RBCC Red Blood Cell Collection

MAP2K1 (MEK1, PRKMK1) [Confidence: low (only semi-automatic identification from reviews)]
Dual specificity mitogen-activated protein kinase kinase 1; MAP kinase kinase 1; MAPKK 1; MKK1; 2.7.12.2 (ERK activator kinase 1; MAPK/ERK kinase 1; MEK 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q02750
ID MP2K1_HUMAN Reviewed; 393 AA.
AC Q02750;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 1;
DE Short=MAP kinase kinase 1;
DE Short=MAPKK 1;
DE Short=MKK1;
DE EC=2.7.12.2;
DE AltName: Full=ERK activator kinase 1;
DE AltName: Full=MAPK/ERK kinase 1;
DE Short=MEK 1;
GN Name=MAP2K1; Synonyms=MEK1, PRKMK1;
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] (ISOFORMS 1 AND 2), PARTIAL PROTEIN
RP SEQUENCE, AND TISSUE SPECIFICITY.
RC TISSUE=T-cell;
RX PubMed=1281467;
RA Seger R., Seger D., Lozeman F.J., Ahn N.G., Graves L.M.,
RA Campbell J.S., Ericsson L., Harrylock M., Jensen A.M., Krebs E.G.;
RT "Human T-cell mitogen-activated protein kinase kinases are related to
RT yeast signal transduction kinases.";
RL J. Biol. Chem. 267:25628-25631(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8388392;
RA Zheng C.-F., Guan K.-L.;
RT "Cloning and characterization of two distinct human extracellular
RT signal-regulated kinase activator kinases, MEK1 and MEK2.";
RL J. Biol. Chem. 268:11435-11439(1993).
RN [3]
RP PHOSPHORYLATION AT SER-218 AND SER-222, AND MUTAGENESIS.
RX PubMed=8131746;
RA Zheng C.-F., Guan K.-L.;
RT "Activation of MEK family kinases requires phosphorylation of two
RT conserved Ser/Thr residues.";
RL EMBO J. 13:1123-1131(1994).
RN [4]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR, AND PROTEIN SEQUENCE OF 9-17.
RX PubMed=9563949; DOI=10.1126/science.280.5364.734;
RA Duesbery N.S., Webb C.P., Leppla S.H., Gordon V.M., Klimpel K.R.,
RA Copeland T.D., Ahn N.G., Oskarsson M.K., Fukasawa K., Paull K.D.,
RA Vande Woude G.F.;
RT "Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal
RT factor.";
RL Science 280:734-737(1998).
RN [5]
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 [6]
RP SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=14737111; DOI=10.1038/sj.onc.1207188;
RA Liu X., Yan S., Zhou T., Terada Y., Erikson R.L.;
RT "The MAP kinase pathway is required for entry into mitosis and cell
RT survival.";
RL Oncogene 23:763-776(2004).
RN [7]
RP PHOSPHORYLATION AT SER-298.
RX PubMed=16129686; DOI=10.1074/jbc.M502306200;
RA Beeser A., Jaffer Z.M., Hofmann C., Chernoff J.;
RT "Role of group A p21-activated kinases in activation of extracellular-
RT regulated kinase by growth factors.";
RL J. Biol. Chem. 280:36609-36615(2005).
RN [8]
RP INTERACTION WITH YOPJ, AND ACETYLATION.
RX PubMed=16728640; DOI=10.1126/science.1126867;
RA Mukherjee S., Keitany G., Li Y., Wang Y., Ball H.L., Goldsmith E.J.,
RA Orth K.;
RT "Yersinia YopJ acetylates and inhibits kinase activation by blocking
RT phosphorylation.";
RL Science 312:1211-1214(2006).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PPARG.
RX PubMed=17101779; DOI=10.1128/MCB.00601-06;
RA Burgermeister E., Chuderland D., Hanoch T., Meyer M., Liscovitch M.,
RA Seger R.;
RT "Interaction with MEK causes nuclear export and downregulation of
RT peroxisome proliferator-activated receptor gamma.";
RL Mol. Cell. Biol. 27:803-817(2007).
RN [10]
RP INTERACTION WITH BIRC6/BRUCE.
RX PubMed=18329369; DOI=10.1016/j.cell.2008.01.012;
RA Pohl C., Jentsch S.;
RT "Final stages of cytokinesis and midbody ring formation are controlled
RT by BRUCE.";
RL Cell 132:832-845(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-286, AND MASS
RP SPECTROMETRY.
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 [12]
RP 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 [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [14]
RP INTERACTION WITH VRK2.
RX PubMed=20679487; DOI=10.1128/MCB.01581-09;
RA Fernandez I.F., Blanco S., Lozano J., Lazo P.A.;
RT "VRK2 inhibits mitogen-activated protein kinase signaling and
RT inversely correlates with ErbB2 in human breast cancer.";
RL Mol. Cell. Biol. 30:4687-4697(2010).
RN [15]
RP REVIEW ON FUNCTION.
RX PubMed=9779990; DOI=10.1038/sj.onc.1202251;
RA Dhanasekaran N., Premkumar Reddy E.;
RT "Signaling by dual specificity kinases.";
RL Oncogene 17:1447-1455(1998).
RN [16]
RP REVIEW ON ENZYME REGULATION.
RX PubMed=15520807; DOI=10.1038/nrm1498;
RA Wellbrock C., Karasarides M., Marais R.;
RT "The RAF proteins take centre stage.";
RL Nat. Rev. Mol. Cell Biol. 5:875-885(2004).
RN [17]
RP REVIEW ON FUNCTION.
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 [18]
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 [19]
RP 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 [20]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 62-392 IN COMPLEX WITH ATP
RP AND INHIBITOR.
RX PubMed=15543157; DOI=10.1038/nsmb859;
RA Ohren J.F., Chen H., Pavlovsky A., Whitehead C., Zhang E., Kuffa P.,
RA Yan C., McConnell P., Spessard C., Banotai C., Mueller W.T.,
RA Delaney A., Omer C., Sebolt-Leopold J., Dudley D.T., Leung I.K.,
RA Flamme C., Warmus J., Kaufman M., Barrett S., Tecle H., Hasemann C.A.;
RT "Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe
RT novel noncompetitive kinase inhibition.";
RL Nat. Struct. Mol. Biol. 11:1192-1197(2004).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP
RP AND INHIBITOR.
RX PubMed=17880056; DOI=10.1021/jm0704548;
RA Spicer J.A., Rewcastle G.W., Kaufman M.D., Black S.L., Plummer M.S.,
RA Denny W.A., Quin J. III, Shahripour A.B., Barrett S.D.,
RA Whitehead C.E., Milbank J.B., Ohren J.F., Gowan R.C., Omer C.,
RA Camp H.S., Esmaeil N., Moore K., Sebolt-Leopold J.S.,
RA Pryzbranowski S., Merriman R.L., Ortwine D.F., Warmus J.S.,
RA Flamme C.M., Pavlovsky A.G., Tecle H.;
RT "4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive
RT inhibitors of mitogen-activated protein kinase kinase.";
RL J. Med. Chem. 50:5090-5102(2007).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.62 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP
RP AND INHIBITOR.
RX PubMed=18951019; DOI=10.1016/j.bmcl.2008.10.015;
