Full text data of MAP2K4
MAP2K4
(JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1)
[Confidence: low (only semi-automatic identification from reviews)]
Dual specificity mitogen-activated protein kinase kinase 4; MAP kinase kinase 4; MAPKK 4; 2.7.12.2 (JNK-activating kinase 1; MAPK/ERK kinase 4; MEK 4; SAPK/ERK kinase 1; SEK1; Stress-activated protein kinase kinase 1; SAPK kinase 1; SAPKK-1; SAPKK1; c-Jun N-terminal kinase kinase 1; JNKK)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Dual specificity mitogen-activated protein kinase kinase 4; MAP kinase kinase 4; MAPKK 4; 2.7.12.2 (JNK-activating kinase 1; MAPK/ERK kinase 4; MEK 4; SAPK/ERK kinase 1; SEK1; Stress-activated protein kinase kinase 1; SAPK kinase 1; SAPKK-1; SAPKK1; c-Jun N-terminal kinase kinase 1; JNKK)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P45985
ID MP2K4_HUMAN Reviewed; 399 AA.
AC P45985; B2R7N7; B3KYB2; D3DTS5; Q5U0B8; Q6FHX4; Q6P9H2; Q6PIE6;
read moreDT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 4;
DE Short=MAP kinase kinase 4;
DE Short=MAPKK 4;
DE EC=2.7.12.2;
DE AltName: Full=JNK-activating kinase 1;
DE AltName: Full=MAPK/ERK kinase 4;
DE Short=MEK 4;
DE AltName: Full=SAPK/ERK kinase 1;
DE Short=SEK1;
DE AltName: Full=Stress-activated protein kinase kinase 1;
DE Short=SAPK kinase 1;
DE Short=SAPKK-1;
DE Short=SAPKK1;
DE AltName: Full=c-Jun N-terminal kinase kinase 1;
DE Short=JNKK;
GN Name=MAP2K4; Synonyms=JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1;
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).
RC TISSUE=Brain;
RX PubMed=7839144; DOI=10.1126/science.7839144;
RA Derijard B., Raingeaud J., Barrett T., Wu I.-H., Han J.,
RA Ulevitch R.J., Davis R.J.;
RT "Independent human MAP-kinase signal transduction pathways defined by
RT MEK and MKK isoforms.";
RL Science 267:682-685(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RX PubMed=7716521; DOI=10.1126/science.7716521;
RA Lin A., Minden A., Martinetto H., Claret F.-X., Lange-Carter C.,
RA Mercurio F., Johnson G.L., Karin M.;
RT "Identification of a dual specificity kinase that activates the Jun
RT kinases and p38-Mpk2.";
RL Science 268:286-290(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9622070;
RA Su G.H., Hilgers W., Shekher M.C., Tang D.J., Yeo C.J., Hruban R.H.,
RA Kern S.E.;
RT "Alterations in pancreatic, biliary, and breast carcinomas support
RT MKK4 as a genetically targeted tumor suppressor gene.";
RL Cancer Res. 58:2339-2342(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain, and Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ARG-16.
RC TISSUE=Brain, and Testis;
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 [11]
RP PHOSPHORYLATION, ENZYME REGULATION, AND INTERACTION WITH MAP3K11/MLK3.
RX PubMed=9003778;
RA Tibbles L.A., Ing Y.L., Kiefer F., Chan J., Iscove N., Woodgett J.R.,
RA Lassam N.J.;
RT "MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and
RT MKK3/6.";
RL EMBO J. 15:7026-7035(1996).
RN [12]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX PubMed=11104681; DOI=10.1042/0264-6021:3520739;
RA Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.;
RT "Susceptibility of mitogen-activated protein kinase kinase family
RT members to proteolysis by anthrax lethal factor.";
RL Biochem. J. 352:739-745(2000).
RN [13]
RP INTERACTION WITH ARRB2.
RX PubMed=11090355; DOI=10.1126/science.290.5496.1574;
RA McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E.,
RA Lin F.-T., Davis R.J., Lefkowitz R.J.;
RT "Beta-arrestin 2: a receptor-regulated MAPK scaffold for the
RT activation of JNK3.";
RL Science 290:1574-1577(2000).
RN [14]
RP INTERACTION WITH MAPK8IP3/JIP3.
RX PubMed=12189133; DOI=10.1074/jbc.M202004200;
RA Matsuura H., Nishitoh H., Takeda K., Matsuzawa A., Amagasa T., Ito M.,
RA Yoshioka K., Ichijo H.;
RT "Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-
RT JNK signaling pathway. A new mode of regulation of the MAP kinase
RT cascade.";
RL J. Biol. Chem. 277:40703-40709(2002).
RN [15]
RP DOMAIN, AND INTERACTION WITH MAPK8/JNK1; MAPK9/JNK2; MAPK10/JNK3;
RP MAPK11 AND MAPK14.
RX PubMed=12788955; DOI=10.1074/jbc.M304229200;
RA Ho D.T., Bardwell A.J., Abdollahi M., Bardwell L.;
RT "A docking site in MKK4 mediates high affinity binding to JNK MAPKs
RT and competes with similar docking sites in JNK substrates.";
RL J. Biol. Chem. 278:32662-32672(2003).
RN [16]
RP DOMAIN.
RX PubMed=15866172; DOI=10.1016/j.molcel.2005.04.001;
RA Takekawa M., Tatebayashi K., Saito H.;
RT "Conserved docking site is essential for activation of mammalian MAP
RT kinase kinases by specific MAP kinase kinase kinases.";
RL Mol. Cell 18:295-306(2005).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90, AND MASS
RP 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 [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [19]
RP INTERACTION WITH ARRB1 AND ARRB2.
RX PubMed=19782076; DOI=10.1016/j.febslet.2009.09.035;
RA Li X., MacLeod R., Dunlop A.J., Edwards H.V., Advant N., Gibson L.C.,
RA Devine N.M., Brown K.M., Adams D.R., Houslay M.D., Baillie G.S.;
RT "A scanning peptide array approach uncovers association sites within
RT the JNK/beta arrestin signalling complex.";
RL FEBS Lett. 583:3310-3316(2009).
RN [20]
RP REVIEW ON ENZYME REGULATION.
RX PubMed=17496909; DOI=10.1038/sj.onc.1210392;
RA Raman M., Chen W., Cobb M.H.;
RT "Differential regulation and properties of MAPKs.";
RL Oncogene 26:3100-3112(2007).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257, 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 [22]
RP REVIEW ON FUNCTION.
RX PubMed=20801953; DOI=10.1093/jb/mvq098;
RA Asaoka Y., Nishina H.;
RT "Diverse physiological functions of MKK4 and MKK7 during early
RT embryogenesis.";
RL J. Biochem. 148:393-401(2010).
RN [23]
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 [24]
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 [25]
RP REVIEW ON REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=21333379; DOI=10.1016/j.ejcb.2010.11.008;
RA Haeusgen W., Herdegen T., Waetzig V.;
RT "The bottleneck of JNK signaling: molecular and functional
RT characteristics of MKK4 and MKK7.";
RL Eur. J. Cell Biol. 90:536-544(2011).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 80-399.
RX PubMed=20732303; DOI=10.1016/j.bbrc.2010.08.071;
RA Matsumoto T., Kinoshita T., Kirii Y., Yokota K., Hamada K., Tada T.;
RT "Crystal structures of MKK4 kinase domain reveal that substrate
RT peptide binds to an allosteric site and induces an auto-inhibition
RT state.";
RL Biochem. Biophys. Res. Commun. 400:369-373(2010).
RN [27]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-142; TRP-154; ILE-234; ASN-251 AND
RP THR-279.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Dual specificity protein kinase which acts as an
CC essential component of the MAP kinase signal transduction pathway.
CC Essential component of the stress-activated protein kinase/c-Jun
CC N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7,
CC is the one of the only known kinase to directly activate the
CC stress-activated protein kinase/c-Jun N-terminal kinases
CC MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and
CC MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they
CC differ in their preference for the phosphorylation site in the
CC Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of
CC the Tyr residue and MAP2K7/MKK7 for the Thr residue. The
CC phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the
CC prerequisite for JNK activation at least in response to
CC proinflammatory cytokines, while other stimuli activate both
CC MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate
CC JNKs. MAP2K4 is required for maintaining peripheral lymphoid
CC homeostasis. The MKK/JNK signaling pathway is also involved in
CC mitochondrial death signaling pathway, including the release
CC cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7
CC exclusively activates JNKs, MAP2K4/MKK4 additionally activates the
CC p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Activated in response to a variety of cellular
CC stresses, including UV and gamma-irradiation, heat shock,
CC hyperosmolarity, T-cell receptor stimulation, peroxide and
CC inflammatory cytokines. Also activated by developmental cues.
