.
DR MIM; 176948; gene.
DR neXtProt; NX_P28482; -.
DR Orphanet; 261330; Distal 22q11.2 microdeletion syndrome.
DR PharmGKB; PA30616; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233024; -.
DR HOVERGEN; HBG014652; -.
DR InParanoid; P28482; -.
DR KO; K04371; -.
DR OMA; VCSAYDR; -.
DR OrthoDB; EOG7M3J0K; -.
DR PhylomeDB; P28482; -.
DR BRENDA; 2.7.11.24; 2681.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P28482; -.
DR ChiTaRS; MAPK1; human.
DR EvolutionaryTrace; P28482; -.
DR GeneWiki; MAPK1; -.
DR GenomeRNAi; 5594; -.
DR NextBio; 21708; -.
DR PRO; PR:P28482; -.
DR ArrayExpress; P28482; -.
DR Bgee; P28482; -.
DR CleanEx; HS_MAPK1; -.
DR Genevestigator; P28482; -.
DR GO; GO:0005901; C:caveola; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
DR GO; GO:0032839; C:dendrite cytoplasm; IEA:Ensembl.
DR GO; GO:0005769; C:early endosome; TAS:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; TAS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; TAS:UniProtKB.
DR GO; GO:0005770; C:late endosome; TAS:UniProtKB.
DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:HPA.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; TAS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0031143; C:pseudopodium; IEA:Ensembl.
DR GO; GO:0005819; C:spindle; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0004707; F:MAP kinase activity; TAS:ProtInc.
DR GO; GO:0008353; F:RNA polymerase II carboxy-terminal domain kinase activity; ISS:UniProtKB.
DR GO; GO:0000187; P:activation of MAPK activity; TAS:Reactome.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0050853; P:B cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0072584; P:caveolin-mediated endocytosis; TAS:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:Ensembl.
DR GO; GO:0019858; P:cytosine metabolic process; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0060397; P:JAK-STAT cascade involved in growth hormone signaling pathway; TAS:Reactome.
DR GO; GO:0060716; P:labyrinthine layer blood vessel development; IEA:Ensembl.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0000189; P:MAPK import into nucleus; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045596; P:negative regulation of cell differentiation; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0009887; P:organ morphogenesis; IEA:Ensembl.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IEA:Ensembl.
DR GO; GO:0045727; P:positive regulation of translation; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
DR GO; GO:0051493; P:regulation of cytoskeleton organization; TAS:UniProtKB.
DR GO; GO:2000641; P:regulation of early endosome to late endosome transport; TAS:UniProtKB.
DR GO; GO:0090170; P:regulation of Golgi inheritance; TAS:UniProtKB.
DR GO; GO:0031647; P:regulation of protein stability; ISS:UniProtKB.
DR GO; GO:0051090; P:regulation of sequence-specific DNA binding transcription factor activity; TAS:Reactome.
DR GO; GO:0032872; P:regulation of stress-activated MAPK cascade; TAS:UniProtKB.
DR GO; GO:0070849; P:response to epidermal growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0043627; P:response to estrogen stimulus; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IEA:Ensembl.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR003527; MAP_kinase_CS.
DR InterPro; IPR008349; MAPK_ERK1/2.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR PRINTS; PR01770; ERK1ERK2MAPK.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS01351; MAPK; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Apoptosis;
KW ATP-binding; Cell cycle; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; DNA-binding; Host-virus interaction;
KW Kinase; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Repressor; Serine/threonine-protein kinase;
KW Transcription; Transcription regulation; Transferase; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 360 Mitogen-activated protein kinase 1.
FT /FTId=PRO_0000186247.
FT DOMAIN 25 313 Protein kinase.
FT NP_BIND 31 39 ATP (By similarity).
FT DNA_BIND 259 277
FT REGION 105 108 Inhibitor-binding.
FT REGION 153 154 Inhibitor-binding.
FT MOTIF 185 187 TXY.
FT MOTIF 318 322 Cytoplasmic retention motif.
FT MOTIF 327 333 Nuclear translocation motif.
FT COMPBIAS 2 9 Poly-Ala.
FT ACT_SITE 149 149 Proton acceptor (By similarity).
FT BINDING 54 54 ATP (By similarity).
FT BINDING 54 54 Inhibitor.
FT BINDING 108 108 Inhibitor; via amide nitrogen and
FT carbonyl oxygen.
FT BINDING 114 114 Inhibitor.
FT BINDING 154 154 Inhibitor.
FT BINDING 166 166 Inhibitor.
FT BINDING 167 167 Inhibitor.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 29 29 Phosphoserine; by SGK1.
FT MOD_RES 185 185 Phosphothreonine; by MAP2K1 and MAP2K2.
FT MOD_RES 187 187 Phosphotyrosine; by MAP2K1 and MAP2K2.
FT MOD_RES 190 190 Phosphothreonine; by autocatalysis.
FT MOD_RES 246 246 Phosphoserine.
FT MOD_RES 248 248 Phosphoserine.
FT MOD_RES 284 284 Phosphoserine.
FT VAR_SEQ 242 285 Missing (in isoform 2).
FT /FTId=VSP_047815.
FT MUTAGEN 54 54 K->R: Does not inhibit interaction with
FT MAP2K1.
FT MUTAGEN 176 179 Missing: Inhibits homodimerization and
FT interaction with TPR.
FT MUTAGEN 185 185 T->A: Inhibits interaction with TPR; when
FT associated with A-187.
FT MUTAGEN 187 187 Y->A: Inhibits interaction with TPR; when
FT associated with A-185.
FT MUTAGEN 234 234 L->A: Inhibits interaction with TPR.
FT MUTAGEN 318 318 D->A: Loss of dephosphorylation by PTPRJ.
FT MUTAGEN 318 318 D->N: Inhibits interaction with MAP2K1
FT but not with TPR; when associated with N-
FT 321.
FT MUTAGEN 321 321 D->N: Inhibits interaction with MAP2K1
FT but not with TPR; when associated with N-
FT 318.
FT CONFLICT 91 91 R -> Q (in Ref. 2; CAA77752).