RA Warmus J.S., Flamme C., Zhang L.Y., Barrett S., Bridges A., Chen H.,
RA Gowan R., Kaufman M., Sebolt-Leopold J., Leopold W., Merriman R.,
RA Ohren J., Pavlovsky A., Przybranowski S., Tecle H., Valik H.,
RA Whitehead C., Zhang E.;
RT "2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-
RT Alkyl benzohydroxamate esters replacements retain the desired
RT inhibition and selectivity against MEK (MAP ERK kinase).";
RL Bioorg. Med. Chem. Lett. 18:6171-6174(2008).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 35-393 IN COMPLEX WITH ADP
RP AND INHIBITOR.
RX PubMed=19161339; DOI=10.1021/bi801898e;
RA Fischmann T.O., Smith C.K., Mayhood T.W., Myers J.E., Reichert P.,
RA Mannarino A., Carr D., Zhu H., Wong J., Yang R.S., Le H.V.,
RA Madison V.S.;
RT "Crystal structures of MEK1 binary and ternary complexes with
RT nucleotides and inhibitors.";
RL Biochemistry 48:2661-2674(2009).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 62-382 IN COMPLEX WITH ATP
RP AND INHIBITOR.
RX PubMed=19019675; DOI=10.1016/j.bmcl.2008.10.108;
RA Tecle H., Shao J., Li Y., Kothe M., Kazmirski S., Penzotti J.,
RA Ding Y.H., Ohren J., Moshinsky D., Coli R., Jhawar N., Bora E.,
RA Jacques-O'Hagan S., Wu J.;
RT "Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized
RT to synthesize novel type III NCKIs? Does the MEK-pocket exist in
RT kinases other than MEK?";
RL Bioorg. Med. Chem. Lett. 19:226-229(2009).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP
RP AND INHIBITOR.
RX PubMed=19706763; DOI=10.1158/0008-5472.CAN-09-0679;
RA Iverson C., Larson G., Lai C., Yeh L.T., Dadson C., Weingarten P.,
RA Appleby T., Vo T., Maderna A., Vernier J.M., Hamatake R., Miner J.N.,
RA Quart B.;
RT "RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of
RT MEK1/2 for the treatment of cancer.";
RL Cancer Res. 69:6839-6847(2009).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 62-382 IN COMPLEX WITH ADP
RP AND INHIBITOR.
RX PubMed=20621728; DOI=10.1016/j.bmcl.2010.05.058;
RA Wallace M.B., Adams M.E., Kanouni T., Mol C.D., Dougan D.R.,
RA Feher V.A., O'Connell S.M., Shi L., Halkowycz P., Dong Q.;
RT "Structure-based design and synthesis of pyrrole derivatives as MEK
RT inhibitors.";
RL Bioorg. Med. Chem. Lett. 20:4156-4158(2010).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 62-382 IN COMPLEX WITH ATP
RP AND INHIBITOR.
RX PubMed=21310613; DOI=10.1016/j.bmcl.2011.01.071;
RA Dong Q., Dougan D.R., Gong X., Halkowycz P., Jin B., Kanouni T.,
RA O'Connell S.M., Scorah N., Shi L., Wallace M.B., Zhou F.;
RT "Discovery of TAK-733, a potent and selective MEK allosteric site
RT inhibitor for the treatment of cancer.";
RL Bioorg. Med. Chem. Lett. 21:1315-1319(2011).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 62-393.
RX PubMed=21316218; DOI=10.1016/j.bmcl.2011.01.062;
RA Isshiki Y., Kohchi Y., Iikura H., Matsubara Y., Asoh K., Murata T.,
RA Kohchi M., Mizuguchi E., Tsujii S., Hattori K., Miura T.,
RA Yoshimura Y., Aida S., Miwa M., Saitoh R., Murao N., Okabe H.,
RA Belunis C., Janson C., Lukacs C., Schuck V., Shimma N.;
RT "Design and synthesis of novel allosteric MEK inhibitor CH4987655 as
RT an orally available anticancer agent.";
RL Bioorg. Med. Chem. Lett. 21:1795-1801(2011).
RN [29]
RP VARIANTS CFC3 SER-53 AND CYS-130.
RX PubMed=16439621; DOI=10.1126/science.1124642;
RA Rodriguez-Viciana P., Tetsu O., Tidyman W.E., Estep A.L., Conger B.A.,
RA Cruz M.S., McCormick F., Rauen K.A.;
RT "Germline mutations in genes within the MAPK pathway cause cardio-
RT facio-cutaneous syndrome.";
RL Science 311:1287-1290(2006).
RN [30]
RP VARIANT CFC3 VAL-128.
RX PubMed=18042262; DOI=10.1111/j.1399-0004.2007.00931.x;
RA Schulz A.L., Albrecht B., Arici C., van der Burgt I., Buske A.,
RA Gillessen-Kaesbach G., Heller R., Horn D., Hubner C.A., Korenke G.C.,
RA Konig R., Kress W., Kruger G., Meinecke P., Mucke J., Plecko B.,
RA Rossier E., Schinzel A., Schulze A., Seemanova E., Seidel H.,
RA Spranger S., Tuysuz B., Uhrig S., Wieczorek D., Kutsche K., Zenker M.;
RT "Mutation and phenotypic spectrum in patients with cardio-facio-
RT cutaneous and Costello syndrome.";
RL Clin. Genet. 73:62-70(2008).
CC -!- FUNCTION: Dual specificity protein kinase which acts as an
CC essential component of the MAP kinase signal transduction pathway.
CC Binding of extracellular ligands such as growth factors, cytokines
CC and hormones to their cell-surface receptors activates RAS and
CC this initiates RAF1 activation. RAF1 then further activates the
CC dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both
CC MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK
CC cascade, and catalyze the concomitant phosphorylation of a
CC threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located
CC in the extracellular signal-regulated kinases MAPK3/ERK1 and
CC MAPK1/ERK2, leading to their activation and further transduction
CC of the signal within the MAPK/ERK cascade. Depending on the
CC cellular context, this pathway mediates diverse biological
CC functions such as cell growth, adhesion, survival and
CC differentiation, predominantly through the regulation of
CC transcription, metabolism and cytoskeletal rearrangements. One
CC target of the MAPK/ERK cascade is peroxisome proliferator-
CC activated receptor gamma (PPARG), a nuclear receptor that promotes
CC differentiation and apoptosis. MAP2K1/MEK1 has been shown to
CC export PPARG from the nucleus. The MAPK/ERK cascade is also
CC involved in the regulation of endosomal dynamics, including
CC lysosome processing and endosome cycling through the perinuclear
CC recycling compartment (PNRC), as well as in the fragmentation of
CC the Golgi apparatus during mitosis.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- ENZYME REGULATION: Ras proteins such as HRAS mediate the
CC activation of RAF proteins such as RAF1 or BRAF which in turn
CC activate extracellular signal-regulated kinases (ERK) through MAPK
CC (mitogen-activated protein kinases) and ERK kinases MAP2K1/MEK1
CC and MAP2K2/MEK2. Activation occurs through phosphorylation of Ser-
CC 218 and Ser-222. MAP2K1/MEK1 is also the target of negative feed-