CC MAP2K4/MKK4 is activated by the majority of MKKKs, such as
CC MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2,
CC MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.
CC -!- SUBUNIT: Interacts with SPAG9 (By similarity). Interacts (via its
CC D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3,
CC MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks
CC activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with
CC ARRB1, ARRB2 and MAPK8IP3/JIP3.
CC -!- INTERACTION:
CC Q13233:MAP3K1; NbExp=3; IntAct=EBI-447868, EBI-49776;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Nucleus (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P45985-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P45985-2; Sequence=VSP_038838;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Abundant expression is seen in the skeletal
CC muscle. It is also widely expressed in other tissues.
CC -!- DOMAIN: The DVD domain (residues 364-387) contains a conserved
CC docking site and is found in the mammalian MAP kinase kinases
CC (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase
CC kinase kinases (MAP3Ks) and are essential for activation.
CC -!- DOMAIN: The D domain (residues 34-52) contains a conserved docking
CC site and is required for the binding to MAPK substrates.
CC -!- PTM: Activated by phosphorylation on Ser-257 and Thr-261 by MAP
CC kinase kinase kinases (MAP3Ks).
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/map2k4/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MAP2K4ID244ch17p12.html";
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DR EMBL; L36870; AAC41719.1; -; mRNA.
DR EMBL; U17743; AAC50127.1; -; mRNA.
DR EMBL; AF070090; AAC24130.1; -; Genomic_DNA.
DR EMBL; AF070080; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070081; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070082; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070083; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070084; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070085; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070086; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070087; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070088; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070089; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; CR536564; CAG38801.1; -; mRNA.
DR EMBL; BT019676; AAV38482.1; -; mRNA.
DR EMBL; AK131544; BAG54774.1; -; mRNA.
DR EMBL; AK313053; BAG35884.1; -; mRNA.
DR EMBL; DQ015703; AAY22176.1; -; Genomic_DNA.
DR EMBL; AC005244; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005410; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471108; EAW89975.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW89974.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW89976.1; -; Genomic_DNA.
DR EMBL; BC036032; AAH36032.1; -; mRNA.
DR EMBL; BC060764; AAH60764.1; -; mRNA.
DR PIR; I38901; I38901.
DR RefSeq; NP_001268364.1; NM_001281435.1.
DR RefSeq; NP_003001.1; NM_003010.3.
DR UniGene; Hs.514681; -.
DR PDB; 3ALN; X-ray; 2.30 A; A/B/C=80-399.
DR PDB; 3ALO; X-ray; 2.60 A; A=80-399.
DR PDB; 3VUT; X-ray; 3.50 A; A/B=80-399.
DR PDBsum; 3ALN; -.
DR PDBsum; 3ALO; -.
DR PDBsum; 3VUT; -.
DR ProteinModelPortal; P45985; -.
DR SMR; P45985; 95-388.
DR IntAct; P45985; 11.
DR MINT; MINT-151438; -.
DR STRING; 9606.ENSP00000262445; -.
DR BindingDB; P45985; -.
DR ChEMBL; CHEMBL2897; -.
DR GuidetoPHARMACOLOGY; 2065; -.
DR PhosphoSite; P45985; -.
DR DMDM; 1170596; -.
DR PaxDb; P45985; -.
DR PRIDE; P45985; -.
DR DNASU; 6416; -.
DR Ensembl; ENST00000353533; ENSP00000262445; ENSG00000065559.
DR Ensembl; ENST00000415385; ENSP00000410402; ENSG00000065559.
DR GeneID; 6416; -.
DR KEGG; hsa:6416; -.
DR UCSC; uc002gnj.3; human.
DR CTD; 6416; -.
DR GeneCards; GC17P011864; -.
DR HGNC; HGNC:6844; MAP2K4.
DR HPA; CAB007751; -.
DR MIM; 601335; gene.
DR neXtProt; NX_P45985; -.
DR PharmGKB; PA30589; -.
DR eggNOG; COG0515; -.
DR HOVERGEN; HBG108518; -.
DR InParanoid; P45985; -.
DR KO; K04430; -.
DR OMA; VMKSNDC; -.
DR OrthoDB; EOG7J9VPW; -.
DR PhylomeDB; P45985; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P45985; -.
DR ChiTaRS; MAP2K4; human.
DR EvolutionaryTrace; P45985; -.
DR GeneWiki; MAP2K4; -.
DR GenomeRNAi; 6416; -.
DR NextBio; 24922; -.
DR PMAP-CutDB; P45985; -.
DR PRO; PR:P45985; -.
DR ArrayExpress; P45985; -.
DR Bgee; P45985; -.
DR CleanEx; HS_MAP2K4; -.
DR Genevestigator; P45985; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0007254; P:JNK cascade; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:GOC.
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:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
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 SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 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; Complete proteome; Cytoplasm; Kinase; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transferase;
KW Tyrosine-protein kinase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 399 Dual specificity mitogen-activated
FT protein kinase kinase 4.
FT /FTId=PRO_0000086381.
FT DOMAIN 102 367 Protein kinase.
FT NP_BIND 108 116 ATP (By similarity).
FT REGION 37 52 D domain.
FT REGION 364 387 DVD domain.
FT COMPBIAS 5 19 Gly/Ser-rich.
FT ACT_SITE 229 229 Proton acceptor (By similarity).
FT BINDING 131 131 ATP (By similarity).
FT SITE 45 46 Cleavage; by anthrax lethal factor.
FT SITE 58 59 Cleavage; by anthrax lethal factor.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 90 90 Phosphoserine.
FT MOD_RES 257 257 Phosphoserine; by MAP3K.
FT MOD_RES 261 261 Phosphothreonine; by MAP3K.
FT VAR_SEQ 39 39 G -> GFQINFCEKAQS (in isoform 2).
FT /FTId=VSP_038838.
FT VARIANT 16 16 S -> R (in dbSNP:rs17855590).
FT /FTId=VAR_062963.
FT VARIANT 142 142 Q -> L (in a lung squamous cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040818.
FT VARIANT 154 154 R -> W (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040819.
FT VARIANT 234 234 N -> I (in an ovarian serous carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040820.
FT VARIANT 251 251 S -> N (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040821.
FT VARIANT 279 279 A -> T (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040822.
FT CONFLICT 118 118 K -> R (in Ref. 4; CAG38801).
FT CONFLICT 179 179 E -> G (in Ref. 6; BAG35884).
FT CONFLICT 356 356 P -> L (in Ref. 10; AAH60764).
FT STRAND 85 88
FT STRAND 93 95
FT STRAND 101 103
FT STRAND 107 110
FT STRAND 112 121
FT TURN 122 124
FT STRAND 127 134
FT HELIX 139 153
FT STRAND 164 169
FT STRAND 171 178
FT STRAND 182 184
FT HELIX 185 194
FT HELIX 202 223
FT HELIX 232 234
FT STRAND 235 237
FT STRAND 243 245
FT STRAND 249 251
FT STRAND 267 270
FT HELIX 272 274
FT HELIX 287 302
FT STRAND 312 314
FT STRAND 316 321
FT HELIX 338 347
FT HELIX 352 354
FT HELIX 358 361
FT HELIX 365 372
FT HELIX 377 387
SQ SEQUENCE 399 AA; 44288 MW; A472537F2F26770B CRC64;
MAAPSPSGGG GSGGGSGSGT PGPVGSPAPG HPAVSSMQGK RKALKLNFAN PPFKSTARFT
LNPNPTGVQN PHIERLRTHS IESSGKLKIS PEQHWDFTAE DLKDLGEIGR GAYGSVNKMV
HKPSGQIMAV KRIRSTVDEK EQKQLLMDLD VVMRSSDCPY IVQFYGALFR EGDCWICMEL
MSTSFDKFYK YVYSVLDDVI PEEILGKITL ATVKALNHLK ENLKIIHRDI KPSNILLDRS
GNIKLCDFGI SGQLVDSIAK TRDAGCRPYM APERIDPSAS RQGYDVRSDV WSLGITLYEL
ATGRFPYPKW NSVFDQLTQV VKGDPPQLSN SEEREFSPSF INFVNLCLTK DESKRPKYKE
LLKHPFILMY EERAVEVACY VCKILDQMPA TPSSPMYVD
//
ID MP2K4_HUMAN Reviewed; 399 AA.
