MP2K1_HUMAN
ID MP2K1_HUMAN Reviewed; 393 AA.
AC Q02750;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 230.
DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 1 {ECO:0000305};
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 {ECO:0000312|HGNC:HGNC:6840}; Synonyms=MEK1, PRKMK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), PARTIAL PROTEIN SEQUENCE,
RP AND TISSUE SPECIFICITY.
RC TISSUE=T-cell;
RX PubMed=1281467; DOI=10.1016/s0021-9258(18)35648-5;
RA Seger R., Seger D., Lozeman F.J., Ahn N.G., Graves L.M., Campbell J.S.,
RA Ericsson L., Harrylock M., Jensen A.M., Krebs E.G.;
RT "Human T-cell mitogen-activated protein kinase kinases are related to yeast
RT signal transduction kinases.";
RL J. Biol. Chem. 267:25628-25631(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8388392; DOI=10.1016/s0021-9258(18)82142-1;
RA Zheng C.-F., Guan K.-L.;
RT "Cloning and characterization of two distinct human extracellular signal-
RT regulated kinase activator kinases, MEK1 and MEK2.";
RL J. Biol. Chem. 268:11435-11439(1993).
RN [3]
RP PROTEIN SEQUENCE OF 35-45; 48-57; 175-183 AND 344-353, INTERACTION WITH
RP KSR1, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-218.
RX PubMed=10409742; DOI=10.1128/mcb.19.8.5523;
RA Stewart S., Sundaram M., Zhang Y., Lee J., Han M., Guan K.L.;
RT "Kinase suppressor of Ras forms a multiprotein signaling complex and
RT modulates MEK localization.";
RL Mol. Cell. Biol. 19:5523-5534(1999).
RN [4]
RP PHOSPHORYLATION AT SER-218 AND SER-222, AND MUTAGENESIS OF LYS-97; SER-150;
RP SER-212; SER-218 AND SER-222.
RX PubMed=8131746; DOI=10.1002/j.1460-2075.1994.tb06361.x;
RA Zheng C.-F., Guan K.-L.;
RT "Activation of MEK family kinases requires phosphorylation of two conserved
RT Ser/Thr residues.";
RL EMBO J. 13:1123-1131(1994).
RN [5]
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 factor.";
RL Science 280:734-737(1998).
RN [6]
RP CLEAVAGE BY ANTHRAX LETHAL FACTOR.
RX PubMed=11104681; DOI=10.1042/bj3520739;
RA Vitale G., Bernardi L., Napolitani G., Mock M., Montecucco C.;
RT "Susceptibility of mitogen-activated protein kinase kinase family members
RT to proteolysis by anthrax lethal factor.";
RL Biochem. J. 352:739-745(2000).
RN [7]
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 [8]
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 [9]
RP INTERACTION WITH YOPJ (MICROBIAL INFECTION), 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 [10]
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 [11]
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 by
RT BRUCE.";
RL Cell 132:832-845(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-286, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [13]
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., Hur G.M.;
RT "Protein kinase SGK1 enhances MEK/ERK complex formation through the
RT phosphorylation of ERK2: implication for the positive regulatory role of
RT SGK1 on the ERK function during liver regeneration.";
RL J. Hepatol. 51:67-76(2009).
RN [14]
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 [15]
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 inversely
RT correlates with ErbB2 in human breast cancer.";
RL Mol. Cell. Biol. 30:4687-4697(2010).
RN [16]
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 [17]
RP REVIEW ON ACTIVITY 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 [18]
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 [19]
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., Buerckstuemmer T.,
RA 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 [20]
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 [21]
RP MUTAGENESIS OF LYS-97, INTERACTION WITH NEK10 AND RAF1, AND
RP PHOSPHORYLATION.
RX PubMed=20956560; DOI=10.1128/mcb.00648-10;
RA Moniz L.S., Stambolic V.;
RT "Nek10 mediates G2/M cell cycle arrest and MEK autoactivation in response
RT to UV irradiation.";
RL Mol. Cell. Biol. 31:30-42(2011).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [23]
RP INTERACTION WITH TRAF3IP3.
RX PubMed=26195727; DOI=10.1084/jem.20150110;
RA Zou Q., Jin J., Xiao Y., Hu H., Zhou X., Jie Z., Xie X., Li J.Y., Cheng X.,
RA Sun S.C.;
RT "T cell development involves TRAF3IP3-mediated ERK signaling in the
RT Golgi.";
RL J. Exp. Med. 212:1323-1336(2015).