CC back regulation by its substrate kinases, such as MAPK1/ERK2.
CC These phosphorylate MAP2K1/MEK1 on Thr-292, thereby facilitating
CC dephosphorylation of the activating residues Ser-218 and Ser-222.
CC Inhibited by serine/threonine phosphatase 2A (By similarity). Many
CC inhibitors have been identified including pyrrole derivatives,
CC TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-
CC 4,7(3H,8H)-dione derivatives), CH4987655 and RDEA119/BAY 869766.
CC -!- SUBUNIT: Found in a complex with at least BRAF, HRAS1, MAP2K1,
CC MAPK3/ERK1 and RGS14 (By similarity). Forms a heterodimer with
CC MAP2K2/MEK2 (By similarity). Forms heterodimers with KSR2 which
CC further dimerize to form tetramers (By similarity). Interacts with
CC ARBB2, LAMTOR3, MAPK1/ERK2, MORG1 and RAF1 (By similarity).
CC Interacts with PPARG and with isoform 1 of VRK2. Interacts with
CC Yersinia yopJ. Interacts with SGK1. Interacts with BIRC6/bruce.
CC -!- INTERACTION:
CC Q9NR09:BIRC6; NbExp=2; IntAct=EBI-492564, EBI-1765160;
CC Q9Y297:BTRC; NbExp=3; IntAct=EBI-492564, EBI-307461;
CC O15519-1:CFLAR; NbExp=3; IntAct=EBI-492564, EBI-4567563;
CC P28482:MAPK1; NbExp=2; IntAct=EBI-492564, EBI-959949;
CC P27361:MAPK3; NbExp=2; IntAct=EBI-492564, EBI-73995;
CC P04049:RAF1; NbExp=5; IntAct=EBI-492564, EBI-365996;
CC Q86Y07:VRK2; NbExp=2; IntAct=EBI-492564, EBI-1207615;
CC Q86Y07-1:VRK2; NbExp=2; IntAct=EBI-492564, EBI-1207633;
CC P46937:YAP1; NbExp=3; IntAct=EBI-492564, EBI-1044059;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome. Cytoplasm, cytoskeleton,
CC microtubule organizing center, spindle pole body. Cytoplasm.
CC Nucleus. Note=Localizes at centrosomes during prometaphase,
CC midzone during anaphase and midbody during telophase/cytokinesis.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=MKK1a;
CC IsoId=Q02750-1; Sequence=Displayed;
CC Name=2; Synonyms=MKK1b;
CC IsoId=Q02750-2; Sequence=VSP_040500;
CC -!- TISSUE SPECIFICITY: Widely expressed, with extremely low levels in
CC brain.
CC -!- DOMAIN: The proline-rich region localized between residues 270 and
CC 307 is important for binding to RAF1 and activation of MAP2K1/MEK1
CC (By similarity).
CC -!- PTM: Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase
CC kinases (RAF or MEKK1) positively regulates kinase activity. Also
CC phosphorylated at Thr-292 by MAPK1/ERK2 and at Ser-298 by PAK.
CC MAPK1/ERK2 phosphorylation of Thr-292 occurs in response to
CC cellular adhesion and leads to inhibition of Ser-298
CC phosphorylation by PAK.
CC -!- PTM: Acetylation by Yersinia yopJ prevents phosphorylation and
CC activation, thus blocking the MAPK signaling pathway.
CC -!- DISEASE: Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A
CC form of cardiofaciocutaneous syndrome, a multiple congenital
CC anomaly disorder characterized by a distinctive facial appearance,
CC heart defects and mental retardation. Heart defects include
CC pulmonic stenosis, atrial septal defects and hypertrophic
CC cardiomyopathy. Some affected individuals present with ectodermal
CC abnormalities such as sparse, friable hair, hyperkeratotic skin
CC lesions and a generalized ichthyosis-like condition. Typical
CC facial features are similar to Noonan syndrome. They include high
CC forehead with bitemporal constriction, hypoplastic supraorbital
CC ridges, downslanting palpebral fissures, a depressed nasal bridge,
CC and posteriorly angulated ears with prominent helices. Distinctive
CC features of CFC3 include macrostomia and horizontal shape of
CC palpebral fissures. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
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=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MAP2K1";
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DR EMBL; L05624; AAA36318.1; -; mRNA.
DR EMBL; L11284; -; NOT_ANNOTATED_CDS; mRNA.
DR PIR; A45100; A45100.
DR RefSeq; NP_002746.1; NM_002755.3.
DR UniGene; Hs.145442; -.
DR PDB; 1S9J; X-ray; 2.40 A; A=62-392.
DR PDB; 2P55; X-ray; 2.80 A; A=62-393.
DR PDB; 3DV3; X-ray; 2.30 A; A=62-382.
DR PDB; 3DY7; X-ray; 2.70 A; A=62-393.
DR PDB; 3E8N; X-ray; 2.50 A; A=62-393.
DR PDB; 3EQB; X-ray; 2.62 A; A=62-393.
DR PDB; 3EQC; X-ray; 1.80 A; A=35-393.
DR PDB; 3EQD; X-ray; 2.10 A; A=35-393.
DR PDB; 3EQF; X-ray; 2.70 A; A=35-393.
DR PDB; 3EQG; X-ray; 2.50 A; A=35-393.
DR PDB; 3EQH; X-ray; 2.00 A; A=35-393.
DR PDB; 3EQI; X-ray; 1.90 A; A=35-393.
DR PDB; 3MBL; X-ray; 2.60 A; A=62-382.
DR PDB; 3ORN; X-ray; 2.80 A; A=62-393.
DR PDB; 3OS3; X-ray; 2.80 A; A=62-393.
DR PDB; 3PP1; X-ray; 2.70 A; A=62-382.
DR PDB; 3SLS; X-ray; 2.30 A; A/B=45-383.
DR PDB; 3V01; X-ray; 2.70 A; A=62-393.
DR PDB; 3V04; X-ray; 2.70 A; A=62-393.
DR PDB; 3VVH; X-ray; 2.00 A; A/B/C=62-393.
DR PDB; 3ZLS; X-ray; 2.50 A; A=37-383.
DR PDB; 3ZLW; X-ray; 2.12 A; A=37-383.
DR PDB; 3ZLX; X-ray; 2.20 A; A=37-383.
DR PDB; 3ZLY; X-ray; 2.11 A; A=37-383.
DR PDB; 3ZM4; X-ray; 2.37 A; A=37-383.
DR PDB; 4AN2; X-ray; 2.50 A; A=61-392.
DR PDB; 4AN3; X-ray; 2.10 A; A=61-392.
DR PDB; 4AN9; X-ray; 2.80 A; A=61-392.
DR PDB; 4ANB; X-ray; 2.20 A; A=61-392.
DR PDB; 4ARK; X-ray; 2.60 A; A=62-393.
DR PDB; 4LMN; X-ray; 2.80 A; A=62-393.
DR PDBsum; 1S9J; -.
DR PDBsum; 2P55; -.
DR PDBsum; 3DV3; -.
DR PDBsum; 3DY7; -.
DR PDBsum; 3E8N; -.
DR PDBsum; 3EQB; -.
DR PDBsum; 3EQC; -.
DR PDBsum; 3EQD; -.
DR PDBsum; 3EQF; -.
DR PDBsum; 3EQG; -.
DR PDBsum; 3EQH; -.
DR PDBsum; 3EQI; -.
DR PDBsum; 3MBL; -.
DR PDBsum; 3ORN; -.
DR PDBsum; 3OS3; -.
DR PDBsum; 3PP1; -.
DR PDBsum; 3SLS; -.
DR PDBsum; 3V01; -.
DR PDBsum; 3V04; -.
DR PDBsum; 3VVH; -.
DR PDBsum; 3ZLS; -.
DR PDBsum; 3ZLW; -.
DR PDBsum; 3ZLX; -.
DR PDBsum; 3ZLY; -.
DR PDBsum; 3ZM4; -.
DR PDBsum; 4AN2; -.
DR PDBsum; 4AN3; -.
DR PDBsum; 4AN9; -.
DR PDBsum; 4ANB; -.
DR PDBsum; 4ARK; -.
DR PDBsum; 4LMN; -.
DR ProteinModelPortal; Q02750; -.
DR SMR; Q02750; 39-381.
DR DIP; DIP-201N; -.
DR IntAct; Q02750; 27.
DR MINT; MINT-99632; -.
DR STRING; 9606.ENSP00000302486; -.
DR BindingDB; Q02750; -.
DR ChEMBL; CHEMBL2111351; -.
DR GuidetoPHARMACOLOGY; 2062; -.
DR PhosphoSite; Q02750; -.
DR DMDM; 400274; -.
DR PaxDb; Q02750; -.
DR PeptideAtlas; Q02750; -.