AC P45985; B2R7N7; B3KYB2; D3DTS5; Q5U0B8; Q6FHX4; Q6P9H2; Q6PIE6;
read moreDT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 22-JAN-2014, entry version 142.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 4;
DE Short=MAP kinase kinase 4;
DE Short=MAPKK 4;
DE EC=2.7.12.2;
DE AltName: Full=JNK-activating kinase 1;
DE AltName: Full=MAPK/ERK kinase 4;
DE Short=MEK 4;
DE AltName: Full=SAPK/ERK kinase 1;
DE Short=SEK1;
DE AltName: Full=Stress-activated protein kinase kinase 1;
DE Short=SAPK kinase 1;
DE Short=SAPKK-1;
DE Short=SAPKK1;
DE AltName: Full=c-Jun N-terminal kinase kinase 1;
DE Short=JNKK;
GN Name=MAP2K4; Synonyms=JNKK1, MEK4, MKK4, PRKMK4, SEK1, SERK1, SKK1;
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).
RC TISSUE=Brain;
RX PubMed=7839144; DOI=10.1126/science.7839144;
RA Derijard B., Raingeaud J., Barrett T., Wu I.-H., Han J.,
RA Ulevitch R.J., Davis R.J.;
RT "Independent human MAP-kinase signal transduction pathways defined by
RT MEK and MKK isoforms.";
RL Science 267:682-685(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RX PubMed=7716521; DOI=10.1126/science.7716521;
RA Lin A., Minden A., Martinetto H., Claret F.-X., Lange-Carter C.,
RA Mercurio F., Johnson G.L., Karin M.;
RT "Identification of a dual specificity kinase that activates the Jun
RT kinases and p38-Mpk2.";
RL Science 268:286-290(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9622070;
RA Su G.H., Hilgers W., Shekher M.C., Tang D.J., Yeo C.J., Hruban R.H.,
RA Kern S.E.;
RT "Alterations in pancreatic, biliary, and breast carcinomas support
RT MKK4 as a genetically targeted tumor suppressor gene.";
RL Cancer Res. 58:2339-2342(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain, and Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP ARG-16.
RC TISSUE=Brain, and Testis;
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 [11]
RP PHOSPHORYLATION, ENZYME REGULATION, AND INTERACTION WITH MAP3K11/MLK3.
RX PubMed=9003778;
RA Tibbles L.A., Ing Y.L., Kiefer F., Chan J., Iscove N., Woodgett J.R.,
RA Lassam N.J.;
RT "MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and
RT MKK3/6.";
RL EMBO J. 15:7026-7035(1996).
RN [12]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX PubMed=11104681; DOI=10.1042/0264-6021:3520739;
RA Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.;
RT "Susceptibility of mitogen-activated protein kinase kinase family
RT members to proteolysis by anthrax lethal factor.";
RL Biochem. J. 352:739-745(2000).
RN [13]
RP INTERACTION WITH ARRB2.
RX PubMed=11090355; DOI=10.1126/science.290.5496.1574;
RA McDonald P.H., Chow C.W., Miller W.E., Laporte S.A., Field M.E.,
RA Lin F.-T., Davis R.J., Lefkowitz R.J.;
RT "Beta-arrestin 2: a receptor-regulated MAPK scaffold for the
RT activation of JNK3.";
RL Science 290:1574-1577(2000).
RN [14]
RP INTERACTION WITH MAPK8IP3/JIP3.
RX PubMed=12189133; DOI=10.1074/jbc.M202004200;
RA Matsuura H., Nishitoh H., Takeda K., Matsuzawa A., Amagasa T., Ito M.,
RA Yoshioka K., Ichijo H.;
RT "Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-
RT JNK signaling pathway. A new mode of regulation of the MAP kinase
RT cascade.";
RL J. Biol. Chem. 277:40703-40709(2002).
RN [15]
RP DOMAIN, AND INTERACTION WITH MAPK8/JNK1; MAPK9/JNK2; MAPK10/JNK3;
RP MAPK11 AND MAPK14.
RX PubMed=12788955; DOI=10.1074/jbc.M304229200;
RA Ho D.T., Bardwell A.J., Abdollahi M., Bardwell L.;
RT "A docking site in MKK4 mediates high affinity binding to JNK MAPKs
RT and competes with similar docking sites in JNK substrates.";
RL J. Biol. Chem. 278:32662-32672(2003).
RN [16]
RP DOMAIN.
RX PubMed=15866172; DOI=10.1016/j.molcel.2005.04.001;
RA Takekawa M., Tatebayashi K., Saito H.;
RT "Conserved docking site is essential for activation of mammalian MAP
RT kinase kinases by specific MAP kinase kinase kinases.";
RL Mol. Cell 18:295-306(2005).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-90, AND MASS
RP 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 [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [19]
RP INTERACTION WITH ARRB1 AND ARRB2.
RX PubMed=19782076; DOI=10.1016/j.febslet.2009.09.035;
RA Li X., MacLeod R., Dunlop A.J., Edwards H.V., Advant N., Gibson L.C.,
RA Devine N.M., Brown K.M., Adams D.R., Houslay M.D., Baillie G.S.;
RT "A scanning peptide array approach uncovers association sites within
RT the JNK/beta arrestin signalling complex.";
RL FEBS Lett. 583:3310-3316(2009).
RN [20]
RP REVIEW ON ENZYME REGULATION.
RX PubMed=17496909; DOI=10.1038/sj.onc.1210392;
RA Raman M., Chen W., Cobb M.H.;
RT "Differential regulation and properties of MAPKs.";
RL Oncogene 26:3100-3112(2007).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257, 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 [22]
RP REVIEW ON FUNCTION.
RX PubMed=20801953; DOI=10.1093/jb/mvq098;
RA Asaoka Y., Nishina H.;
RT "Diverse physiological functions of MKK4 and MKK7 during early
RT embryogenesis.";
RL J. Biochem. 148:393-401(2010).
RN [23]
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 [24]
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 [25]
RP REVIEW ON REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=21333379; DOI=10.1016/j.ejcb.2010.11.008;
RA Haeusgen W., Herdegen T., Waetzig V.;
RT "The bottleneck of JNK signaling: molecular and functional
RT characteristics of MKK4 and MKK7.";
RL Eur. J. Cell Biol. 90:536-544(2011).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 80-399.
RX PubMed=20732303; DOI=10.1016/j.bbrc.2010.08.071;
RA Matsumoto T., Kinoshita T., Kirii Y., Yokota K., Hamada K., Tada T.;
RT "Crystal structures of MKK4 kinase domain reveal that substrate
RT peptide binds to an allosteric site and induces an auto-inhibition
RT state.";
RL Biochem. Biophys. Res. Commun. 400:369-373(2010).
RN [27]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-142; TRP-154; ILE-234; ASN-251 AND
RP THR-279.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Dual specificity protein kinase which acts as an
CC essential component of the MAP kinase signal transduction pathway.
CC Essential component of the stress-activated protein kinase/c-Jun
CC N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7,
CC is the one of the only known kinase to directly activate the
CC stress-activated protein kinase/c-Jun N-terminal kinases
CC MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and
CC MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they
CC differ in their preference for the phosphorylation site in the
CC Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of
CC the Tyr residue and MAP2K7/MKK7 for the Thr residue. The
CC phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the
CC prerequisite for JNK activation at least in response to
CC proinflammatory cytokines, while other stimuli activate both
CC MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate
CC JNKs. MAP2K4 is required for maintaining peripheral lymphoid
CC homeostasis. The MKK/JNK signaling pathway is also involved in
CC mitochondrial death signaling pathway, including the release
CC cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7
CC exclusively activates JNKs, MAP2K4/MKK4 additionally activates the
CC p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Activated in response to a variety of cellular
CC stresses, including UV and gamma-irradiation, heat shock,
CC hyperosmolarity, T-cell receptor stimulation, peroxide and
CC inflammatory cytokines. Also activated by developmental cues.
CC MAP2K4/MKK4 is activated by the majority of MKKKs, such as
CC MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K7/TAK1, MAP3K10/MLK2,
CC MAP3K11/MLK3, MAP3K12/DLK and MAP3K13/LZK.
CC -!- SUBUNIT: Interacts with SPAG9 (By similarity). Interacts (via its
CC D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3,
CC MAPK11 and MAPK14. Interacts (via its DVD domain) with MAP3Ks
CC activators like MAP3K1/MEKK1 and MAP3K11/MLK3. Interacts with
CC ARRB1, ARRB2 and MAPK8IP3/JIP3.
CC -!- INTERACTION:
CC Q13233:MAP3K1; NbExp=3; IntAct=EBI-447868, EBI-49776;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Nucleus (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P45985-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P45985-2; Sequence=VSP_038838;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Abundant expression is seen in the skeletal
CC muscle. It is also widely expressed in other tissues.
CC -!- DOMAIN: The DVD domain (residues 364-387) contains a conserved
CC docking site and is found in the mammalian MAP kinase kinases
CC (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase
CC kinase kinases (MAP3Ks) and are essential for activation.