RN [24]
RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH BRAF; KSR1 AND KSR2,
RP PHOSPHORYLATION AT SER-218 AND SER-222, AND MUTAGENESIS OF LYS-97; SER-218;
RP MET-219; ALA-220; ASN-221; SER-222 AND PHE-311.
RX PubMed=29433126; DOI=10.1038/nature25478;
RA Lavoie H., Sahmi M., Maisonneuve P., Marullo S.A., Thevakumaran N., Jin T.,
RA Kurinov I., Sicheri F., Therrien M.;
RT "MEK drives BRAF activation through allosteric control of KSR proteins.";
RL Nature 554:549-553(2018).
RN [25]
RP INTERACTION WITH MAPK1.
RX PubMed=32721402; DOI=10.1016/j.ajhg.2020.06.018;
RA Motta M., Pannone L., Pantaleoni F., Bocchinfuso G., Radio F.C.,
RA Cecchetti S., Ciolfi A., Di Rocco M., Elting M.W., Brilstra E.H., Boni S.,
RA Mazzanti L., Tamburrino F., Walsh L., Payne K., Fernandez-Jaen A.,
RA Ganapathi M., Chung W.K., Grange D.K., Dave-Wala A., Reshmi S.C.,
RA Bartholomew D.W., Mouhlas D., Carpentieri G., Bruselles A., Pizzi S.,
RA Bellacchio E., Piceci-Sparascio F., Lissewski C., Brinkmann J.,
RA Waclaw R.R., Waisfisz Q., van Gassen K., Wentzensen I.M., Morrow M.M.,
RA Alvarez S., Martinez-Garcia M., De Luca A., Memo L., Zampino G., Rossi C.,
RA Seri M., Gelb B.D., Zenker M., Dallapiccola B., Stella L., Prada C.E.,
RA Martinelli S., Flex E., Tartaglia M.;
RT "Enhanced MAPK1 function causes a neurodevelopmental disorder within the
RT RASopathy clinical spectrum.";
RL Am. J. Hum. Genet. 107:499-513(2020).
RN [26] {ECO:0007744|PDB:1S9J}
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 62-392 IN COMPLEX WITH ATP AND
RP 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., Delaney A.,
RA Omer C., Sebolt-Leopold J., Dudley D.T., Leung I.K., Flamme C., Warmus J.,
RA Kaufman M., Barrett S., Tecle H., Hasemann C.A.;
RT "Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel
RT noncompetitive kinase inhibition.";
RL Nat. Struct. Mol. Biol. 11:1192-1197(2004).
RN [27] {ECO:0007744|PDB:2P55}
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND
RP 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., Whitehead C.E.,
RA Milbank J.B., Ohren J.F., Gowan R.C., Omer C., Camp H.S., Esmaeil N.,
RA Moore K., Sebolt-Leopold J.S., Pryzbranowski S., Merriman R.L.,
RA Ortwine D.F., Warmus J.S., 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 [28] {ECO:0007744|PDB:3EQB}
RP X-RAY CRYSTALLOGRAPHY (2.62 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND
RP 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., Ohren J.,
RA Pavlovsky A., Przybranowski S., Tecle H., Valik H., Whitehead C., Zhang E.;
RT "2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl
RT benzohydroxamate esters replacements retain the desired inhibition and
RT selectivity against MEK (MAP ERK kinase).";
RL Bioorg. Med. Chem. Lett. 18:6171-6174(2008).
RN [29] {ECO:0007744|PDB:3EQC, ECO:0007744|PDB:3EQD, ECO:0007744|PDB:3EQF, ECO:0007744|PDB:3EQG, ECO:0007744|PDB:3EQH, ECO:0007744|PDB:3EQI}
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 35-393 IN COMPLEX WITH ADP AND
RP 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., Madison V.S.;
RT "Crystal structures of MEK1 binary and ternary complexes with nucleotides
RT and inhibitors.";
RL Biochemistry 48:2661-2674(2009).
RN [30] {ECO:0007744|PDB:3DV3, ECO:0007744|PDB:3DY7}
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 62-382 IN COMPLEX WITH ATP AND
RP 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., Ding Y.H.,
RA Ohren J., Moshinsky D., Coli R., Jhawar N., Bora E., Jacques-O'Hagan S.,
RA Wu J.;
RT "Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized to
RT synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other
RT than MEK?";
RL Bioorg. Med. Chem. Lett. 19:226-229(2009).