DR PRIDE; Q02750; -.
DR DNASU; 5604; -.
DR Ensembl; ENST00000307102; ENSP00000302486; ENSG00000169032.
DR GeneID; 5604; -.
DR KEGG; hsa:5604; -.
DR UCSC; uc010bhq.3; human.
DR CTD; 5604; -.
DR GeneCards; GC15P066679; -.
DR HGNC; HGNC:6840; MAP2K1.
DR HPA; CAB003834; -.
DR HPA; HPA026430; -.
DR MIM; 176872; gene.
DR MIM; 615279; phenotype.
DR neXtProt; NX_Q02750; -.
DR Orphanet; 1340; Cardiofaciocutaneous syndrome.
DR PharmGKB; PA30584; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000234206; -.
DR HOVERGEN; HBG108518; -.
DR InParanoid; Q02750; -.
DR KO; K04368; -.
DR OMA; RDKHAIM; -.
DR OrthoDB; EOG7HF1KZ; -.
DR PhylomeDB; Q02750; -.
DR BRENDA; 2.7.12.2; 2681.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q02750; -.
DR ChiTaRS; MAP2K1; human.
DR EvolutionaryTrace; Q02750; -.
DR GeneWiki; MAP2K1; -.
DR GenomeRNAi; 5604; -.
DR NextBio; 21776; -.
DR PMAP-CutDB; Q02750; -.
DR PRO; PR:Q02750; -.
DR ArrayExpress; Q02750; -.
DR Bgee; Q02750; -.
DR CleanEx; HS_MAP2K1; -.
DR Genevestigator; Q02750; -.
DR GO; GO:0005938; C:cell cortex; IEA:Ensembl.
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:0005739; C:mitochondrion; TAS:UniProtKB.
DR GO; GO:0005634; C:nucleus; TAS:UniProtKB.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005816; C:spindle pole body; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004708; F:MAP kinase kinase activity; IDA:UniProtKB.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:Reactome.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004728; F:receptor signaling protein tyrosine phosphatase activity; IEA:Ensembl.
DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007050; P:cell cycle arrest; IMP:BHF-UCL.
DR GO; GO:0048870; P:cell motility; IEA:Ensembl.
DR GO; GO:0008283; P:cell proliferation; IEA:Ensembl.
DR GO; GO:0090398; P:cellular senescence; IMP:BHF-UCL.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048313; P:Golgi inheritance; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl.
DR GO; GO:0060711; P:labyrinthine layer development; IEA:Ensembl.
DR GO; GO:0032402; P:melanosome transport; IEA:Ensembl.
DR GO; GO:0007067; P:mitosis; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:BHF-UCL.
DR GO; GO:0034111; P:negative regulation of homotypic cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:GOC.
DR GO; GO:0060674; P:placenta blood vessel development; IEA:Ensembl.
DR GO; GO:0045597; P:positive regulation of cell differentiation; IEA:Ensembl.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0032320; P:positive regulation of Ras GTPase activity; IEA:Ensembl.
DR GO; GO:0046579; P:positive regulation of Ras protein signal transduction; IEA:Ensembl.
DR GO; GO:0032968; P:positive regulation of transcription elongation from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
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:0032872; P:regulation of stress-activated MAPK cascade; TAS:UniProtKB.
DR GO; GO:0003056; P:regulation of vascular smooth muscle contraction; IEA:Ensembl.
DR GO; GO:0048678; P:response to axon injury; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
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 GO; GO:0047496; P:vesicle transport along microtubule; IEA:Ensembl.
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; ATP-binding;
KW Cardiomyopathy; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Ectodermal dysplasia;
KW Kinase; Mental retardation; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Tyrosine-protein kinase.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 393 Dual specificity mitogen-activated
FT protein kinase kinase 1.
FT /FTId=PRO_0000086365.
FT DOMAIN 68 361 Protein kinase.
FT NP_BIND 74 82 ATP.
FT NP_BIND 143 146 ATP.
FT NP_BIND 150 153 ATP.
FT NP_BIND 192 195 ATP.
FT REGION 77 78 Inhibitor binding.
FT REGION 144 146 Inhibitor binding.
FT REGION 208 212 Inhibitor binding.
FT REGION 270 307 RAF1-binding (By similarity).
FT COMPBIAS 262 307 Pro-rich.
FT ACT_SITE 190 190 Proton acceptor (By similarity).
FT BINDING 77 77 Inhibitor; via carbonyl oxygen.
FT BINDING 78 78 Inhibitor; via amide nitrogen and
FT carbonyl oxygen.
FT BINDING 97 97 ATP.
FT BINDING 97 97 Inhibitor.
FT BINDING 190 190 Inhibitor.
FT BINDING 194 194 Inhibitor; via carbonyl oxygen.
FT BINDING 208 208 ATP.
FT BINDING 208 208 Inhibitor.
FT BINDING 212 212 Inhibitor; via amide nitrogen.
FT SITE 8 9 Cleavage; by anthrax lethal factor.
FT MOD_RES 218 218 Phosphoserine; by RAF.
FT MOD_RES 222 222 Phosphoserine; by RAF.
FT MOD_RES 286 286 Phosphothreonine.
FT MOD_RES 292 292 Phosphothreonine; by MAPK1 (By
FT similarity).
FT MOD_RES 298 298 Phosphoserine; by PAK.
FT VAR_SEQ 147 172 Missing (in isoform 2).
FT /FTId=VSP_040500.
FT VARIANT 53 53 F -> S (in CFC3).
FT /FTId=VAR_035093.
FT VARIANT 128 128 G -> V (in CFC3).
FT /FTId=VAR_069780.
FT VARIANT 130 130 Y -> C (in CFC3).
FT /FTId=VAR_035094.
FT MUTAGEN 97 97 K->R: Inactivation.
FT MUTAGEN 150 150 S->A: No loss of activity.
FT MUTAGEN 212 212 S->A: No loss of activity.
FT MUTAGEN 218 218 S->A: Inactivation.
FT MUTAGEN 222 222 S->A: Inactivation.
FT HELIX 44 58
FT HELIX 65 67
FT STRAND 68 76
FT STRAND 81 87
FT TURN 88 90
FT STRAND 93 100
FT HELIX 105 115
FT HELIX 116 120
FT STRAND 129 135
FT STRAND 138 143
FT HELIX 151 158
FT HELIX 163 184
FT HELIX 193 195
FT STRAND 196 198
FT TURN 200 202
FT STRAND 204 206
FT HELIX 213 218
FT TURN 220 222
FT HELIX 227 229
FT HELIX 232 235
FT HELIX 242 258
FT HELIX 268 275
FT HELIX 310 319
FT TURN 327 329
FT HELIX 332 342
FT TURN 346 348
FT HELIX 352 356
FT HELIX 359 366
FT HELIX 371 379
SQ SEQUENCE 393 AA; 43439 MW; 0344118FFC842D51 CRC64;
MPKKKPTPIQ LNPAPDGSAV NGTSSAETNL EALQKKLEEL ELDEQQRKRL EAFLTQKQKV
GELKDDDFEK ISELGAGNGG VVFKVSHKPS GLVMARKLIH LEIKPAIRNQ IIRELQVLHE
CNSPYIVGFY GAFYSDGEIS ICMEHMDGGS LDQVLKKAGR IPEQILGKVS IAVIKGLTYL
REKHKIMHRD VKPSNILVNS RGEIKLCDFG VSGQLIDSMA NSFVGTRSYM SPERLQGTHY
SVQSDIWSMG LSLVEMAVGR YPIPPPDAKE LELMFGCQVE GDAAETPPRP RTPGRPLSSY
GMDSRPPMAI FELLDYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA DLKQLMVHAF
IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA AGV
//