CC -!- DOMAIN: The D domain (residues 34-52) contains a conserved docking
CC site and is required for the binding to MAPK substrates.
CC -!- PTM: Activated by phosphorylation on Ser-257 and Thr-261 by MAP
CC kinase kinase kinases (MAP3Ks).
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. MAP kinase kinase subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/map2k4/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MAP2K4ID244ch17p12.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; L36870; AAC41719.1; -; mRNA.
DR EMBL; U17743; AAC50127.1; -; mRNA.
DR EMBL; AF070090; AAC24130.1; -; Genomic_DNA.
DR EMBL; AF070080; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070081; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070082; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070083; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070084; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070085; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070086; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070087; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070088; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; AF070089; AAC24130.1; JOINED; Genomic_DNA.
DR EMBL; CR536564; CAG38801.1; -; mRNA.
DR EMBL; BT019676; AAV38482.1; -; mRNA.
DR EMBL; AK131544; BAG54774.1; -; mRNA.
DR EMBL; AK313053; BAG35884.1; -; mRNA.
DR EMBL; DQ015703; AAY22176.1; -; Genomic_DNA.
DR EMBL; AC005244; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005410; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471108; EAW89975.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW89974.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW89976.1; -; Genomic_DNA.
DR EMBL; BC036032; AAH36032.1; -; mRNA.
DR EMBL; BC060764; AAH60764.1; -; mRNA.
DR PIR; I38901; I38901.
DR RefSeq; NP_001268364.1; NM_001281435.1.
DR RefSeq; NP_003001.1; NM_003010.3.
DR UniGene; Hs.514681; -.
DR PDB; 3ALN; X-ray; 2.30 A; A/B/C=80-399.
DR PDB; 3ALO; X-ray; 2.60 A; A=80-399.
DR PDB; 3VUT; X-ray; 3.50 A; A/B=80-399.
DR PDBsum; 3ALN; -.
DR PDBsum; 3ALO; -.
DR PDBsum; 3VUT; -.
DR ProteinModelPortal; P45985; -.
DR SMR; P45985; 95-388.
DR IntAct; P45985; 11.
DR MINT; MINT-151438; -.
DR STRING; 9606.ENSP00000262445; -.
DR BindingDB; P45985; -.
DR ChEMBL; CHEMBL2897; -.
DR GuidetoPHARMACOLOGY; 2065; -.
DR PhosphoSite; P45985; -.
DR DMDM; 1170596; -.
DR PaxDb; P45985; -.
DR PRIDE; P45985; -.
DR DNASU; 6416; -.
DR Ensembl; ENST00000353533; ENSP00000262445; ENSG00000065559.
DR Ensembl; ENST00000415385; ENSP00000410402; ENSG00000065559.
DR GeneID; 6416; -.
DR KEGG; hsa:6416; -.
DR UCSC; uc002gnj.3; human.
DR CTD; 6416; -.
DR GeneCards; GC17P011864; -.
DR HGNC; HGNC:6844; MAP2K4.
DR HPA; CAB007751; -.
DR MIM; 601335; gene.
DR neXtProt; NX_P45985; -.
DR PharmGKB; PA30589; -.
DR eggNOG; COG0515; -.
DR HOVERGEN; HBG108518; -.
DR InParanoid; P45985; -.
DR KO; K04430; -.
DR OMA; VMKSNDC; -.
DR OrthoDB; EOG7J9VPW; -.
DR PhylomeDB; P45985; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P45985; -.
DR ChiTaRS; MAP2K4; human.
DR EvolutionaryTrace; P45985; -.
DR GeneWiki; MAP2K4; -.
DR GenomeRNAi; 6416; -.
DR NextBio; 24922; -.
DR PMAP-CutDB; P45985; -.
DR PRO; PR:P45985; -.
DR ArrayExpress; P45985; -.
DR Bgee; P45985; -.
DR CleanEx; HS_MAP2K4; -.
DR Genevestigator; P45985; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0007254; P:JNK cascade; TAS:Reactome.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:GOC.
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:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR011009; Kinase-like_dom.
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 SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 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; Complete proteome; Cytoplasm; Kinase; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transferase;
KW Tyrosine-protein kinase.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 399 Dual specificity mitogen-activated
FT protein kinase kinase 4.
FT /FTId=PRO_0000086381.
FT DOMAIN 102 367 Protein kinase.
FT NP_BIND 108 116 ATP (By similarity).
FT REGION 37 52 D domain.
FT REGION 364 387 DVD domain.
FT COMPBIAS 5 19 Gly/Ser-rich.
FT ACT_SITE 229 229 Proton acceptor (By similarity).
FT BINDING 131 131 ATP (By similarity).
FT SITE 45 46 Cleavage; by anthrax lethal factor.
FT SITE 58 59 Cleavage; by anthrax lethal factor.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 90 90 Phosphoserine.
FT MOD_RES 257 257 Phosphoserine; by MAP3K.
FT MOD_RES 261 261 Phosphothreonine; by MAP3K.
FT VAR_SEQ 39 39 G -> GFQINFCEKAQS (in isoform 2).
FT /FTId=VSP_038838.
FT VARIANT 16 16 S -> R (in dbSNP:rs17855590).
FT /FTId=VAR_062963.
FT VARIANT 142 142 Q -> L (in a lung squamous cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040818.
FT VARIANT 154 154 R -> W (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040819.
FT VARIANT 234 234 N -> I (in an ovarian serous carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040820.
FT VARIANT 251 251 S -> N (in a metastatic melanoma sample;
FT somatic mutation).
FT /FTId=VAR_040821.
FT VARIANT 279 279 A -> T (in a colorectal adenocarcinoma
FT sample; somatic mutation).
FT /FTId=VAR_040822.
FT CONFLICT 118 118 K -> R (in Ref. 4; CAG38801).
FT CONFLICT 179 179 E -> G (in Ref. 6; BAG35884).
FT CONFLICT 356 356 P -> L (in Ref. 10; AAH60764).
FT STRAND 85 88
FT STRAND 93 95
FT STRAND 101 103
FT STRAND 107 110
FT STRAND 112 121
FT TURN 122 124
FT STRAND 127 134
FT HELIX 139 153
FT STRAND 164 169
FT STRAND 171 178
FT STRAND 182 184
FT HELIX 185 194
FT HELIX 202 223
FT HELIX 232 234
FT STRAND 235 237
FT STRAND 243 245
FT STRAND 249 251
FT STRAND 267 270
FT HELIX 272 274
FT HELIX 287 302
FT STRAND 312 314
FT STRAND 316 321
FT HELIX 338 347
FT HELIX 352 354
FT HELIX 358 361
FT HELIX 365 372
FT HELIX 377 387
SQ SEQUENCE 399 AA; 44288 MW; A472537F2F26770B CRC64;
MAAPSPSGGG GSGGGSGSGT PGPVGSPAPG HPAVSSMQGK RKALKLNFAN PPFKSTARFT
LNPNPTGVQN PHIERLRTHS IESSGKLKIS PEQHWDFTAE DLKDLGEIGR GAYGSVNKMV
HKPSGQIMAV KRIRSTVDEK EQKQLLMDLD VVMRSSDCPY IVQFYGALFR EGDCWICMEL
MSTSFDKFYK YVYSVLDDVI PEEILGKITL ATVKALNHLK ENLKIIHRDI KPSNILLDRS
GNIKLCDFGI SGQLVDSIAK TRDAGCRPYM APERIDPSAS RQGYDVRSDV WSLGITLYEL
ATGRFPYPKW NSVFDQLTQV VKGDPPQLSN SEEREFSPSF INFVNLCLTK DESKRPKYKE
LLKHPFILMY EERAVEVACY VCKILDQMPA TPSSPMYVD
//
MIM
601335
*RECORD*
*FIELD* NO
601335
*FIELD* TI
*601335 MITOGEN-ACTIVATED PROTEIN KINASE KINASE 4; MAP2K4
;;SAPK/ERK KINASE 1; SERK1; SEK1;;
read morePROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 4; PRKMK4;;
MKK4; MAPKK4;;
MAPK/ERK KINASE 4; MEK4;;
JNK-ACTIVATED KINASE 1; JNKK1
*FIELD* TX
DESCRIPTION
At least 3 mitogen-activated protein kinase (MAPK) cascades exist in
mammals, each consisting of a 3-kinase module composed of a MAPK, a MAPK
kinase (MAPKK), and a MAPKK kinase (MAPKKK). JUN N-terminal kinases
(JNKs; see 601158) are MAPKs that stimulate transcriptional activity of
JUN (165160) in response to growth factors, proinflammatory cytokines,
and certain environmental stresses, such as ultraviolet light or osmotic
shock. MAP2K4 is a MAPKK that directly activates the JNKs, as well as
the related MAPK p38 (MAPK14; 600289) (Wu et al., 1997).