RN [31] {ECO:0007744|PDB:3E8N}
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND
RP 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 MEK1/2
RT for the treatment of cancer.";
RL Cancer Res. 69:6839-6847(2009).
RN [32] {ECO:0007744|PDB:3MBL}
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 62-382 IN COMPLEX WITH ADP AND
RP 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., Feher V.A.,
RA 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 [33] {ECO:0007744|PDB:3PP1}
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 62-382 IN COMPLEX WITH ATP AND
RP 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 inhibitor
RT for the treatment of cancer.";
RL Bioorg. Med. Chem. Lett. 21:1315-1319(2011).
RN [34] {ECO:0007744|PDB:3ORN, ECO:0007744|PDB:3OS3}
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 62-393 IN COMPLEX WITH ATP AND
RP INHIBITOR.
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., Yoshimura Y.,
RA Aida S., Miwa M., Saitoh R., Murao N., Okabe H., Belunis C., Janson C.,
RA Lukacs C., Schuck V., Shimma N.;
RT "Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an
RT orally available anticancer agent.";
RL Bioorg. Med. Chem. Lett. 21:1795-1801(2011).
RN [35]
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-facio-
RT cutaneous syndrome.";
RL Science 311:1287-1290(2006).
RN [36]
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., Spranger S.,
RA Tuysuz B., Uhrig S., Wieczorek D., Kutsche K., Zenker M.;
RT "Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous
RT and Costello syndrome.";
RL Clin. Genet. 73:62-70(2008).
RN [37]
RP INVOLVEMENT IN MEL, VARIANTS MEL PRO-56; ASN-57 AND GLU-57, AND
RP CHARACTERIZATION OF VARIANT MEL ASN-57.
RX PubMed=29643386; DOI=10.1038/s41467-018-03720-z;
RA Kang H., Jha S., Deng Z., Fratzl-Zelman N., Cabral W.A., Ivovic A.,
RA Meylan F., Hanson E.P., Lange E., Katz J., Roschger P., Klaushofer K.,
RA Cowen E.W., Siegel R.M., Marini J.C., Bhattacharyya T.;
RT "Somatic activating mutations in MAP2K1 cause melorheostosis.";
RL Nat. Commun. 9:1390-1390(2018).
CC -!- FUNCTION: Dual specificity protein kinase which acts as an essential
CC component of the MAP kinase signal transduction pathway. Binding of
CC extracellular ligands such as growth factors, cytokines and hormones to
CC their cell-surface receptors activates RAS and this initiates RAF1
CC activation. RAF1 then further activates the dual-specificity protein
CC kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2
CC function specifically in the MAPK/ERK cascade, and catalyze the
CC concomitant phosphorylation of a threonine and a tyrosine residue in a
CC Thr-Glu-Tyr sequence located in the extracellular signal-regulated
CC kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and
CC further transduction of the signal within the MAPK/ERK cascade.
CC Activates BRAF in a KSR1 or KSR2-dependent manner; by binding to KSR1
CC or KSR2 releases the inhibitory intramolecular interaction between KSR1
CC or KSR2 protein kinase and N-terminal domains which promotes KSR1 or
CC KSR2-BRAF dimerization and BRAF activation (PubMed:29433126). Depending
CC on the cellular context, this pathway mediates diverse biological
CC functions such as cell growth, adhesion, survival and differentiation,
CC predominantly through the regulation of transcription, metabolism and
CC cytoskeletal rearrangements. One target of the MAPK/ERK cascade is
CC peroxisome proliferator-activated receptor gamma (PPARG), a nuclear
CC receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has
CC been shown to export PPARG from the nucleus. The MAPK/ERK cascade is
CC also 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 the
CC Golgi apparatus during mitosis. {ECO:0000269|PubMed:14737111,
CC ECO:0000269|PubMed:17101779, ECO:0000269|PubMed:29433126}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.12.2;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.12.2;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.12.2;
CC -!- ACTIVITY REGULATION: Ras proteins such as HRAS mediate the activation
CC of RAF proteins such as RAF1 or BRAF which in turn activate
CC extracellular signal-regulated kinases (ERK) through MAPK (mitogen-
CC activated protein kinases) and ERK kinases MAP2K1/MEK1 and MAP2K2/MEK2
CC (PubMed:29433126). Activation occurs through phosphorylation of Ser-218
CC and Ser-222 (By similarity). MAP2K1/MEK1 binds KSR1 or KSR2 releasing
CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein
CC kinase and N-terminal domains (PubMed:29433126). This allows KSR1 or
CC KSR2 dimerization with BRAF leading to BRAF activation and
CC phosphorylation of MAP2K1 (PubMed:29433126). MAP2K1/MEK1 is also the
CC target of negative feed-back regulation by its substrate kinases, such
CC as MAPK1/ERK2. These phosphorylate MAP2K1/MEK1 on Thr-292, thereby
CC facilitating dephosphorylation of the activating residues Ser-218 and
CC Ser-222. Inhibited by serine/threonine phosphatase 2A (By similarity).