MIM 176872
*RECORD*
*FIELD* NO
176872
*FIELD* TI
*176872 MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1
;;PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 1; PRKMK1;;
read moreMKK1; MAPKK1;;
MAPK/ERK KINASE 1; MEK1
*FIELD* TX

CLONING

Mitogen-activated protein (MAP) kinases, also known as extracellular
signal-regulated kinases (ERKs) (see ERK2, or MAPK1; 176948), are
thought to act as an integration point for multiple biochemical signals
because they are activated by a wide variety of extracellular signals,
are rapidly phosphorylated on threonine and tyrosine residues, and are
highly conserved in evolution (Crews et al., 1992). A critical protein
kinase lies upstream of MAP kinase and stimulates the enzymatic activity
of MAP kinase. Crews et al. (1992) cloned a mouse cDNA, denoted Mek1
(for Map/Erk kinase-1) by them, that encodes a member of this protein
kinase family. The 393-amino acid, 43.5-kD protein is most closely
related in size and sequence to the product encoded by the byr1 gene of
S. pombe. The Mek1 gene was highly expressed in murine brain.

Seger et al. (1992) cloned a cDNA encoding the human homolog of Mek1,
symbolized MKK1 by them, from a human T-cell cDNA library. The predicted
protein has a calculated molecular mass of 43 kD. They also isolated a
related cDNA, called MKK1b, that appears to be an alternatively spliced
form of MKK1. Seger et al. (1992) detected a 2.6-kb MKK1 transcript by
Northern blot analysis in all tissues examined.

Zheng and Guan (1993) also cloned a human cDNA corresponding to MEK1.
They noted that the 393-amino acid protein shares 99% amino acid
identity with murine Mek1 and 80% homology with human MEK2 (601263). The
authors characterized biochemically the human MEK1 and MEK2 gene
products. The gene is also symbolized MAP2K1, or PRKMK1.

MAPPING

Using radiation hybrid mapping, Rampoldi et al. (1997) localized the
MAP2K1 gene to 15q22.1-q22.33. By somatic cell hybrid analysis and FISH,
Meloche et al. (2000) mapped MAP2K1 to 15q21 and a pseudogene, MAP2K1P1,
to 8p21. Brott et al. (1993) mapped the mouse Mek1 gene to chromosome 9.

GENE FUNCTION

Crews et al. (1992) found that the mouse Mek1 protein expressed in
bacteria phosphorylated the Erk gene product in vitro.

Seger et al. (1992) found that overexpression of MKK1 in COS cells led
to increased phorbol ester-stimulated MAP kinase kinase activity. Seger
and Krebs (1995) reviewed the MAP kinase signaling cascade.

Ryan et al. (2000) showed that inhibition of MEK1 blocks p53
(191170)-induced NF-kappa-B activation and apoptosis but not cell cycle
arrest. They demonstrated that p53 activates NF-kappa-B through the
RAF/MEK1/p90(rsk) (see 601684) pathway rather than the TNFR1
(191190)/TRAF2 (601895)/IKK (e.g., 600664) pathway used by TNFA
(191160).

To elucidate the mechanism through which MAPK signaling regulates the
MYOD (159970) family of transcription factors, Perry et al. (2001)
investigated the role of the signaling intermediate MEK1 in myogenesis.
Transfection of activated MEK1 strongly repressed gene activation and
myogenic conversion by the MYOD family. This repression was not mediated
by direct phosphorylation of MYOD or by changes in MYOD stability or
subcellular distribution. Deletion mapping revealed that MEK1-mediated
repression required the MYOD N-terminal transactivation domain.
Moreover, activated MEK1 was nuclearly localized and bound a complex
containing MYOD in a manner that was dependent on the presence of the
MYOD N terminus. These data demonstrated that MEK1 signaling has a
strong negative effect on MYOD activity via a mechanism involving
binding of MEK1 to the nuclear MYOD transcriptional complex.