FT STRAND 12 19
FT TURN 22 24
FT STRAND 25 33
FT STRAND 38 44
FT TURN 45 48
FT STRAND 49 56
FT STRAND 59 61
FT HELIX 62 77
FT STRAND 88 90
FT TURN 95 97
FT STRAND 101 106
FT STRAND 109 111
FT HELIX 112 118
FT HELIX 123 142
FT HELIX 152 154
FT STRAND 155 157
FT TURN 159 161
FT STRAND 163 165
FT HELIX 168 170
FT HELIX 176 178
FT TURN 181 185
FT HELIX 191 193
FT HELIX 196 200
FT STRAND 202 205
FT HELIX 208 223
FT HELIX 233 244
FT HELIX 249 252
FT STRAND 253 255
FT HELIX 258 266
FT HELIX 275 278
FT STRAND 279 282
FT HELIX 284 293
FT HELIX 298 300
FT HELIX 304 308
FT HELIX 311 313
FT TURN 314 316
FT HELIX 319 321
FT TURN 335 337
FT HELIX 340 351
FT HELIX 352 354
FT TURN 356 358
SQ SEQUENCE 360 AA; 41390 MW; E85D0B2A5D2D724E CRC64;
MAAAAAAGAG PEMVRGQVFD VGPRYTNLSY IGEGAYGMVC SAYDNVNKVR VAIKKISPFE
HQTYCQRTLR EIKILLRFRH ENIIGINDII RAPTIEQMKD VYIVQDLMET DLYKLLKTQH
LSNDHICYFL YQILRGLKYI HSANVLHRDL KPSNLLLNTT CDLKICDFGL ARVADPDHDH
TGFLTEYVAT RWYRAPEIML NSKGYTKSID IWSVGCILAE MLSNRPIFPG KHYLDQLNHI
LGILGSPSQE DLNCIINLKA RNYLLSLPHK NKVPWNRLFP NADSKALDLL DKMLTFNPHK
RIEVEQALAH PYLEQYYDPS DEPIAEAPFK FDMELDDLPK EKLKELIFEE TARFQPGYRS
//
MIM
176948
*RECORD*
*FIELD* NO
176948
*FIELD* TI
*176948 MITOGEN-ACTIVATED PROTEIN KINASE 1; MAPK1
;;PROTEIN KINASE, MITOGEN-ACTIVATED, 1; PRKM1;;
read morePROTEIN KINASE, MITOGEN-ACTIVATED, 2; PRKM2;;
EXTRACELLULAR SIGNAL-REGULATED KINASE 2; ERK2;;
PROTEIN TYROSINE KINASE ERK2;;
p42MAPK
*FIELD* TX
CLONING
Boulton et al. (1991) cloned 2 rat enzymes that are S6 kinases and a
third related kinase and named them extracellular signal-regulated
kinase (Erk)-1, -2, and -3.
Owaki et al. (1992) isolated cDNAs for human ERK1 (MAPK3; 601795) and
ERK2. The deduced 360-amino acid human ERK2 protein shares 98% identity
with rat Erk2.
MAPPING
By a combination of fluorescence in situ hybridization and Southern blot
analysis of genomic DNA from a panel of human/hamster cell hybrids, Li
et al. (1994) mapped the MAPK1 gene to 22q11.2. Saba-El-Leil et al.
(1997) mapped the mouse Mapk1 gene to chromosome 16, in a region showing
homology of synteny with human 22q11.2.
GENE FUNCTION
ERKs are also known as maturation- or mitogen-activated protein (MAP)
kinases. Cobb et al. (1991) provided a review. Thomas (1992) gave a
review of MAP kinases and Seger and Krebs (1995) reviewed the MAP kinase
signaling cascade.
The MAP kinase ERK2 is widely involved in eukaryotic signal
transduction. Upon activation, it translocates to the nucleus of the
stimulated cell, where it phosphorylates nuclear targets. Khokhlatchev
et al. (1998) found that nuclear accumulation of microinjected ERK2
depends on its phosphorylation state rather than on its activity or on
upstream components of its signaling pathway. Phosphorylated ERK2 forms
dimers with phosphorylated and unphosphorylated ERK2 partners.
Disruption of dimerization by mutagenesis of ERK2 reduces its ability to
accumulate in the nucleus, suggesting that dimerization is essential for
its normal ligand-dependent relocalization. Other MAP kinase family
members also form dimers. Khokhlatchev et al. (1998) concluded that
dimerization is part of the mechanism of action of the MAP kinase
family.
Influenza A viruses are significant causes of morbidity and mortality
worldwide. Annually updated vaccines may prevent disease, and antivirals
are effective treatment early in disease when symptoms are often
nonspecific. Viral replication is supported by intracellular signaling
events. Using U0126, a nontoxic inhibitor of MEK1 (176872) and MEK2
(601263), and thus an inhibitor of the RAF1 (164760)/MEK/ERK pathway
(see Favata et al. (1998)), Pleschka et al. (2001) examined the cellular
response to infection with influenza A. U0126 suppressed both the early
and late ERK activation phases after virus infection. Inhibition of the
signaling pathway occurred without impairing the synthesis of viral RNA
or protein, or the import of viral ribonucleoprotein complexes (RNP)
into the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the
export of viral RNP without affecting the cellular mRNA export pathway.
Pleschka et al. (2001) proposed that ERK regulates a cellular factor
involved in the viral nuclear export protein function. They suggested
that local application of MEK inhibitors may have only minor toxic
effects on the host while inhibiting viral replication without giving
rise to drug-resistant virus variants.
Stefanovsky et al. (2001) showed that epidermal growth factor (131530)
induces immediate, ERK1/ERK2-dependent activation of endogenous
ribosomal transcription, while inactivation of ERK1/ERK2 causes an
equally immediate reversion to the basal transcription level. ERK1/ERK2
was found to phosphorylate the architectural transcription factor UBF
(600673) at amino acids 117 and 201 within HMG boxes 1 and 2, preventing
their interaction with DNA. Mutation of these sites inhibited
transcription activation and abrogated the transcriptional response to
ERK1/ERK2. Thus, growth factor regulation of ribosomal transcription
likely acts by a cyclic modulation of DNA architecture. The data
suggested a central role for ribosome biogenesis in growth regulation.
Using a 2-hybrid screen and in vitro association experiments, Waskiewicz
et al. (1997) identified Mnk1 (MKNK1; 606724) and Mnk2 (MKNK2; 605069)
as Erk2-binding proteins in mouse.
Forcet et al. (2002) showed that in embryonic kidney cells expressing
full-length, but not cytoplasmic domain-truncated, DCC (120470), NTN1
(601614) causes increased transient phosphorylation and activity of ERK1
and ERK2, but not of JNK1 (601158), JNK2 (602896), or p38 (MAPK14;
600289). This phosphorylation was mediated by MEK1 and/or MEK2. NTN1
also activated the transcription factor ELK1 (311040) and serum response
element-regulated gene expression. Immunoprecipitation analysis showed
interaction of full-length DCC with MEK1/2 in the presence or absence of
NTN1. Forcet et al. (2002) showed that activation of Dcc by Ntn1 in rat
embryonic day-13 dorsal spinal cord stimulates and is required for the
outgrowth of commissural axons and Erk1/2 activation.