CLONING
By screening a human T-lymphocyte Jurkat cDNA library with a mouse cDNA
encoding Mma1-Sek1, a potential MAPKK, Lin et al. (1995) identified a
human homolog of Mma1-Sek1, which they named JNKK. The deduced 399-amino
acid JNKK protein shares more than 95% sequence similarity with
Mma1-Sek1 in the kinase domain. JNKK is also similar to S. cerevisiae
Pbs2.
GENE FUNCTION
One Ras-dependent protein kinase cascade leading from growth factor
receptors to the extracellular signal-regulated kinase (ERK) subgroup of
MAPKs is dependent on the protein kinase RAF1 (164760), which activates
the MAPK/ERK kinase (MEK) dual-specificity kinases. A second protein
kinase cascade leading to activation of the JNKs is dependent on MEK
kinase (MEKK). Lin et al. (1995) found that JNKK was a dual-specificity
kinase that activated JNK and functioned between MEKK and JNK. JNKK
activated the JNKs, but not the ERKs, and was unresponsive to RAF1 in
transfected HeLa cells. It also activated another MAPK, p38, whose
activity is regulated similarly to that of the JNKs. Lin et al. (1995)
also showed that human JNKK could partially complement Pbs2 deficiency
in yeast.
The stress-activated protein kinase (SAPK) and MAPK pathways are signal
transduction cascades with distinct functions in mammals. White et al.
(1996) noted that they are structurally related in their phosphorylation
activity but differ in the events leading to phosphorylation. MAPKs are
rapidly phosphorylated and activated in response to various
extracellular stimuli. MAPK is regulated by its own phosphorylation by
MAPK kinases (MAP2Ks), e.g., MAP2K1 (176872) and MAP2K6 (601254). In the
SAPK pathway, SAPKs are the dominant JNKs activated in response to a
variety of cellular stresses, including treatment with interleukin-beta
(147720) and tumor necrosis factor-alpha (TNFA, or TNF; 191160). MAP2K4,
or SERK1, is a potent physiologic activator of SAPKs.
Wu et al. (1997) showed that JNKK1 was a specific activator of JNK1
(601158), JNK2 (602896), and p38, but not of ERK2 (176948). Among MEKK1
(600982), MEKK2 (MAP3K2; 609487), GCK, and ASK (MEKK5), MEKK1 was the
most potent activator of JNKK1, followed by MEKK2; GCK and ASK only
slightly activated JNKK1.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD
protein that perturbs a multiplicity of signaling pathways. These
include inhibition of the ERK, JNK, and p38 MAPK pathways and inhibition
of the nuclear factor kappa B (NF-kappa-B) pathway. The expression of
YopJ has been correlated with the induction of apoptosis by Yersinia.
Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a
HeLa cDNA library, Orth et al. (1999) identified mammalian binding
partners of YopJ. These included the fusion proteins of the GAL4
activation domain with MAPK kinases MKK1 (176872), MKK2 (601263), and
MKK4/SEK1. YopJ was found to bind directly to MKKs in vitro, including
MKK1, MKK3 (602315), MKK4, and MKK5 (602448). Binding of YopJ to the MKK
blocked both phosphorylation and subsequent activation of the MKKs.
These results explain the diverse activities of YopJ in inhibiting the
ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine
synthesis and promoting apoptosis. YopJ-related proteins that are found
in a number of bacterial pathogens of animals and plants may function to
block MKKs so that host signaling responses can be modulated upon
infection.
Using a yeast 2-hybrid screen, McDonald et al. (2000) identified JNK3
(602897) as a binding partner of beta-arrestin-2 (ARBB2; 107941). These
results were confirmed by coimmunoprecipitation from mouse brain
extracts and cotransfection in COS-7 cells. The upstream JNK activators
apoptosis signal-regulating kinase-1 (ASK1; 602448) and MKK4 were also
found in complex with ARBB2. Cellular transfection of ARBB2 caused
cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated
by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor
(AGTR1; 106165) activated JNK3 and triggered the colocalization of ARBB2
and active JNK3 to intracellular vesicles. Thus, McDonald et al. (2000)
concluded that ARBB2 acts as a scaffold protein, which brings the
spatial distribution and activity of this MAPK module under the control
of a G protein-coupled receptor.
Kan et al. (2010) reported the identification of 2,576 somatic mutations
across approximately 1,800 megabases of DNA representing 1,507 coding
genes from 441 tumors comprising breast, lung, ovarian, and prostate
cancer types and subtypes. Integrated analysis of somatic mutations and
copy number alterations identified 35 significantly altered genes
including GNAS (see 139320), indicating an expanded role for G-alpha
subunits in multiple cancer types. Experimental analyses demonstrated
the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 in
oncogenesis.
Toll-like receptors (TLRs; see 603030) play a critical role in the
initiation of immune responses against invading pathogens. Lai et al.
(2013) found that stimulation of mouse peritoneal macrophages with
various TLR ligands reduced expression of microRNA-92A (MIR92A; see
609422) and most Mir92a family members. Decreased Mir92a expression
enhanced TLR-associated signaling events by increasing activation of the
JNK pathway, thereby promoting production of proinflammatory cytokines,
such as Il6 (147620) and Tnfa. Luciferase and knockdown analyses showed
that Mir92a directly targeted mouse Mkk4 and reduced TLR-induced
inflammatory responses.
MAPPING
By radiation hybrid mapping, Rampoldi et al. (1997) assigned genes
involved in the MAPK cascade to specific chromosomal sites, including
MEK4, which they mapped to chromosome 17p12.
White et al. (1996) mapped the human and mouse genes encoding MAP2K4,
which they called SERK1. The human gene was assigned to chromosome 17 by
PCR analysis of hamster/human somatic cell hybrids containing a single
human chromosome. White et al. (1996) stated that MAP2K4 localized to
chromosome 17p11 by fluorescence in situ hybridization. In mouse, they
mapped the Map2k4 gene to chromosome 11 by analysis of interspecific
backcrosses. The mouse gene maps to a region with extensive homology of
synteny to human chromosome 17p11.2.
MOLECULAR GENETICS
- Somatic Mutations in Pancreatic Cancer
Biankin et al. (2012) performed exome sequencing and copy number
analysis to define genomic aberrations in a prospectively accrued
clinical cohort of 142 patients with early (stage I and II) sporadic
pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative
tumors identified substantial heterogeneity with 2,016 nonsilent
mutations and 1,628 copy number variations. Biankin et al. (2012)
defined 16 significantly mutated genes, reaffirming known mutations and
uncovering novel mutated genes including additional genes involved in
chromatin modification (EPC1, 610999 and ARID2, 609539), DNA damage
repair (ATM; 607585), and other mechanisms (ZIM2 (see 601483); MAP2K4;
NALCN, 611549; SLC16A4, 603878; and MAGEA6, 300176). Integrative
analysis with in vitro functional data and animal models provided
supportive evidence for potential roles for these genetic aberrations in
carcinogenesis. Pathway-based analysis of recurrently mutated genes
recapitulated clustering in core signaling pathways in pancreatic ductal
adenocarcinoma, and identified new mutated genes in each pathway.
Biankin et al. (2012) also identified frequent and diverse somatic
aberrations in genes described traditionally as embryonic regulators of
axon guidance, particularly SLIT/ROBO (see 603742) signaling, which was
also evident in murine Sleeping Beauty transposon-mediated somatic
mutagenesis models of pancreatic cancer, providing further supportive
evidence for the potential involvement of axon guidance genes in
pancreatic carcinogenesis.
ANIMAL MODEL
To define the role of SEK1 in vivo, Ganiatsas et al. (1998) studied
stress-induced signaling in embryonic stem and fibroblast cells
homozygous for an Sek1 knockout and evaluated the phenotype of Sek1 -/-
mouse embryos during development. Sek1-deficient embryonic stem cells
showed defects in stimulated SAPK phosphorylation but not in the
phosphorylation of p38 kinase. In contrast, Sek1-deficient fibroblasts
exhibited defects in both SAPK and p38 phosphorylation, demonstrating
that crosstalk exists between the stress-activated cascades. Tumor
necrosis factor-alpha and interleukin-1 (see 147760) stimulation of both
stress-activated cascades was severely affected in the Sek1-deficient
fibroblasts. Sek1 deficiency led to embryonic lethality after embryonic
day 12.5 and was associated with abnormal liver development. The
phenotype was similar to that of the Jun-null mouse embryos (165160) and
suggested that SEK1 is required for phosphorylation and activation of
JUN during organogenesis of the liver.