Takekawa et al. (2005) identified a conserved docking site, which they
termed 'domain for versatile docking' (DVD), immediately C terminal to
the catalytic domains of mammalian MAPKKs, including MEK1. They
determined that DVD sites contain about 20 amino acids and bind to
specific upstream MAPKKKs. DVD site mutations strongly inhibited MAPKKs
from binding to and being activated by their specific MAPKKKs, both in
vitro and in vivo. MAPKKs containing DVD site mutations could not be
activated by various external stimuli in vivo, and synthetic DVD
oligopeptides inhibited specific MAPKK activation, both in vitro and in
vivo. Takekawa et al. (2005) concluded that DVD docking is critically
important in MAPK signaling.

Scholl et al. (2007) found that conditional deletion of either Mek1 or
Mek2 in mouse skin had no effect on epidermal development, but combined
Mek1/Mek2 deletion during embryonic development or in adulthood
abolished Erk1 (MAPK3; 601795)/Erk2 phosphorylation and led to
hypoproliferation, apoptosis, skin barrier defects, and death.
Conversely, a single copy of either allele was sufficient for normal
development. Combined Mek1/Mek2 loss also abolished Raf (RAF1;
164760)-induced hyperproliferation. To examine the effect of combined
MEK deletion on human skin, Scholl et al. (2007) used small interfering
RNA to delete MEK1 and MEK2 expression in normal primary human
keratinocytes and used these cells to regenerate human epidermal tissue
on human dermis, which was grafted onto immune-deficient mice. Control
keratinocytes or those lacking either MEK1 or MEK2 were able to
regenerate 6 days after grafting. In contrast, combined depletion of
MEK1 and MEK2 led to either graft failure or markedly hypoplastic
epidermis that nonetheless contained an intact stratum corneum. ERK2
expression rescued the defect. Scholl et al. (2007) concluded that MEK1
and MEK2 are functionally redundant in the epidermis and function in a
linear relay in the MAPK pathway.

Imai et al. (2008) used mouse models to explore the mechanism whereby
obesity enhances pancreatic beta cell mass, pathophysiologic
compensation for insulin resistance. Imai et al. (2008) found that
hepatic activation of extracellular regulated kinase (ERK1; 601795)
signaling by expression of constitutively active MEK1 induced pancreatic
beta cell proliferation through a neuronal-mediated relay of metabolic
signals. This metabolic relay from the liver to the pancreas is involved
in obesity-induced islet expansion. In mouse models of insulin-deficient
diabetes, liver-selective activation of ERK signaling increased beta
cell mass and normalized serum glucose levels. Thus, Imai et al. (2008)
concluded that interorgan metabolic relay systems may serve as valuable
targets in regenerative treatments for diabetes.

Chuderland et al. (2008) identified an SPS motif in ERK2 and SMAD3
(603109) and a similar TPT motif in MEK1 that directed protein nuclear
accumulation when phosphorylated.

BIOCHEMICAL FEATURES

- Crystal Structure

Brennan et al. (2011) integrated structural and biochemical studies to
understand how kinase suppressor of Ras (KSR) promotes stimulatory Raf
phosphorylation of MEK. They showed, from the crystal structure of the
kinase domain (KD) of human KSR2 (610737) in complex with rabbit MEK1,
that interactions between KSR2(KD) and MEK1 are mediated by their
respective activation segments and C-lobe alpha-G helices. Analogous to
BRAF (164757), KSR2 self-associates through a side-to-side interface
involving arg718, a residue identified in a genetic screen as a
suppressor of Ras signaling. ATP is bound to the KSR2 (KD) catalytic
site, and Brennan et al. (2011) demonstrated KSR2 kinase activity
towards MEK1 by in vitro assays and chemical genetics. In the
KSR2(KD)-MEK1 complex, the activation segments of both kinases are
mutually constrained, and KSR2 adopts an inactive conformation. BRAF
allosterically stimulates the kinase activity of KSR2, which is
dependent on formation of a side-to-side KSR2-BRAF heterodimer.
Furthermore, KSR2-BRAF heterodimerization results in an increase of
BRAF-induced MEK phosphorylation via the KSR2-mediated relay of a signal
from BRAF to release the activation segment of MEK for phosphorylation.
Brennan et al. (2011) proposed that KSR interacts with a regulatory Raf
molecule in cis to induce a conformational switch of MEK, facilitating
MEK's phosphorylation by a separate catalytic Raf molecule in trans.

MOLECULAR GENETICS

- Cardiofaciocutaneous Syndrome

In 2 patients with cardiofaciocutaneous syndrome (CFC3; 615279),
Rodriguez-Viciana et al. (2006) identified mutations (F53S, 176872.0001;
Y130C, 176872.0002) in the MEK1 gene. Interestingly, 1 patient had a
mutation at phe53 (F53), which is equivalent to phe57 (F57) in the MEK2
gene, where another CFC patient had a missense mutation (F57C;
601263.0001).

Schulz et al. (2008) identified mutations in the MAP2K1 gene (see, e.g.,
176872.0003) in 5 (9.8%) of 51 CFC patients.

- Somatic Mutation in Melanoma

Nikolaev et al. (2012) performed exome sequencing to detect somatic
mutations in protein-coding regions in 7 melanoma cell lines and
donor-matched germline cells. All melanoma samples had high numbers of
somatic mutations, which showed the hallmark of UV-induced DNA repair.
Such a hallmark was absent in tumor sample-specific mutations in 2
metastases derived from the same individual. Two melanomas with
noncanonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2
(MEK2; 601263) mutations, resulting in constitutive ERK phosphorylation
and higher resistance to MEK inhibitors. Screening a larger cohort of
individuals with melanoma revealed the presence of recurring somatic
MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of
8%.

OTHER FEATURES

Constitutive activation of MEK1 results in cellular transformation. This
protein kinase therefore represents a likely target for pharmacologic
intervention in proliferative disease. To identity small-molecule
inhibitors of this pathway, Sebolt-Leopold et al. (1999) developed an in
vitro cascade assay using bacterially purified glutathione-S-transferase
fusion proteins of MEK1 and MAPK. Sebolt-Leopold et al. (1999) reported
the discovery of a highly potent and selective inhibitor of MEK1, which
they called PD184352 and which is, in fact,
2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide.
PD184352 is orally active. Tumor growth was inhibited as much as 80% in
mice with colon carcinomas of both mouse and human origin after
treatment with this inhibitor. Efficacy was achieved with a wide range
of doses (with a 50% inhibitory concentration of 17 nanomolar) with no
signs of toxicity, and correlated with a reduction in levels of MAPK in
excised tumors. Sebolt-Leopold et al. (1999) concluded that these data
indicate that MEK inhibitors represent a promising, noncytotoxic
approach to the clinical management of colon cancer.