Immunohistochemical analysis demonstrated expression of activated Erk1/2
in embryonic commissural axons, and this expression was diminished in
Dcc or Ntn1 knockout animals. Forcet et al. (2002) concluded that the
MAPK pathway is involved in responses to NTN1 and proposed that ERK
activation affects axonal growth by phosphorylation of
microtubule-associated proteins and neurofilaments.
The MAP kinase 1,2/protein kinase C (see 176960) system is an
intracellular signaling network that regulates many cellular machines,
including the cell cycle machinery and autocrine/paracrine factor
synthesizing machinery. Bhalla et al. (2002) used a combination of
computational analysis and experiments in NIH-3T3 fibroblasts to
understand the design principles of this controller network. Bhalla et
al. (2002) found that the growth factor-stimulated signaling network
controlled by MAPK 1,2/PKC can operate with 1 or 2 stable states. At low
concentrations of MAPK phosphatase (600714), the system exhibits
bistable behavior, such that brief stimulus results in sustained MAPK
activation. The MAPK-induced increase in the amounts of MAPK phosphatase
eliminates the prolonged response capability and moves the network to a
monostable state, in which it behaves as a proportional response system
responding acutely to stimuli. Thus, the MAPK 1,2/PKC controller network
is flexibly designed, and MAPK phosphatase may be critical for this
flexible response.
In rat neuronal cell cultures, Paul et al. (2003) showed that
glutamate-mediated activation of N-methyl-D-aspartate (NMDA) receptors
(see 138249) leads to the rapid but transient phosphorylation of ERK2.
NMDA-mediated influx of calcium, but not increased intracellular calcium
from other sources, led to activation of the calcium-dependent
phosphatase calcineurin and the subsequent dephosphorylation and
activation of the protein-tyrosine phosphatase STEP (176879). STEP then
inactivated ERK2 through dephosphorylation of the tyrosine residue in
its activation domain and blocked nuclear translocation of the kinase.
Thus, STEP is important in regulating the duration of ERK activation and
downstream signaling in neurons.
Chuderland et al. (2008) identified an SPS motif within the kinase
domain of rodent Erk2 that was phosphorylated upon stimulation to induce
nuclear Erk2 translocation. A 19-amino acid stretch containing the STS
motif directed nuclear accumulation of a nonnuclear test protein.
Immunoprecipitation analysis and small interfering RNA experiments in
HeLa cells indicated that phosphorylation of ERK2 on the SPS motif
caused nuclear ERK2 transport via release of ERK2 from the nuclear pore
protein NUP153 (603948) and interaction of ERK2 with importin-7 (IPO7;
605586).
During early lung development, airway tubes change shape. Tube length
increases more than circumference as a large proportion of lung
epithelial cells divide parallel to the airway longitudinal axis. Tang
et al. (2011) showed that this bias is lost in mutants with increased
ERK1 (601795) and ERK2 activity, revealing a link between the ERK1/2
signaling pathway and the control of mitotic spindle orientation. Using
a mathematical model, Tang et al. (2011) demonstrated that change in
airway shape can occur as a function of spindle angle distribution
determined by ERK1/2 signaling, independent of effects on cell
proliferation or cell size and shape. Tang et al. (2011) identified
sprouty genes (SPRY1, 602465; SPRY2, 602466), which encode negative
regulators of fibroblast growth factor-10 (FGF10; 602115)-mediated
RAS-regulated ERK1/2 signaling, as essential for controlling airway
shape change during development through an effect on mitotic spindle
orientation.
ANIMAL MODEL
Experience-dependent plasticity in the developing visual cortex depends
on electrical activity and molecular signals involved in stabilization
or removal of inputs. ERK1 and ERK2 activation in the cortex is
regulated by both factors. Di Cristo et al. (2001) demonstrated that 2
different inhibitors of the ERK pathway suppress the induction of 2
forms of long-term potentiation in rat cortical slices and that their
intracortical administration to monocularly deprived rats prevents the
shift in ocular dominance towards the nondeprived eye. Di Cristo et al.
(2001) concluded that the ERK pathway is necessary for
experience-dependent plasticity and for long-term potentiation of
synaptic transmission in the developing visual cortex.
Anthrax lethal toxin (LT), a critical virulence factor of Bacillus
anthracis, is a complex of lethal factor (LF) and protective antigen
(PA). PA binds to the anthrax receptor (ATR; 606410) to facilitate the
entry of LF into the cell. LT disrupts the MAPK signaling pathway in
macrophages (Park et al., 2002). Agrawal et al. (2003) showed that, in
mice, LT impairs the function of dendritic cells (DCs), inhibiting the
upregulation of costimulatory molecules, such as CD40 (109535), CD80
(112203), and CD86 (601020), as well as cytokine secretion, in response
to lipopolysaccharide stimulation. LT-exposed DCs failed to stimulate
antigen-specific T and B cells in vivo, resulting in significant
reductions of circulating IgG antibody. Western blot analysis indicated
that LF severely impairs phosphorylation of p38, ERK1, and ERK2. A
cocktail of synthetic MAPK inhibitors inhibited cytokine production in a
manner similar to that of LF. Using a mutant form of LF lacking a
catalytic site necessary for cleavage of MEK1, MEK2, and MEK3 (602314),
the upstream activators of ERK1, ERK2, and p38, respectively, Agrawal et
al. (2003) found that cleavage of these MEKs is essential for
suppression of dendritic cell function. They proposed that this
mechanism might operate early in infection, when LT levels are low, to
impair immunity. Later in infection, Agrawal et al. (2003) noted, LT
might have quite different inflammatory effects.
Glutamine-103 in rat Erk2 is a gatekeeper residue that confers
selectivity for binding nucleotides and small-molecule inhibitors.
Emrick et al. (2006) found that mutation of glutamine-103 to alanine or
glycine increased the basal kinase activity of Erk2 through
autoactivation via enhanced autophosphorylation of regulatory tyrosine
and threonine sites within the Erk2 activation lip that controls its
kinase activity. Using hydrogen exchange, mass spectroscopy,
steady-state kinetics, and mutagenesis, Emrick et al. (2006) determined
that an N-terminal hydrophobic cluster that includes the gatekeeper
forms a structural unit that functions to maintain the off state of ERK2
before cell signal activation.
A surge of luteinizing hormone (LH; see 152780) from the pituitary gland
triggers ovulation, oocyte maturation, and luteinization for successful
reproduction in mammals. Because the signaling molecules RAS (190020)
and ERK1/2 are activated by an LH surge in granulosa cells of
preovulatory follicles, Fan et al. (2009) disrupted Erk1/2 in mouse
granulosa cells and provided in vivo evidence that these kinases are
necessary for LH-induced oocyte resumption of meiosis, ovulation, and
luteinization. In addition, biochemical analyses and selected disruption
of the Cebpb gene (189965) in granulosa cells demonstrated that
C/EBP-beta is a critical downstream mediator of ERK1/2 activation. Thus,
Fan et al. (2009) concluded that ERK1/2 and C/EBP-beta constitute an in
vivo LH-regulated signaling pathway that controls ovulation- and
luteinization-related events.