CC Many inhibitors have been identified including pyrrole derivatives,
CC TAK-733 (one of a series of 8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-
CC dione derivatives), CH4987655 and RDEA119/BAY 869766 (PubMed:21310613,
CC PubMed:20621728, PubMed:19706763, PubMed:19019675, PubMed:19161339,
CC PubMed:18951019, PubMed:17880056, PubMed:15543157).
CC {ECO:0000250|UniProtKB:Q01986, ECO:0000269|PubMed:15543157,
CC ECO:0000269|PubMed:17880056, ECO:0000269|PubMed:18951019,
CC ECO:0000269|PubMed:19019675, ECO:0000269|PubMed:19161339,
CC ECO:0000269|PubMed:19706763, ECO:0000269|PubMed:20621728,
CC ECO:0000269|PubMed:21310613, ECO:0000269|PubMed:29433126}.
CC -!- SUBUNIT: Found in a complex with at least BRAF, HRAS, MAP2K1,
CC MAPK3/ERK1 and RGS14 (By similarity). Forms a heterodimer with
CC MAP2K2/MEK2 (By similarity). Forms heterodimers with KSR2 which further
CC dimerize to form tetramers (By similarity). Interacts with KSR1 or KSR2
CC and BRAF; the interaction with KSR1 or KSR2 mediates KSR1-BRAF or KSR2-
CC BRAF dimerization (PubMed:10409742, PubMed:29433126). Interacts with
CC ARBB2, LAMTOR3 and RAF1 (By similarity). Interacts with MAPK1/ERK2
CC (PubMed:32721402). Interacts with MORG1 (By similarity). Interacts with
CC PPARG (PubMed:17101779). Interacts with isoform 1 of VRK2
CC (PubMed:20679487). Interacts with SGK1 (PubMed:19447520). Interacts
CC with BIRC6/bruce (PubMed:18329369). Interacts with KAT7; the
CC interaction promotes KAT7 phosphorylation (By similarity). Interacts
CC with RAF1 and NEK10; the interaction is required for ERK1/2-signaling
CC pathway activation in response to UV irradiation (PubMed:20956560).
CC Interacts with TRAF3IP3 (PubMed:26195727).
CC {ECO:0000250|UniProtKB:P29678, ECO:0000250|UniProtKB:P31938,
CC ECO:0000250|UniProtKB:Q01986, ECO:0000269|PubMed:10409742,
CC ECO:0000269|PubMed:17101779, ECO:0000269|PubMed:18329369,
CC ECO:0000269|PubMed:19447520, ECO:0000269|PubMed:20679487,
CC ECO:0000269|PubMed:20956560, ECO:0000269|PubMed:26195727,
CC ECO:0000269|PubMed:29433126, ECO:0000269|PubMed:32721402}.
CC -!- SUBUNIT: (Microbial infection) Interacts with Yersinia YopJ.
CC {ECO:0000269|PubMed:16728640}.
CC -!- INTERACTION:
CC Q02750; Q8N9N5: BANP; NbExp=3; IntAct=EBI-492564, EBI-744695;
CC Q02750; Q8N9N5-2: BANP; NbExp=3; IntAct=EBI-492564, EBI-11524452;
CC Q02750; Q9NR09: BIRC6; NbExp=2; IntAct=EBI-492564, EBI-1765160;
CC Q02750; P15056: BRAF; NbExp=62; IntAct=EBI-492564, EBI-365980;
CC Q02750; Q9Y297: BTRC; NbExp=3; IntAct=EBI-492564, EBI-307461;
CC Q02750; O15519-1: CFLAR; NbExp=3; IntAct=EBI-492564, EBI-4567563;
CC Q02750; P28482: MAPK1; NbExp=2; IntAct=EBI-492564, EBI-959949;
CC Q02750; P27361: MAPK3; NbExp=2; IntAct=EBI-492564, EBI-73995;
CC Q02750; Q13526: PIN1; NbExp=5; IntAct=EBI-492564, EBI-714158;
CC Q02750; Q9H8W4: PLEKHF2; NbExp=3; IntAct=EBI-492564, EBI-742388;
CC Q02750; P04049: RAF1; NbExp=38; IntAct=EBI-492564, EBI-365996;
CC Q02750; Q8WWU5-7: TCP11; NbExp=3; IntAct=EBI-492564, EBI-17721485;
CC Q02750; Q86Y07: VRK2; NbExp=2; IntAct=EBI-492564, EBI-1207615;
CC Q02750; Q86Y07-1: VRK2; NbExp=2; IntAct=EBI-492564, EBI-1207633;
CC Q02750; P46937: YAP1; NbExp=3; IntAct=EBI-492564, EBI-1044059;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, microtubule organizing
CC center, centrosome {ECO:0000269|PubMed:14737111}. Cytoplasm,
CC cytoskeleton, microtubule organizing center, spindle pole body
CC {ECO:0000269|PubMed:14737111}. Cytoplasm {ECO:0000269|PubMed:10409742,
CC ECO:0000269|PubMed:17101779}. Nucleus {ECO:0000269|PubMed:17101779}.