A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD
protein that perturbs a multiplicity of signaling pathways. These
include inhibition of the extracellular signal-regulated kinase ERK,
c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein
kinase pathways and inhibition of the nuclear factor kappa B
(NF-kappa-B; see 164011) 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, MKK2 (601263), and MKK4/SEK1 (601335). 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.

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 and MEK2, and thus an
inhibitor of the RAF1/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.

ANIMAL MODEL

Giroux et al. (1999) disrupted the mouse Mek1 gene by insertional
mutagenesis. The null mutation was recessive lethal, and homozygous
mutant embryos died at 10.5 days of gestation. Histopathologic analysis
revealed a marked decrease of vascular endothelial cells in the
labyrinthine region, resulting in reduced vascularization of the
placenta. Failure to establish a functional placenta was considered a
likely cause of embryonic death. Cell migration assays indicated that
Mek1-null fibroblasts could not be induced to migrate by fibronectin
(135600), and reintroduction of Mek1 expression restored their ability
to migrate.

*FIELD* AV
.0001
CARDIOFACIOCUTANEOUS SYNDROME 3
MAP2K1, PHE53SER

In a patient with cardiofaciocutaneous syndrome (CFC3; 615279),
Rodriguez-Viciana et al. (2006) identified a T-to-C transition at
nucleotide 158 of the MEK1 gene resulting in a phenylalanine-to-serine
substitution at codon 53 (F53S). This mutation was not identified in
either of the patient's parents. Interestingly, a mutation at the
equivalent codon in MEK2 (601263) was found in another CFC patient
(F57C; 601263.0001).

By in vitro studies, Senawong et al. (2008) found that MEK1 mutants F53S
and Y130C and the MEK2 mutant F57C could not induce ERK signaling unless
phosphorylated by RAF at 2 homologous serine residues in the regulatory
loop. When these serine residues were replaced with alanines, ERK
phosphorylation was significantly reduced in the presence of RAF.
However, the F57C MEK2 mutant was less dependent on RAF signaling than
the other mutants. This difference resulted in F57C MEK2 being resistant
to the selective RAF inhibitor SB-590885. However, all 3 mutants were
sensitive to the MEK inhibitor U0126. Senawong et al. (2008) suggested
that MEK inhibition could have potential therapeutic value in CFC.

.0002
CARDIOFACIOCUTANEOUS SYNDROME 3
MAP2K1, TYR130CYS

In a patient with cardiofaciocutaneous syndrome (CFC3; 615279),
Rodriguez-Viciana et al. (2006) identified an A-to-G transition at
nucleotide 389 of the MEK1 gene, resulting in a tyrosine-to-cysteine
substitution at codon 130 (Y130C) in the protein kinase domain.

.0003
CARDIOFACIOCUTANEOUS SYNDROME 3
MAP2K1, GLY128VAL

In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Schulz
et al. (2008) identified a heterozygous 383G-T transversion in exon 3 of
the MAP2K1 gene, resulting in a gly128-to-val (G128V) substitution.

*FIELD* RF
1. Brennan, D. F.; Dar, A. C.; Hertz, N. T.; Chao, W. C. H.; Burlingame,
A. L.; Shokat, K. M.; Barford, D.: A Raf-induced allosteric transition
of KSR stimulates phosphorylation of MEK. Nature 472: 366-369, 2011.

2. Brott, B. K.; Alessandrini, A.; Largaespada, D. A.; Copeland, N.
G.; Jenkins, N. A.; Crews, C. M.; Erikson, R. L.: MEK2 is a kinase
related to MEK1 and is differentially expressed in murine tissues. Cell
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3. Chuderland, D.; Konson, A.; Seger, R.: Identification and characterization
of a general nuclear translocation signal in signaling proteins. Molec.
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4. Crews, C. M.; Alessandrini, A.; Erikson, R. L.: The primary structure
of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258:
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5. 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.

6. Giroux, S.; Tremblay, M.; Bernard, D.; Cadrin-Girard, J.-F.; Aubry,
S.; Larouche, L.; Rousseau, S.; Huot, J.; Landry, J.; Jeannotte, L.;
Charron, J.: Embryonic death of Mek1-deficient mice reveals a role
for this kinase in angiogenesis in the labyrinthine region of the
placenta. Curr. Biol. 9: 369-372, 1999.

7. Imai, J.; Katagiri, H.; Yamada, T.; Ishigaki, Y.; Suzuki, T.; Kudo,
H.; Uno, K.; Hasegawa, Y.; Gao, J.; Kaneko, K.; Ishihara, H.; Niijima,
A.; Nakazato, M.; Asano, T.; Minokoshi, Y.; Oka, Y.: Regulation of
pancreatic beta cell mass by neuronal signals from the liver. Science 322:
1250-1254, 2008.

8. Meloche, S.; Gopalbhai, K.; Beatty, B. G.; Scherer, S. W.; Pellerin,
J.: Chromosome mapping of the human genes encoding the MAP kinase
kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32. Cytogenet.
Cell Genet. 88: 249-252, 2000.

9. Nikolaev, S. I.; Rimoldi, D.; Iseli, C.; Valsesia, A.; Robyr, D.;
Gehrig, C.; Harshman, K.; Guipponi, M.; Bukach, O.; Zoete, V.; Michielin,
O.; Muehlethaler, K.; Speiser, D.; Beckmann, J. S.; Xenarios, I.;
Halazonetis, T. D.; Jongeneel, C. V.; Stevenson, B. J.; Antonarakis,
S. E.: Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2
mutations in melanoma. Nature Genet. 44: 133-139, 2012.

10. 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.

11. Perry, R. L. S.; Parker, M. H.; Rudnicki, M. A.: Activated MEK1
binds the nuclear MyoD transcriptional complex to repress transactivation. Molec.
Cell 8: 291-301, 2001.

12. 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.

13. 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.

14. Rodriguez-Viciana, P.; Tetsu, O.; Tidyman, W. E.; Estep, A. L.;
Conger, B. A.; Santa Cruz, M.; McCormick, F.; Rauen, K. A.: Germline
mutations in genes within the MAPK pathway cause cardio-facio-cutaneous
syndrome. Science 311: 1287-1290, 2006.

15. Ryan, K. M.; Ernst, M. K.; Rice, N. R.; Vousden, K. H.: Role
of NF-kappa-B in p53-mediated programmed cell death. Nature 404:
892-897, 2000.

16. Scholl, F. A.; Dumesic, P. A.; Barragan, D. I.; Harada, K.; Bissonauth,
V.; Charron, J.; Khavari, P. A.: Mek1/2 MAPK kinases are essential
for mammalian development, homeostasis, and Raf-induced hyperplasia. Dev.
Cell 12: 615-629, 2007.