Using a forward genetic screen of C. elegans mutants, Kim et al. (2002)
showed that viable worms lacking esp2 and esp8, homologs of the
mammalian MAP kinases SEK1 and ASK1, were highly susceptible to and died
more rapidly from both a gram-negative bacterium, P. aeruginosa, and a
gram-positive organism, E. faecalis, than wildtype worms.
RNA-interference and biochemical analyses likewise implicated the p38
MAP kinase (MAPK14; 600289) homolog, pmk1, in susceptibility to these
pathogens. Kim et al. (2002) concluded that MAP kinase signaling, which
is also involved in plant pathogen resistance, is a conserved element in
innate metazoan immunity to diverse pathogens.
Wang et al. (2007) targeted Mkk4 deletion to the neural lineage in mice.
Homozygous mutant mice were indistinguishable from control littermates
at birth, but they stopped growing a few days later and died. Mutant
mice displayed severe neurologic defects, including misalignment of
Purkinje cells in cerebellum and delayed radial migration in cerebral
cortex. Decreased Jnk activity due to Mkk4 deficiency correlated with
impaired phosphorylation of a subset of Jnk substrates and with altered
gene expression.
Knockout of Fah (613871) causes liver failure in mice due to
accumulation of intermediary hepatotoxins generated during incomplete
tyrosine catabolism. Lethality can be prevented by continuous treatment
with the drug nitisinone (NTBC). Wuestefeld et al. (2013) coupled NTBC
withdrawal in Fah -/- mice with short hairpin RNAs to identify genes
that influence liver failure and regeneration. They found that stable
knockdown of Mkk4 robustly increased the regenerative capacity of
hepatocytes and reduced the number of apoptotic hepatocytes in Fah -/-
mice following NTBC withdrawal, as well as in mouse models of acute and
chronic liver failure. Inhibition of Mkk4 resulted in faster cell-cycle
entry and progression of hepatocytes during liver regeneration by
compensatory upregulation of Mkk7 (MAP2K7; 603014) and Jnk1-dependent
activation of Atf2 (123811) and Elk1 (311040). Inhibition of Jnk1, but
not Jnk2, abolished the proregenerative effect of Mkk4 knockdown.
Wuestefeld et al. (2013) concluded that MKK4 is a master regulator of
liver regeneration.
*FIELD* RF
1. Biankin, A. V.; Waddell, N.; Kassahn, K. S.; Gingras, M.-C.; Muthuswamy,
L. B.; Johns, A. L.; Miller, D. K.; Wilson, P. J.; Patch, A.-M.; Wu,
J.; Chang, D. K.; Cowley, M. J.; and 116 others: Pancreatic cancer
genomes reveal aberrations in axon guidance pathway genes. Nature 491:
399-405, 2012.
2. Ganiatsas, S.; Kwee, L.; Fujiwara, Y.; Perkins, A.; Ikeda, T.;
Labow, M. A.; Zon, L. I.: SEK1 deficiency reveals mitogen-activated
protein kinase cascade crossregulation and leads to abnormal hepatogenesis. Proc.
Nat. Acad. Sci. 95: 6881-6886, 1998.
3. Kan, Z.; Jaiswal, B. S.; Stinson, J.; Janakiraman, V.; Bhatt, D.;
Stern, H. M.; Yue, P.; Haverty, P. M.; Bourgon, R.; Zheng, J.; Moorhead,
M.; Chaudhuri, S.; and 20 others: Diverse somatic mutation patterns
and pathway alterations in human cancers. Nature 466: 869-873, 2010.
4. Kim, D. H.; Feinbaum, R.; Alloing, G.; Emerson, F. E.; Garsin,
D. A.; Inoue, H.; Tanaka-Hino, M.; Hisamoto, N.; Matsumoto, K.; Tan,
M.-W.; Ausubel, F. M.: A conserved p38 MAP kinase pathway in Caenorhabditis
elegans innate immunity. Science 297: 623-626, 2002.
5. Lai, L.; Song, Y.; Liu, Y.; Chen, Q.; Han, Q.; Chen, W.; Pan, T.;
Zhang, Y.; Cao, X.; Wang, Q.: MicroRNA-92a negatively regulates Toll-like
receptor (TLR)-triggered inflammatory response in macrophages by targeting
MKK4 kinase. J. Biol. Chem. 288: 7956-7967, 2013.
6. Lin, A.; Minden, A.; Martinetto, H.; Claret, F.-X.; Lange-Carter,
C.; Mercurio, F.; Johnson, G. L.; Karin, M.: Identification of a
dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science 268:
286-290, 1995.
7. McDonald, P. H.; Chow, C.-W.; Miller, W. E.; Laporte, S. A.; Field,
M. E.; Lin, F.-T.; Davis, R. J.; Lefkowitz, R. J.: Beta-arrestin
2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290:
1574-1577, 2000.
8. Orth, K.; Palmer, L. E.; Bao, Z. Q.; Stewart, S.; Rudolph, A. E.;
Bliska, J. B.; Dixon, J. E.: Inhibition of the mitogen-activated
protein kinase kinase superfamily by a Yersinia effector. Science 285:
1920-1923, 1999.
9. Rampoldi, L.; Zimbello, R.; Bortoluzzi, S.; Tiso, N.; Valle, G.;
Lanfranchi, G.; Danieli, G. A.: Chromosomal localization of four
MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet.
Cell Genet. 78: 301-303, 1997.
10. Wang, X.; Nadarajah, B.; Robinson, A. C.; McColl, B. W.; Jin,
J.-W.; Dajas-Bailador, F.; Boot-Handford, R. P.; Tournier, C.: Targeted
deletion of the mitogen-activated protein kinase kinase 4 gene in
the nervous system causes severe brain developmental defects and premature
death. Molec. Cell. Biol. 27: 7935-7946, 2007.
11. White, R. A.; Hughes, R. T.; Adkison, L. R.; Bruns, G.; Zon, L.
I.: The gene encoding protein kinase SEK1 maps to mouse chromosome
11 and human chromosome 17. Genomics 34: 430-432, 1996.
12. Wu, Z.; Wu, J.; Jacinto, E.; Karin, M.: Molecular cloning and
characterization of human JNKK2, a novel jun NH(2)-terminal kinase-specific
kinase. Molec. Cell. Biol. 17: 7407-7416, 1997.
13. Wuestefeld, T.; Pesic, M.; Rudalska, R.; Dauch, D.; Longerich,
T.; Kang, T.-W.; Yevsa, T.; Heinzmann, F.; Hoenicke, L.; Hohmeyer,
A.; Potapova, A.; Rittelmeier, I.; and 11 others: A direct in vivo
RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153:
389-401, 2013.
*FIELD* CN
Patricia A. Hartz - updated: 06/06/2013
Paul J. Converse - updated: 3/28/2013
Ada Hamosh - updated: 12/18/2012
Ada Hamosh - updated: 9/21/2010
Paul J. Converse - updated: 9/4/2002
Ada Hamosh - updated: 12/4/2000
Patti M. Sherman - updated: 6/23/2000
Ada Hamosh - updated: 9/15/1999
Patti M. Sherman - updated: 9/2/1998
Victor A. McKusick - updated: 6/30/1998
Victor A. McKusick - updated: 3/17/1998
*FIELD* CD
Victor A. McKusick: 7/5/1996
*FIELD* ED
mgross: 06/06/2013
mgross: 4/1/2013
terry: 3/28/2013
alopez: 12/18/2012
alopez: 9/23/2010
terry: 9/21/2010
alopez: 2/4/2009
mgross: 9/24/2008
mgross: 7/21/2005
terry: 7/19/2004
mgross: 9/4/2002
joanna: 2/27/2001
joanna: 12/4/2000
mcapotos: 6/26/2000
psherman: 6/23/2000
alopez: 2/28/2000
carol: 9/17/1999
terry: 9/15/1999
mgross: 9/14/1999
alopez: 9/22/1998
alopez: 7/6/1998
terry: 6/30/1998
psherman: 3/17/1998
dholmes: 3/9/1998
mark: 4/9/1997
mark: 7/8/1996
*RECORD*
*FIELD* NO
601335
*FIELD* TI
*601335 MITOGEN-ACTIVATED PROTEIN KINASE KINASE 4; MAP2K4
;;SAPK/ERK KINASE 1; SERK1; SEK1;;
read morePROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 4; PRKMK4;;
MKK4; MAPKK4;;
MAPK/ERK KINASE 4; MEK4;;
JNK-ACTIVATED KINASE 1; JNKK1
*FIELD* TX
DESCRIPTION
At least 3 mitogen-activated protein kinase (MAPK) cascades exist in
mammals, each consisting of a 3-kinase module composed of a MAPK, a MAPK
kinase (MAPKK), and a MAPKK kinase (MAPKKK). JUN N-terminal kinases
(JNKs; see 601158) are MAPKs that stimulate transcriptional activity of
JUN (165160) in response to growth factors, proinflammatory cytokines,
and certain environmental stresses, such as ultraviolet light or osmotic
shock. MAP2K4 is a MAPKK that directly activates the JNKs, as well as
the related MAPK p38 (MAPK14; 600289) (Wu et al., 1997).