In mouse hearts with pressure-induced cardiac hypertrophy, Lorenz et al.
(2009) observed strong phosphorylation of ERK1/ERK2 at thr183, and in
failing human hearts, they found an approximately 5-fold increase in
thr188 phosphorylation compared to controls. The authors demonstrated
that thr188 autophosphorylation directs ERK1/ERK2 to phosphorylate
nuclear targets known to cause cardiac hypertrophy, and that thr188
phosphorylation requires activation and assembly of the entire
RAF-MEK-ERK kinase cascade, phosphorylation of the TEY motif,
dimerization of ERK1/ERK2, and binding to G protein beta-gamma subunits
(see 139390) released from activated Gq (see 600998). Experiments using
transgenic mouse models carrying mutations at thr188 suggested a causal
relationship to cardiac hypertrophy. Lorenz et al. (2009) proposed that
specific phosphorylation events on ERK1/ERK2 integrate differing
upstream signals to induce cardiac hypertrophy.
Holm et al. (2011) showed that Erk1/2 and Smad2 (601366) are activated
in a mouse model of Marfan syndrome (154700), and both are inhibited by
therapies directed against Tgf-beta (190180). Whereas selective
inhibition of Erk1/2 activation ameliorated aortic growth, Smad4
(600993) deficiency exacerbated aortic disease and caused premature
death in Marfan syndrome mice. Smad4-deficient Marfan syndrome mice
uniquely showed activation of Jnk1 (601158), and a Jnk antagonist
ameliorated aortic growth in Marfan mice that lacked or retained full
Smad4 expression. Thus, Holm et al. (2011) concluded that noncanonical
(Smad-independent) Tgf-beta signaling is a prominent driver of aortic
disease in Marfan syndrome mice, and inhibition of the ERK1/2 or JNK1
pathways is a potential therapeutic strategy for the disease.
*FIELD* RF
1. Agrawal, A.; Lingappa, J.; Leppla, S. H.; Agrawal, S.; Jabbar,
A.; Quinn, C.; Pulendran, B.: Impairment of dendritic cells and adaptive
immunity by anthrax lethal toxin. Nature 424: 329-334, 2003.
2. Bhalla, U. S.; Ram, P. T.; Iyengar, R.: MAP kinase phosphatase
as a locus of flexibility in a mitogen-activated protein kinase signaling
network. Science 297: 1018-1023, 2002.
3. Boulton, T. G.; Nye, S. H.; Robbins, D. J.; Ip, N. Y.; Radziejewska,
E.; Morgenbesser, S. D.; DePinho, R. A.; Panayotatos, N.; Cobb, M.
H.; Yancopoulos, G. D.: ERKs: a family of protein-serine/threonine
kinases that are activated and tyrosine phosphorylated in response
to insulin and NGF. Cell 65: 663-675, 1991.
4. Chuderland, D.; Konson, A.; Seger, R.: Identification and characterization
of a general nuclear translocation signal in signaling proteins. Molec.
Cell 31: 850-861, 2008.
5. Cobb, M. H.; Boulton, T. G.; Robbins, D. J.: Extracellular signal-regulated
kinases: ERKs in progress. Cell Regul. 2: 965-978, 1991.
6. Di Cristo, G.; Berardi, N.; Cancedda, L.; Pizzorusso, T.; Putignano,
E.; Ratto, G. M.; Maffei, L.: Requirement of ERK activation for visual
cortical plasticity. Science 292: 2337-2340, 2001.
7. Emrick, M. A.; Lee, T.; Starkey, P. J.; Mumby, M. C.; Resing, K.
A.; Ahn, N. G.: The gatekeeper residue controls autoactivation of
ERK2 via a pathway of intramolecular connectivity. Proc. Nat. Acad.
Sci. 103: 18101-18106, 2006.
8. Fan, H.-Y.; Liu, Z.; Shimada, M.; Sterneck, E.; Johnson, P. F.;
Hedrick, S. M.; Richards, J. S.: MAPK3/1 (ERK1/2) in ovarian granulosa
cells are essential for female fertility. Science 324: 938-941,
2009.
9. Favata, M. F.; Horiuchi, K. Y.; Manos, E. J.; Daulerio, A. J.;
Stradley, D. A.; Feeser, W. S.; Van Dyk, D. E.; Pitts, W. J.; Earl,
R. A.; Hobbs, F.; Copeland, R. A.; Magolda, R. L.; Scherle, P. A.;
Trzaskos, J. M.: Identification of a novel inhibitor of mitogen-activated
protein kinase kinase. J. Biol. Chem. 273: 18623-18632, 1998.
10. Forcet, C.; Stein, E.; Pays, L.; Corset, V.; Llambi, F.; Tessier-Lavigne,
M.; Mehlen, P.: Netrin-1-mediated axon outgrowth requires deleted
in colorectal cancer-dependent MAPK activation. Nature 417: 443-447,
2002.
11. Holm, T. M.; Habashi, J. P.; Doyle, J. J.; Bedja, D.; Chen, Y.;
van Erp, C.; Lindsay, M. E.; Kim, D.; Schoenhoff, F.; Cohn, R. D.;
Loeys, B. L.; Thomas, C. J.; Patnaik, S.; Marugan, J. J.; Judge, D.
P.; Dietz, H. C.: Noncanonical TGF-beta signaling contributes to
aortic aneurysm progression in Marfan syndrome mice. Science 332:
358-361, 2011.
12. Khokhlatchev, A. V.; Canagarajah, B.; Wilsbacher, J.; Robinson,
M.; Atkinson, M.; Goldsmith, E.; Cobb, M. H.: Phosphorylation of
the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 93:
605-615, 1998.
13. Li, L.; Wysk, M.; Gonzalez, F. A.; Davis, R. J.: Genomic loci
of human mitogen-activated protein kinases. Oncogene 9: 647-649,
1994.
14. Lorenz, K.; Schmitt, J. P.; Schmitteckert, E. M.; Lohse, M. J.
: A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nature
Med. 15: 75-83, 2009.
15. Owaki, H.; Makar, R.; Boulton, T. G.; Cobb, M. H.; Geppert, T.
D.: Extracellular signal-regulated kinases in T cells: characterization
of human ERK1 and ERK2 cDNAs. Biochem. Biophys. Res. Commun. 182:
1416-1422, 1992.
16. Park, J. M.; Greten, F. R.; Li, Z. W.; Karin, M.: Macrophage
apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297:
2048-2051, 2002.