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A.; Gillessen-Kaesbach, G.; Heller, R.; Horn, D.; Hubner, C. A.; Korenke,
G. C.; Konig, R.; Kress, W.; and 15 others: Mutation and phenotypic
spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin.
Genet. 73: 62-70, 2008.

18. Sebolt-Leopold, J. S.; Dudley, D. T.; Herrera, R.; Van Becelaere,
K.; Wiland, A.; Gowan, R. C.; Tecle, H.; Barrett, S. D.; Bridges,
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20. Seger, R.; Seger, D.; Lozeman, F. J.; Ahn, N. G.; Graves, L. M.;
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*FIELD* CN
Ada Hamosh - updated: 2/1/2013
Ada Hamosh - updated: 7/8/2011
Cassandra L. Kniffin - updated: 1/11/2010
Patricia A. Hartz - updated: 5/29/2009
Ada Hamosh - updated: 12/30/2008
Cassandra L. Kniffin - updated: 3/17/2008
Patricia A. Hartz - updated: 5/4/2007
Ada Hamosh - updated: 4/19/2006
Patricia A. Hartz - updated: 5/26/2005
Patricia A. Hartz - updated: 3/25/2003
Stylianos E. Antonarakis - updated: 10/23/2001
Joanna S. Amberger - updated: 3/6/2001
Paul J. Converse - updated: 3/2/2001
Paul J. Converse - updated: 4/19/2000
Ada Hamosh - updated: 9/15/1999
Ada Hamosh - updated: 7/9/1999
Victor A. McKusick - updated: 3/16/1998
Alan F. Scott - updated: 9/17/1996
Mark H. Paalman - updated: 5/20/1996
Mark H. Paalman - updated: 5/13/1996

*FIELD* CD
Victor A. McKusick: 11/2/1992

*FIELD* ED
alopez: 06/20/2013
alopez: 2/6/2013
terry: 2/1/2013
alopez: 7/12/2011
terry: 7/8/2011
wwang: 1/22/2010
ckniffin: 1/11/2010
mgross: 6/2/2009
terry: 5/29/2009
alopez: 1/5/2009
terry: 12/30/2008
wwang: 3/19/2008
ckniffin: 3/17/2008
mgross: 5/23/2007
terry: 5/4/2007
alopez: 4/20/2006
terry: 4/19/2006
mgross: 6/6/2005
terry: 5/26/2005
mgross: 3/25/2003
terry: 2/1/2002
mgross: 12/10/2001
mgross: 10/23/2001
terry: 3/7/2001
joanna: 3/6/2001
mgross: 3/2/2001
mgross: 12/5/2000
terry: 12/4/2000
alopez: 4/19/2000
alopez: 2/28/2000
carol: 9/17/1999
terry: 9/15/1999
mgross: 9/14/1999
alopez: 7/9/1999
terry: 7/9/1999
psherman: 4/21/1998
psherman: 3/16/1998
terry: 3/4/1998
mark: 3/16/1997
mark: 9/17/1996
mark: 5/20/1996
terry: 5/17/1996
mark: 5/13/1996
carol: 11/4/1994
carol: 6/9/1993
carol: 3/18/1993
carol: 12/14/1992
carol: 11/2/1992

MIM 615279
*RECORD*
*FIELD* NO
615279
*FIELD* TI
#615279 CARDIOFACIOCUTANEOUS SYNDROME 3; CFC3
*FIELD* TX
A number sign (#) is used with this entry because this form of
read morecardiofaciocutaneous syndrome (CFC3) is caused by heterozygous mutation
in the MAP2K1 gene (176872) on chromosome 15q22.31.

For a general phenotypic description and a discussion of genetic
heterogeneity of cardiofaciocutaneous syndrome, see CFC1 (115150).

DESCRIPTION

Cardiofaciocutaneous syndrome (CFC) is a complex developmental disorder
involving characteristic craniofacial features, cardiac anomalies, hair
and skin abnormalities, postnatal growth deficiency, hypotonia, and
developmental delay. Distinctive features of CFC3 include macrostomia
and horizontal shape of palpebral fissures (Schulz et al., 2008).

CLINICAL FEATURES

Rodriguez-Viciana et al. (2006) reported 3 patients with CFC3. The first
had characteristic craniofacial features, ectodermal abnormalities
(curly hair, hyperkeratosis, hyperkeratosis pilaris, and progressive
nevi formation with age), pulmonic stenosis and hypertrophic
cardiomyopathy, failure to thrive, scoliosis, pectus excavatum, diffuse
skeletal demineralization, ocular nystagmus, focal atrophy of the left
cerebral hemisphere with prominence of the lateral ventricles, seizures,
and developmental delay. The second patient had characteristic but mild
features, including few nevi and hemangiomas and mild thinning of the
corpus callosum. Both patients had hypotonia, heat intolerance, and
excessive sweating.

In a comparison of 51 individuals with CFC carrying mutations in BRAF
(164757), KRAS (190070), or MAP2K1, Schulz et al. (2008) found that
MAP2K1 mutation-positive cases show some specific features, such as
macrostomia and horizontal shape of palpebral fissures.

MOLECULAR GENETICS

In 5 of 23 CFC patients screened for BRAF mutations (22%),
Rodriguez-Viciana et al. (2006) identified no BRAF mutation. Three of
these individuals had missense mutations in MEK1 (176872) or MEK2
(601263), which encode downstream effectors of BRAF. Two individuals had
missense mutations in MEK1 and 1 had a missense mutation in MEK2. One
mutation in MEK1 was a phe53-to-ser substitution (F53S; 176872.0001);
phe53 is the equivalent position to the codon changed in the MEK2
mutation, phe57 to cys (F57C; 601263.0001). Rodriguez-Viciana et al.
(2006) suggested that substitutions of this residue may have similar
functional consequences in the 2 family isoforms. All 3 MEK mutations
were found to be more active than wildtype MEK in stimulating ERK
phosphorylation.

*FIELD* RF
1. Rodriguez-Viciana, P.; Tetsu, O.; Tidyman, W. E.; Estep, A. L.;
Conger, B. A.; Santa Cruz, M.; McCormick, F.; Rauen, K. A.: Germline
mutations in genes within the MAPK pathway cause cardio-facio-cutaneous
syndrome. Science 311: 1287-1290, 2006.

2. Schulz, A. L.; Albrecht, B.; Arici, C.; van der Burgt, I.; Buske,
A.; Gillessen-Kaesbach, G.; Heller, R.; Horn, D.; Hubner, C. A.; Korenke,
G. C.; Konig, R.; Kress, W.; and 15 others: Mutation and phenotypic
spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin.
Genet. 73: 62-70, 2008.

*FIELD* CD
Anne M. Stumpf: 6/17/2013

*FIELD* ED
alopez: 06/21/2013
alopez: 6/20/2013