CLONING
By screening a human T-lymphocyte Jurkat cDNA library with a mouse cDNA
encoding Mma1-Sek1, a potential MAPKK, Lin et al. (1995) identified a
human homolog of Mma1-Sek1, which they named JNKK. The deduced 399-amino
acid JNKK protein shares more than 95% sequence similarity with
Mma1-Sek1 in the kinase domain. JNKK is also similar to S. cerevisiae
Pbs2.
GENE FUNCTION
One Ras-dependent protein kinase cascade leading from growth factor
receptors to the extracellular signal-regulated kinase (ERK) subgroup of
MAPKs is dependent on the protein kinase RAF1 (164760), which activates
the MAPK/ERK kinase (MEK) dual-specificity kinases. A second protein
kinase cascade leading to activation of the JNKs is dependent on MEK
kinase (MEKK). Lin et al. (1995) found that JNKK was a dual-specificity
kinase that activated JNK and functioned between MEKK and JNK. JNKK
activated the JNKs, but not the ERKs, and was unresponsive to RAF1 in
transfected HeLa cells. It also activated another MAPK, p38, whose
activity is regulated similarly to that of the JNKs. Lin et al. (1995)
also showed that human JNKK could partially complement Pbs2 deficiency
in yeast.
The stress-activated protein kinase (SAPK) and MAPK pathways are signal
transduction cascades with distinct functions in mammals. White et al.
(1996) noted that they are structurally related in their phosphorylation
activity but differ in the events leading to phosphorylation. MAPKs are
rapidly phosphorylated and activated in response to various
extracellular stimuli. MAPK is regulated by its own phosphorylation by
MAPK kinases (MAP2Ks), e.g., MAP2K1 (176872) and MAP2K6 (601254). In the
SAPK pathway, SAPKs are the dominant JNKs activated in response to a
variety of cellular stresses, including treatment with interleukin-beta
(147720) and tumor necrosis factor-alpha (TNFA, or TNF; 191160). MAP2K4,
or SERK1, is a potent physiologic activator of SAPKs.
Wu et al. (1997) showed that JNKK1 was a specific activator of JNK1
(601158), JNK2 (602896), and p38, but not of ERK2 (176948). Among MEKK1
(600982), MEKK2 (MAP3K2; 609487), GCK, and ASK (MEKK5), MEKK1 was the
most potent activator of JNKK1, followed by MEKK2; GCK and ASK only
slightly activated JNKK1.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD
protein that perturbs a multiplicity of signaling pathways. These
include inhibition of the ERK, JNK, and p38 MAPK pathways and inhibition
of the nuclear factor kappa B (NF-kappa-B) pathway. The expression of
YopJ has been correlated with the induction of apoptosis by Yersinia.
Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a
HeLa cDNA library, Orth et al. (1999) identified mammalian binding
partners of YopJ. These included the fusion proteins of the GAL4
activation domain with MAPK kinases MKK1 (176872), MKK2 (601263), and
MKK4/SEK1. YopJ was found to bind directly to MKKs in vitro, including
MKK1, MKK3 (602315), MKK4, and MKK5 (602448). Binding of YopJ to the MKK
blocked both phosphorylation and subsequent activation of the MKKs.
These results explain the diverse activities of YopJ in inhibiting the
ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine
synthesis and promoting apoptosis. YopJ-related proteins that are found
in a number of bacterial pathogens of animals and plants may function to
block MKKs so that host signaling responses can be modulated upon
infection.
Using a yeast 2-hybrid screen, McDonald et al. (2000) identified JNK3
(602897) as a binding partner of beta-arrestin-2 (ARBB2; 107941). These
results were confirmed by coimmunoprecipitation from mouse brain
extracts and cotransfection in COS-7 cells. The upstream JNK activators
apoptosis signal-regulating kinase-1 (ASK1; 602448) and MKK4 were also
found in complex with ARBB2. Cellular transfection of ARBB2 caused
cytosolic retention of JNK3 and enhanced JNK3 phosphorylation stimulated
by ASK1. Moreover, stimulation of the angiotensin II type 1A receptor
(AGTR1; 106165) activated JNK3 and triggered the colocalization of ARBB2
and active JNK3 to intracellular vesicles. Thus, McDonald et al. (2000)
concluded that ARBB2 acts as a scaffold protein, which brings the
spatial distribution and activity of this MAPK module under the control
of a G protein-coupled receptor.
Kan et al. (2010) reported the identification of 2,576 somatic mutations
across approximately 1,800 megabases of DNA representing 1,507 coding
genes from 441 tumors comprising breast, lung, ovarian, and prostate
cancer types and subtypes. Integrated analysis of somatic mutations and
copy number alterations identified 35 significantly altered genes
including GNAS (see 139320), indicating an expanded role for G-alpha
subunits in multiple cancer types. Experimental analyses demonstrated
the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 in
oncogenesis.
Toll-like receptors (TLRs; see 603030) play a critical role in the
initiation of immune responses against invading pathogens. Lai et al.
(2013) found that stimulation of mouse peritoneal macrophages with
various TLR ligands reduced expression of microRNA-92A (MIR92A; see
609422) and most Mir92a family members. Decreased Mir92a expression
enhanced TLR-associated signaling events by increasing activation of the
JNK pathway, thereby promoting production of proinflammatory cytokines,
such as Il6 (147620) and Tnfa. Luciferase and knockdown analyses showed
that Mir92a directly targeted mouse Mkk4 and reduced TLR-induced
inflammatory responses.
MAPPING
By radiation hybrid mapping, Rampoldi et al. (1997) assigned genes
involved in the MAPK cascade to specific chromosomal sites, including
MEK4, which they mapped to chromosome 17p12.
White et al. (1996) mapped the human and mouse genes encoding MAP2K4,
which they called SERK1. The human gene was assigned to chromosome 17 by
PCR analysis of hamster/human somatic cell hybrids containing a single
human chromosome. White et al. (1996) stated that MAP2K4 localized to
chromosome 17p11 by fluorescence in situ hybridization. In mouse, they
mapped the Map2k4 gene to chromosome 11 by analysis of interspecific
backcrosses. The mouse gene maps to a region with extensive homology of
synteny to human chromosome 17p11.2.
MOLECULAR GENETICS
- Somatic Mutations in Pancreatic Cancer
Biankin et al. (2012) performed exome sequencing and copy number
analysis to define genomic aberrations in a prospectively accrued
clinical cohort of 142 patients with early (stage I and II) sporadic
pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative
tumors identified substantial heterogeneity with 2,016 nonsilent
mutations and 1,628 copy number variations. Biankin et al. (2012)
defined 16 significantly mutated genes, reaffirming known mutations and
uncovering novel mutated genes including additional genes involved in
chromatin modification (EPC1, 610999 and ARID2, 609539), DNA damage
repair (ATM; 607585), and other mechanisms (ZIM2 (see 601483); MAP2K4;
NALCN, 611549; SLC16A4, 603878; and MAGEA6, 300176). Integrative
analysis with in vitro functional data and animal models provided
supportive evidence for potential roles for these genetic aberrations in
carcinogenesis. Pathway-based analysis of recurrently mutated genes
recapitulated clustering in core signaling pathways in pancreatic ductal
adenocarcinoma, and identified new mutated genes in each pathway.
Biankin et al. (2012) also identified frequent and diverse somatic
aberrations in genes described traditionally as embryonic regulators of
axon guidance, particularly SLIT/ROBO (see 603742) signaling, which was
also evident in murine Sleeping Beauty transposon-mediated somatic
mutagenesis models of pancreatic cancer, providing further supportive
evidence for the potential involvement of axon guidance genes in
pancreatic carcinogenesis.