17. Paul, S.; Nairn, A. C.; Wang, P.; Lombroso, P. J.: NMDA-mediated
activation of the tyrosine phosphatase STEP regulates the duration
of ERK signaling. Nature Neurosci. 6: 34-42, 2003.
18. Pleschka, S.; Wolff, T.; Ehrhardt, C.; Hobom, G.; Planz, O.; Rapp,
U. R.; Ludwig, S.: Influenza virus propagation is impaired by inhibition
of the Raf/MEK/ERK signalling cascade. Nature Cell Biol. 3: 301-305,
2001.
19. Saba-El-Leil, M. K.; Malo, D.; Meloche, S.: Chromosomal localization
of the mouse genes encoding the ERK1 and ERK2 isoforms of MAP kinases. Mammalian
Genome 8: 141-142, 1997.
20. Seger, R.; Krebs, E. G.: The MAPK signaling cascade. FASEB J. 9:
726-735, 1995.
21. Stefanovsky, V. Y.; Pelletier, G.; Hannan, R.; Gagnon-Kugler,
T.; Rothblum, L. I.; Moss, T.: An immediate response of ribosomal
transcription to growth factor stimulation in mammals is mediated
by ERK phosphorylation of UBF. Molec. Cell 8: 1063-1073, 2001.
22. Tang, N.; Marshall, W. F.; McMahon, M.; Metzger, R. J.; Martin,
G. R.: Control of mitotic spindle angle by the RAS-regulated ERK1/2
pathway determines lung tube shape. Science 333: 342-345, 2011.
23. Thomas, G.: MAP kinase by any other name smells just as sweet. Cell 68:
3-6, 1992.
24. Waskiewicz, A. J.; Flynn, A.; Proud, C. G.; Cooper, J. A.: Mitogen-activated
protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO
J. 16: 1909-1920, 1997.
*FIELD* CN
Ada Hamosh - updated: 8/4/2011
Ada Hamosh - updated: 6/7/2011
Ada Hamosh - updated: 8/17/2009
Patricia A. Hartz - updated: 5/29/2009
Marla J. F. O'Neill - updated: 2/27/2009
Patricia A. Hartz - updated: 1/29/2007
Paul J. Converse - updated: 7/17/2003
Cassandra L. Kniffin - updated: 3/19/2003
Ada Hamosh - updated: 9/11/2002
Paul J. Converse - updated: 5/6/2002
Dawn Watkins-Chow - updated: 2/27/2002
Stylianos E. Antonarakis - updated: 1/3/2002
Ada Hamosh - updated: 6/27/2001
Paul J. Converse - updated: 3/2/2001
Stylianos E. Antonarakis - updated: 6/4/1998
Victor A. McKusick - updated: 4/9/1997
*FIELD* CD
Victor A. McKusick: 12/16/1992
*FIELD* ED
alopez: 08/16/2011
terry: 8/4/2011
alopez: 6/10/2011
terry: 6/7/2011
mgross: 2/9/2011
terry: 2/7/2011
mgross: 1/26/2010
terry: 1/20/2010
alopez: 8/21/2009
terry: 8/17/2009
mgross: 6/2/2009
terry: 5/29/2009
wwang: 3/5/2009
terry: 2/27/2009
alopez: 1/29/2007
wwang: 10/27/2005
alopez: 7/28/2003
mgross: 7/17/2003
tkritzer: 4/8/2003
tkritzer: 4/7/2003
ckniffin: 3/19/2003
alopez: 9/12/2002
cwells: 9/11/2002
alopez: 6/7/2002
mgross: 5/6/2002
mgross: 2/27/2002
mgross: 1/3/2002
alopez: 7/3/2001
terry: 6/27/2001
mgross: 3/2/2001
carol: 3/27/2000
alopez: 2/10/2000
alopez: 12/28/1999
psherman: 9/9/1999
psherman: 9/8/1999
carol: 8/26/1998
alopez: 7/29/1998
carol: 6/9/1998
terry: 6/4/1998
psherman: 4/21/1998
mark: 5/26/1997
terry: 5/3/1997
mark: 4/9/1997
terry: 4/3/1997
mark: 5/17/1996
carol: 6/9/1993
carol: 12/16/1992
*RECORD*
*FIELD* NO
176948
*FIELD* TI
*176948 MITOGEN-ACTIVATED PROTEIN KINASE 1; MAPK1
;;PROTEIN KINASE, MITOGEN-ACTIVATED, 1; PRKM1;;
read morePROTEIN KINASE, MITOGEN-ACTIVATED, 2; PRKM2;;
EXTRACELLULAR SIGNAL-REGULATED KINASE 2; ERK2;;
PROTEIN TYROSINE KINASE ERK2;;
p42MAPK
*FIELD* TX
CLONING
Boulton et al. (1991) cloned 2 rat enzymes that are S6 kinases and a
third related kinase and named them extracellular signal-regulated
kinase (Erk)-1, -2, and -3.
Owaki et al. (1992) isolated cDNAs for human ERK1 (MAPK3; 601795) and
ERK2. The deduced 360-amino acid human ERK2 protein shares 98% identity
with rat Erk2.
MAPPING
By a combination of fluorescence in situ hybridization and Southern blot
analysis of genomic DNA from a panel of human/hamster cell hybrids, Li
et al. (1994) mapped the MAPK1 gene to 22q11.2. Saba-El-Leil et al.
(1997) mapped the mouse Mapk1 gene to chromosome 16, in a region showing
homology of synteny with human 22q11.2.
GENE FUNCTION
ERKs are also known as maturation- or mitogen-activated protein (MAP)
kinases. Cobb et al. (1991) provided a review. Thomas (1992) gave a
review of MAP kinases and Seger and Krebs (1995) reviewed the MAP kinase
signaling cascade.
The MAP kinase ERK2 is widely involved in eukaryotic signal
transduction. Upon activation, it translocates to the nucleus of the
stimulated cell, where it phosphorylates nuclear targets. Khokhlatchev
et al. (1998) found that nuclear accumulation of microinjected ERK2
depends on its phosphorylation state rather than on its activity or on
upstream components of its signaling pathway. Phosphorylated ERK2 forms
dimers with phosphorylated and unphosphorylated ERK2 partners.
Disruption of dimerization by mutagenesis of ERK2 reduces its ability to
accumulate in the nucleus, suggesting that dimerization is essential for
its normal ligand-dependent relocalization. Other MAP kinase family
members also form dimers. Khokhlatchev et al. (1998) concluded that
dimerization is part of the mechanism of action of the MAP kinase
family.
Influenza A viruses are significant causes of morbidity and mortality
worldwide. Annually updated vaccines may prevent disease, and antivirals
are effective treatment early in disease when symptoms are often
nonspecific. Viral replication is supported by intracellular signaling
events. Using U0126, a nontoxic inhibitor of MEK1 (176872) and MEK2
(601263), and thus an inhibitor of the RAF1 (164760)/MEK/ERK pathway
(see Favata et al. (1998)), Pleschka et al. (2001) examined the cellular
response to infection with influenza A. U0126 suppressed both the early
and late ERK activation phases after virus infection. Inhibition of the
signaling pathway occurred without impairing the synthesis of viral RNA
or protein, or the import of viral ribonucleoprotein complexes (RNP)
into the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the
export of viral RNP without affecting the cellular mRNA export pathway.
Pleschka et al. (2001) proposed that ERK regulates a cellular factor
involved in the viral nuclear export protein function. They suggested
that local application of MEK inhibitors may have only minor toxic
effects on the host while inhibiting viral replication without giving
rise to drug-resistant virus variants.
Stefanovsky et al. (2001) showed that epidermal growth factor (131530)
induces immediate, ERK1/ERK2-dependent activation of endogenous
ribosomal transcription, while inactivation of ERK1/ERK2 causes an
equally immediate reversion to the basal transcription level. ERK1/ERK2
was found to phosphorylate the architectural transcription factor UBF
(600673) at amino acids 117 and 201 within HMG boxes 1 and 2, preventing
their interaction with DNA. Mutation of these sites inhibited
transcription activation and abrogated the transcriptional response to
ERK1/ERK2. Thus, growth factor regulation of ribosomal transcription
likely acts by a cyclic modulation of DNA architecture. The data
suggested a central role for ribosome biogenesis in growth regulation.
Using a 2-hybrid screen and in vitro association experiments, Waskiewicz
et al. (1997) identified Mnk1 (MKNK1; 606724) and Mnk2 (MKNK2; 605069)
as Erk2-binding proteins in mouse.
Forcet et al. (2002) showed that in embryonic kidney cells expressing
full-length, but not cytoplasmic domain-truncated, DCC (120470), NTN1
(601614) causes increased transient phosphorylation and activity of ERK1
and ERK2, but not of JNK1 (601158), JNK2 (602896), or p38 (MAPK14;
600289). This phosphorylation was mediated by MEK1 and/or MEK2. NTN1
also activated the transcription factor ELK1 (311040) and serum response
element-regulated gene expression. Immunoprecipitation analysis showed
interaction of full-length DCC with MEK1/2 in the presence or absence of
NTN1. Forcet et al. (2002) showed that activation of Dcc by Ntn1 in rat
embryonic day-13 dorsal spinal cord stimulates and is required for the
outgrowth of commissural axons and Erk1/2 activation.
Immunohistochemical analysis demonstrated expression of activated Erk1/2
in embryonic commissural axons, and this expression was diminished in
Dcc or Ntn1 knockout animals. Forcet et al. (2002) concluded that the
MAPK pathway is involved in responses to NTN1 and proposed that ERK
activation affects axonal growth by phosphorylation of
microtubule-associated proteins and neurofilaments.
The MAP kinase 1,2/protein kinase C (see 176960) system is an
intracellular signaling network that regulates many cellular machines,
including the cell cycle machinery and autocrine/paracrine factor
synthesizing machinery. Bhalla et al. (2002) used a combination of
computational analysis and experiments in NIH-3T3 fibroblasts to
understand the design principles of this controller network. Bhalla et
al. (2002) found that the growth factor-stimulated signaling network
controlled by MAPK 1,2/PKC can operate with 1 or 2 stable states. At low
concentrations of MAPK phosphatase (600714), the system exhibits
bistable behavior, such that brief stimulus results in sustained MAPK
activation. The MAPK-induced increase in the amounts of MAPK phosphatase
eliminates the prolonged response capability and moves the network to a
monostable state, in which it behaves as a proportional response system
responding acutely to stimuli. Thus, the MAPK 1,2/PKC controller network
is flexibly designed, and MAPK phosphatase may be critical for this
flexible response.
In rat neuronal cell cultures, Paul et al. (2003) showed that
glutamate-mediated activation of N-methyl-D-aspartate (NMDA) receptors
(see 138249) leads to the rapid but transient phosphorylation of ERK2.
NMDA-mediated influx of calcium, but not increased intracellular calcium
from other sources, led to activation of the calcium-dependent
phosphatase calcineurin and the subsequent dephosphorylation and
activation of the protein-tyrosine phosphatase STEP (176879). STEP then
inactivated ERK2 through dephosphorylation of the tyrosine residue in
its activation domain and blocked nuclear translocation of the kinase.
Thus, STEP is important in regulating the duration of ERK activation and
downstream signaling in neurons.
Chuderland et al. (2008) identified an SPS motif within the kinase
domain of rodent Erk2 that was phosphorylated upon stimulation to induce
nuclear Erk2 translocation. A 19-amino acid stretch containing the STS
motif directed nuclear accumulation of a nonnuclear test protein.
Immunoprecipitation analysis and small interfering RNA experiments in
HeLa cells indicated that phosphorylation of ERK2 on the SPS motif
caused nuclear ERK2 transport via release of ERK2 from the nuclear pore
protein NUP153 (603948) and interaction of ERK2 with importin-7 (IPO7;
605586).
During early lung development, airway tubes change shape. Tube length
increases more than circumference as a large proportion of lung
epithelial cells divide parallel to the airway longitudinal axis. Tang
et al. (2011) showed that this bias is lost in mutants with increased
ERK1 (601795) and ERK2 activity, revealing a link between the ERK1/2
signaling pathway and the control of mitotic spindle orientation. Using
a mathematical model, Tang et al. (2011) demonstrated that change in
airway shape can occur as a function of spindle angle distribution
determined by ERK1/2 signaling, independent of effects on cell
proliferation or cell size and shape. Tang et al. (2011) identified
sprouty genes (SPRY1, 602465; SPRY2, 602466), which encode negative
regulators of fibroblast growth factor-10 (FGF10; 602115)-mediated
RAS-regulated ERK1/2 signaling, as essential for controlling airway
shape change during development through an effect on mitotic spindle
orientation.
ANIMAL MODEL
Experience-dependent plasticity in the developing visual cortex depends
on electrical activity and molecular signals involved in stabilization
or removal of inputs. ERK1 and ERK2 activation in the cortex is
regulated by both factors. Di Cristo et al. (2001) demonstrated that 2
different inhibitors of the ERK pathway suppress the induction of 2
forms of long-term potentiation in rat cortical slices and that their
intracortical administration to monocularly deprived rats prevents the
shift in ocular dominance towards the nondeprived eye. Di Cristo et al.
(2001) concluded that the ERK pathway is necessary for
experience-dependent plasticity and for long-term potentiation of
synaptic transmission in the developing visual cortex.