ANIMAL MODEL
To define the role of SEK1 in vivo, Ganiatsas et al. (1998) studied
stress-induced signaling in embryonic stem and fibroblast cells
homozygous for an Sek1 knockout and evaluated the phenotype of Sek1 -/-
mouse embryos during development. Sek1-deficient embryonic stem cells
showed defects in stimulated SAPK phosphorylation but not in the
phosphorylation of p38 kinase. In contrast, Sek1-deficient fibroblasts
exhibited defects in both SAPK and p38 phosphorylation, demonstrating
that crosstalk exists between the stress-activated cascades. Tumor
necrosis factor-alpha and interleukin-1 (see 147760) stimulation of both
stress-activated cascades was severely affected in the Sek1-deficient
fibroblasts. Sek1 deficiency led to embryonic lethality after embryonic
day 12.5 and was associated with abnormal liver development. The
phenotype was similar to that of the Jun-null mouse embryos (165160) and
suggested that SEK1 is required for phosphorylation and activation of
JUN during organogenesis of the liver.
Using a forward genetic screen of C. elegans mutants, Kim et al. (2002)
showed that viable worms lacking esp2 and esp8, homologs of the
mammalian MAP kinases SEK1 and ASK1, were highly susceptible to and died
more rapidly from both a gram-negative bacterium, P. aeruginosa, and a
gram-positive organism, E. faecalis, than wildtype worms.
RNA-interference and biochemical analyses likewise implicated the p38
MAP kinase (MAPK14; 600289) homolog, pmk1, in susceptibility to these
pathogens. Kim et al. (2002) concluded that MAP kinase signaling, which
is also involved in plant pathogen resistance, is a conserved element in
innate metazoan immunity to diverse pathogens.
Wang et al. (2007) targeted Mkk4 deletion to the neural lineage in mice.
Homozygous mutant mice were indistinguishable from control littermates
at birth, but they stopped growing a few days later and died. Mutant
mice displayed severe neurologic defects, including misalignment of
Purkinje cells in cerebellum and delayed radial migration in cerebral
cortex. Decreased Jnk activity due to Mkk4 deficiency correlated with
impaired phosphorylation of a subset of Jnk substrates and with altered
gene expression.
Knockout of Fah (613871) causes liver failure in mice due to
accumulation of intermediary hepatotoxins generated during incomplete
tyrosine catabolism. Lethality can be prevented by continuous treatment
with the drug nitisinone (NTBC). Wuestefeld et al. (2013) coupled NTBC
withdrawal in Fah -/- mice with short hairpin RNAs to identify genes
that influence liver failure and regeneration. They found that stable
knockdown of Mkk4 robustly increased the regenerative capacity of
hepatocytes and reduced the number of apoptotic hepatocytes in Fah -/-
mice following NTBC withdrawal, as well as in mouse models of acute and
chronic liver failure. Inhibition of Mkk4 resulted in faster cell-cycle
entry and progression of hepatocytes during liver regeneration by
compensatory upregulation of Mkk7 (MAP2K7; 603014) and Jnk1-dependent
activation of Atf2 (123811) and Elk1 (311040). Inhibition of Jnk1, but
not Jnk2, abolished the proregenerative effect of Mkk4 knockdown.
Wuestefeld et al. (2013) concluded that MKK4 is a master regulator of
liver regeneration.
*FIELD* RF
1. Biankin, A. V.; Waddell, N.; Kassahn, K. S.; Gingras, M.-C.; Muthuswamy,
L. B.; Johns, A. L.; Miller, D. K.; Wilson, P. J.; Patch, A.-M.; Wu,
J.; Chang, D. K.; Cowley, M. J.; and 116 others: Pancreatic cancer
genomes reveal aberrations in axon guidance pathway genes. Nature 491:
399-405, 2012.
2. Ganiatsas, S.; Kwee, L.; Fujiwara, Y.; Perkins, A.; Ikeda, T.;
Labow, M. A.; Zon, L. I.: SEK1 deficiency reveals mitogen-activated
protein kinase cascade crossregulation and leads to abnormal hepatogenesis. Proc.
Nat. Acad. Sci. 95: 6881-6886, 1998.
3. Kan, Z.; Jaiswal, B. S.; Stinson, J.; Janakiraman, V.; Bhatt, D.;
Stern, H. M.; Yue, P.; Haverty, P. M.; Bourgon, R.; Zheng, J.; Moorhead,
M.; Chaudhuri, S.; and 20 others: Diverse somatic mutation patterns
and pathway alterations in human cancers. Nature 466: 869-873, 2010.
4. Kim, D. H.; Feinbaum, R.; Alloing, G.; Emerson, F. E.; Garsin,
D. A.; Inoue, H.; Tanaka-Hino, M.; Hisamoto, N.; Matsumoto, K.; Tan,
M.-W.; Ausubel, F. M.: A conserved p38 MAP kinase pathway in Caenorhabditis
elegans innate immunity. Science 297: 623-626, 2002.
5. Lai, L.; Song, Y.; Liu, Y.; Chen, Q.; Han, Q.; Chen, W.; Pan, T.;
Zhang, Y.; Cao, X.; Wang, Q.: MicroRNA-92a negatively regulates Toll-like
receptor (TLR)-triggered inflammatory response in macrophages by targeting
MKK4 kinase. J. Biol. Chem. 288: 7956-7967, 2013.
6. Lin, A.; Minden, A.; Martinetto, H.; Claret, F.-X.; Lange-Carter,
C.; Mercurio, F.; Johnson, G. L.; Karin, M.: Identification of a
dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science 268:
286-290, 1995.
7. McDonald, P. H.; Chow, C.-W.; Miller, W. E.; Laporte, S. A.; Field,
M. E.; Lin, F.-T.; Davis, R. J.; Lefkowitz, R. J.: Beta-arrestin
2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290:
1574-1577, 2000.
8. Orth, K.; Palmer, L. E.; Bao, Z. Q.; Stewart, S.; Rudolph, A. E.;
Bliska, J. B.; Dixon, J. E.: Inhibition of the mitogen-activated
protein kinase kinase superfamily by a Yersinia effector. Science 285:
1920-1923, 1999.
9. Rampoldi, L.; Zimbello, R.; Bortoluzzi, S.; Tiso, N.; Valle, G.;
Lanfranchi, G.; Danieli, G. A.: Chromosomal localization of four
MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet.
Cell Genet. 78: 301-303, 1997.
10. Wang, X.; Nadarajah, B.; Robinson, A. C.; McColl, B. W.; Jin,
J.-W.; Dajas-Bailador, F.; Boot-Handford, R. P.; Tournier, C.: Targeted
deletion of the mitogen-activated protein kinase kinase 4 gene in
the nervous system causes severe brain developmental defects and premature
death. Molec. Cell. Biol. 27: 7935-7946, 2007.
11. White, R. A.; Hughes, R. T.; Adkison, L. R.; Bruns, G.; Zon, L.
I.: The gene encoding protein kinase SEK1 maps to mouse chromosome
11 and human chromosome 17. Genomics 34: 430-432, 1996.
12. Wu, Z.; Wu, J.; Jacinto, E.; Karin, M.: Molecular cloning and
characterization of human JNKK2, a novel jun NH(2)-terminal kinase-specific
kinase. Molec. Cell. Biol. 17: 7407-7416, 1997.
13. Wuestefeld, T.; Pesic, M.; Rudalska, R.; Dauch, D.; Longerich,
T.; Kang, T.-W.; Yevsa, T.; Heinzmann, F.; Hoenicke, L.; Hohmeyer,
A.; Potapova, A.; Rittelmeier, I.; and 11 others: A direct in vivo
RNAi screen identifies MKK4 as a key regulator of liver regeneration. Cell 153:
389-401, 2013.
*FIELD* CN
Patricia A. Hartz - updated: 06/06/2013
Paul J. Converse - updated: 3/28/2013
Ada Hamosh - updated: 12/18/2012
Ada Hamosh - updated: 9/21/2010
Paul J. Converse - updated: 9/4/2002
Ada Hamosh - updated: 12/4/2000
Patti M. Sherman - updated: 6/23/2000
Ada Hamosh - updated: 9/15/1999
Patti M. Sherman - updated: 9/2/1998
Victor A. McKusick - updated: 6/30/1998
Victor A. McKusick - updated: 3/17/1998
*FIELD* CD
Victor A. McKusick: 7/5/1996
*FIELD* ED
mgross: 06/06/2013
mgross: 4/1/2013
terry: 3/28/2013
alopez: 12/18/2012
alopez: 9/23/2010
terry: 9/21/2010
alopez: 2/4/2009
mgross: 9/24/2008
mgross: 7/21/2005
terry: 7/19/2004
mgross: 9/4/2002
joanna: 2/27/2001
joanna: 12/4/2000
mcapotos: 6/26/2000
psherman: 6/23/2000
alopez: 2/28/2000
carol: 9/17/1999
terry: 9/15/1999
mgross: 9/14/1999
alopez: 9/22/1998
alopez: 7/6/1998
terry: 6/30/1998
psherman: 3/17/1998
dholmes: 3/9/1998
mark: 4/9/1997
mark: 7/8/1996