Anthrax lethal toxin (LT), a critical virulence factor of Bacillus
anthracis, is a complex of lethal factor (LF) and protective antigen
(PA). PA binds to the anthrax receptor (ATR; 606410) to facilitate the
entry of LF into the cell. LT disrupts the MAPK signaling pathway in
macrophages (Park et al., 2002). Agrawal et al. (2003) showed that, in
mice, LT impairs the function of dendritic cells (DCs), inhibiting the
upregulation of costimulatory molecules, such as CD40 (109535), CD80
(112203), and CD86 (601020), as well as cytokine secretion, in response
to lipopolysaccharide stimulation. LT-exposed DCs failed to stimulate
antigen-specific T and B cells in vivo, resulting in significant
reductions of circulating IgG antibody. Western blot analysis indicated
that LF severely impairs phosphorylation of p38, ERK1, and ERK2. A
cocktail of synthetic MAPK inhibitors inhibited cytokine production in a
manner similar to that of LF. Using a mutant form of LF lacking a
catalytic site necessary for cleavage of MEK1, MEK2, and MEK3 (602314),
the upstream activators of ERK1, ERK2, and p38, respectively, Agrawal et
al. (2003) found that cleavage of these MEKs is essential for
suppression of dendritic cell function. They proposed that this
mechanism might operate early in infection, when LT levels are low, to
impair immunity. Later in infection, Agrawal et al. (2003) noted, LT
might have quite different inflammatory effects.
Glutamine-103 in rat Erk2 is a gatekeeper residue that confers
selectivity for binding nucleotides and small-molecule inhibitors.
Emrick et al. (2006) found that mutation of glutamine-103 to alanine or
glycine increased the basal kinase activity of Erk2 through
autoactivation via enhanced autophosphorylation of regulatory tyrosine
and threonine sites within the Erk2 activation lip that controls its
kinase activity. Using hydrogen exchange, mass spectroscopy,
steady-state kinetics, and mutagenesis, Emrick et al. (2006) determined
that an N-terminal hydrophobic cluster that includes the gatekeeper
forms a structural unit that functions to maintain the off state of ERK2
before cell signal activation.
A surge of luteinizing hormone (LH; see 152780) from the pituitary gland
triggers ovulation, oocyte maturation, and luteinization for successful
reproduction in mammals. Because the signaling molecules RAS (190020)
and ERK1/2 are activated by an LH surge in granulosa cells of
preovulatory follicles, Fan et al. (2009) disrupted Erk1/2 in mouse
granulosa cells and provided in vivo evidence that these kinases are
necessary for LH-induced oocyte resumption of meiosis, ovulation, and
luteinization. In addition, biochemical analyses and selected disruption
of the Cebpb gene (189965) in granulosa cells demonstrated that
C/EBP-beta is a critical downstream mediator of ERK1/2 activation. Thus,
Fan et al. (2009) concluded that ERK1/2 and C/EBP-beta constitute an in
vivo LH-regulated signaling pathway that controls ovulation- and
luteinization-related events.
In mouse hearts with pressure-induced cardiac hypertrophy, Lorenz et al.
(2009) observed strong phosphorylation of ERK1/ERK2 at thr183, and in
failing human hearts, they found an approximately 5-fold increase in
thr188 phosphorylation compared to controls. The authors demonstrated
that thr188 autophosphorylation directs ERK1/ERK2 to phosphorylate
nuclear targets known to cause cardiac hypertrophy, and that thr188
phosphorylation requires activation and assembly of the entire
RAF-MEK-ERK kinase cascade, phosphorylation of the TEY motif,
dimerization of ERK1/ERK2, and binding to G protein beta-gamma subunits
(see 139390) released from activated Gq (see 600998). Experiments using
transgenic mouse models carrying mutations at thr188 suggested a causal
relationship to cardiac hypertrophy. Lorenz et al. (2009) proposed that
specific phosphorylation events on ERK1/ERK2 integrate differing
upstream signals to induce cardiac hypertrophy.
Holm et al. (2011) showed that Erk1/2 and Smad2 (601366) are activated
in a mouse model of Marfan syndrome (154700), and both are inhibited by
therapies directed against Tgf-beta (190180). Whereas selective
inhibition of Erk1/2 activation ameliorated aortic growth, Smad4
(600993) deficiency exacerbated aortic disease and caused premature
death in Marfan syndrome mice. Smad4-deficient Marfan syndrome mice
uniquely showed activation of Jnk1 (601158), and a Jnk antagonist
ameliorated aortic growth in Marfan mice that lacked or retained full
Smad4 expression. Thus, Holm et al. (2011) concluded that noncanonical
(Smad-independent) Tgf-beta signaling is a prominent driver of aortic
disease in Marfan syndrome mice, and inhibition of the ERK1/2 or JNK1
pathways is a potential therapeutic strategy for the disease.
*FIELD* RF
1. Agrawal, A.; Lingappa, J.; Leppla, S. H.; Agrawal, S.; Jabbar,
A.; Quinn, C.; Pulendran, B.: Impairment of dendritic cells and adaptive
immunity by anthrax lethal toxin. Nature 424: 329-334, 2003.
2. Bhalla, U. S.; Ram, P. T.; Iyengar, R.: MAP kinase phosphatase
as a locus of flexibility in a mitogen-activated protein kinase signaling
network. Science 297: 1018-1023, 2002.
3. Boulton, T. G.; Nye, S. H.; Robbins, D. J.; Ip, N. Y.; Radziejewska,
E.; Morgenbesser, S. D.; DePinho, R. A.; Panayotatos, N.; Cobb, M.
H.; Yancopoulos, G. D.: ERKs: a family of protein-serine/threonine
kinases that are activated and tyrosine phosphorylated in response
to insulin and NGF. Cell 65: 663-675, 1991.
4. Chuderland, D.; Konson, A.; Seger, R.: Identification and characterization
of a general nuclear translocation signal in signaling proteins. Molec.
Cell 31: 850-861, 2008.
5. Cobb, M. H.; Boulton, T. G.; Robbins, D. J.: Extracellular signal-regulated
kinases: ERKs in progress. Cell Regul. 2: 965-978, 1991.
6. Di Cristo, G.; Berardi, N.; Cancedda, L.; Pizzorusso, T.; Putignano,
E.; Ratto, G. M.; Maffei, L.: Requirement of ERK activation for visual
cortical plasticity. Science 292: 2337-2340, 2001.
7. Emrick, M. A.; Lee, T.; Starkey, P. J.; Mumby, M. C.; Resing, K.
A.; Ahn, N. G.: The gatekeeper residue controls autoactivation of
ERK2 via a pathway of intramolecular connectivity. Proc. Nat. Acad.
Sci. 103: 18101-18106, 2006.
8. Fan, H.-Y.; Liu, Z.; Shimada, M.; Sterneck, E.; Johnson, P. F.;
Hedrick, S. M.; Richards, J. S.: MAPK3/1 (ERK1/2) in ovarian granulosa
cells are essential for female fertility. Science 324: 938-941,
2009.
9. Favata, M. F.; Horiuchi, K. Y.; Manos, E. J.; Daulerio, A. J.;
Stradley, D. A.; Feeser, W. S.; Van Dyk, D. E.; Pitts, W. J.; Earl,
R. A.; Hobbs, F.; Copeland, R. A.; Magolda, R. L.; Scherle, P. A.;
Trzaskos, J. M.: Identification of a novel inhibitor of mitogen-activated
protein kinase kinase. J. Biol. Chem. 273: 18623-18632, 1998.
10. Forcet, C.; Stein, E.; Pays, L.; Corset, V.; Llambi, F.; Tessier-Lavigne,
M.; Mehlen, P.: Netrin-1-mediated axon outgrowth requires deleted
in colorectal cancer-dependent MAPK activation. Nature 417: 443-447,
2002.
11. Holm, T. M.; Habashi, J. P.; Doyle, J. J.; Bedja, D.; Chen, Y.;
van Erp, C.; Lindsay, M. E.; Kim, D.; Schoenhoff, F.; Cohn, R. D.;
Loeys, B. L.; Thomas, C. J.; Patnaik, S.; Marugan, J. J.; Judge, D.
P.; Dietz, H. C.: Noncanonical TGF-beta signaling contributes to
aortic aneurysm progression in Marfan syndrome mice. Science 332:
358-361, 2011.
12. Khokhlatchev, A. V.; Canagarajah, B.; Wilsbacher, J.; Robinson,
M.; Atkinson, M.; Goldsmith, E.; Cobb, M. H.: Phosphorylation of
the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell 93:
605-615, 1998.
13. Li, L.; Wysk, M.; Gonzalez, F. A.; Davis, R. J.: Genomic loci
of human mitogen-activated protein kinases. Oncogene 9: 647-649,
1994.
14. Lorenz, K.; Schmitt, J. P.; Schmitteckert, E. M.; Lohse, M. J.
: A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nature
Med. 15: 75-83, 2009.
15. Owaki, H.; Makar, R.; Boulton, T. G.; Cobb, M. H.; Geppert, T.
D.: Extracellular signal-regulated kinases in T cells: characterization
of human ERK1 and ERK2 cDNAs. Biochem. Biophys. Res. Commun. 182:
1416-1422, 1992.
16. Park, J. M.; Greten, F. R.; Li, Z. W.; Karin, M.: Macrophage
apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297:
2048-2051, 2002.
17. Paul, S.; Nairn, A. C.; Wang, P.; Lombroso, P. J.: NMDA-mediated
activation of the tyrosine phosphatase STEP regulates the duration
of ERK signaling. Nature Neurosci. 6: 34-42, 2003.
18. Pleschka, S.; Wolff, T.; Ehrhardt, C.; Hobom, G.; Planz, O.; Rapp,
U. R.; Ludwig, S.: Influenza virus propagation is impaired by inhibition
of the Raf/MEK/ERK signalling cascade. Nature Cell Biol. 3: 301-305,
2001.
19. Saba-El-Leil, M. K.; Malo, D.; Meloche, S.: Chromosomal localization
of the mouse genes encoding the ERK1 and ERK2 isoforms of MAP kinases. Mammalian
Genome 8: 141-142, 1997.
20. Seger, R.; Krebs, E. G.: The MAPK signaling cascade. FASEB J. 9:
726-735, 1995.
21. Stefanovsky, V. Y.; Pelletier, G.; Hannan, R.; Gagnon-Kugler,
T.; Rothblum, L. I.; Moss, T.: An immediate response of ribosomal
transcription to growth factor stimulation in mammals is mediated
by ERK phosphorylation of UBF. Molec. Cell 8: 1063-1073, 2001.
22. Tang, N.; Marshall, W. F.; McMahon, M.; Metzger, R. J.; Martin,
G. R.: Control of mitotic spindle angle by the RAS-regulated ERK1/2
pathway determines lung tube shape. Science 333: 342-345, 2011.
23. Thomas, G.: MAP kinase by any other name smells just as sweet. Cell 68:
3-6, 1992.
24. Waskiewicz, A. J.; Flynn, A.; Proud, C. G.; Cooper, J. A.: Mitogen-activated
protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO
J. 16: 1909-1920, 1997.
*FIELD* CN
Ada Hamosh - updated: 8/4/2011
Ada Hamosh - updated: 6/7/2011
Ada Hamosh - updated: 8/17/2009
Patricia A. Hartz - updated: 5/29/2009
Marla J. F. O'Neill - updated: 2/27/2009
Patricia A. Hartz - updated: 1/29/2007
Paul J. Converse - updated: 7/17/2003
Cassandra L. Kniffin - updated: 3/19/2003
Ada Hamosh - updated: 9/11/2002
Paul J. Converse - updated: 5/6/2002
Dawn Watkins-Chow - updated: 2/27/2002
Stylianos E. Antonarakis - updated: 1/3/2002
Ada Hamosh - updated: 6/27/2001
Paul J. Converse - updated: 3/2/2001
Stylianos E. Antonarakis - updated: 6/4/1998
Victor A. McKusick - updated: 4/9/1997
*FIELD* CD
Victor A. McKusick: 12/16/1992
*FIELD* ED
alopez: 08/16/2011
terry: 8/4/2011
alopez: 6/10/2011
terry: 6/7/2011
mgross: 2/9/2011
terry: 2/7/2011
mgross: 1/26/2010
terry: 1/20/2010
alopez: 8/21/2009
terry: 8/17/2009
mgross: 6/2/2009
terry: 5/29/2009
wwang: 3/5/2009
terry: 2/27/2009
alopez: 1/29/2007
wwang: 10/27/2005
alopez: 7/28/2003
mgross: 7/17/2003
tkritzer: 4/8/2003
tkritzer: 4/7/2003
ckniffin: 3/19/2003
alopez: 9/12/2002
cwells: 9/11/2002
alopez: 6/7/2002
mgross: 5/6/2002
mgross: 2/27/2002
mgross: 1/3/2002
alopez: 7/3/2001
terry: 6/27/2001
mgross: 3/2/2001
carol: 3/27/2000
alopez: 2/10/2000
alopez: 12/28/1999
psherman: 9/9/1999
psherman: 9/8/1999
carol: 8/26/1998
alopez: 7/29/1998
carol: 6/9/1998
terry: 6/4/1998
psherman: 4/21/1998
mark: 5/26/1997
terry: 5/3/1997
mark: 4/9/1997
terry: 4/3/1997
mark: 5/17/1996
carol: 6/9/1993
carol: 12/16/1992