CC Membrane {ECO:0000269|PubMed:10409742}; Peripheral membrane protein
CC {ECO:0000269|PubMed:10409742}. Note=Localizes at centrosomes during
CC prometaphase, midzone during anaphase and midbody during
CC telophase/cytokinesis (PubMed:14737111). Membrane localization is
CC probably regulated by its interaction with KSR1 (PubMed:10409742).
CC {ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:14737111}.
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. {ECO:0000269|PubMed:1281467}.
CC -!- DOMAIN: The proline-rich region localized between residues 270 and 307
CC is important for binding to RAF1 and activation of MAP2K1/MEK1.
CC {ECO:0000250}.
CC -!- PTM: Phosphorylation at Ser-218 and Ser-222 by MAP kinase kinase
CC kinases (BRAF or MEKK1) positively regulates kinase activity
CC (PubMed:29433126, PubMed:8131746). Also phosphorylated at Thr-292 by
CC MAPK1/ERK2 and at Ser-298 by PAK (PubMed:16129686). MAPK1/ERK2
CC phosphorylation of Thr-292 occurs in response to cellular adhesion and
CC leads to inhibition of Ser-298 phosphorylation by PAK
CC (PubMed:16129686). Autophosphorylated at Ser-218 and Ser-222,
CC autophosphosphorylation is promoted by NEK10 following UV irradiation
CC (PubMed:20956560). {ECO:0000269|PubMed:16129686,
CC ECO:0000269|PubMed:20956560, ECO:0000269|PubMed:29433126,
CC ECO:0000269|PubMed:8131746}.
CC -!- PTM: (Microbial infection) Acetylation by Yersinia YopJ prevents
CC phosphorylation and activation, thus blocking the MAPK signaling
CC pathway. {ECO:0000269|PubMed:16728640}.
CC -!- DISEASE: Cardiofaciocutaneous syndrome 3 (CFC3) [MIM:615279]: A form of
CC cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder
CC characterized by a distinctive facial appearance, heart defects and
CC intellectual disability. Heart defects include pulmonic stenosis,
CC atrial septal defects and hypertrophic cardiomyopathy. Some affected
CC individuals present with ectodermal abnormalities such as sparse,
CC friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-
CC like condition. Typical facial features are similar to Noonan syndrome.
CC They include high forehead with bitemporal constriction, hypoplastic
CC supraorbital ridges, downslanting palpebral fissures, a depressed nasal
CC bridge, and posteriorly angulated ears with prominent helices.
CC Distinctive features of CFC3 include macrostomia and horizontal shape
CC of palpebral fissures. {ECO:0000269|PubMed:16439621,
CC ECO:0000269|PubMed:18042262}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Melorheostosis, isolated (MEL) [MIM:155950]: A sclerosing bone
CC disorder characterized by hyperostosis of the cortex of tubular bones,
CC frequently involving one limb. The lesions may be accompanied by
CC abnormalities of adjacent soft tissue, joint contractures,
CC sclerodermatous skin lesions, muscle atrophy, or hemangioma.
CC {ECO:0000269|PubMed:29643386}. Note=The disease is caused by variants
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. {ECO:0000305}.
CC ---------------------------------------------------------------------------
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DR EMBL; L05624; AAA36318.1; -; mRNA.
DR EMBL; L11284; -; NOT_ANNOTATED_CDS; mRNA.
DR CCDS; CCDS10216.1; -. [Q02750-1]
DR PIR; A45100; A45100.
DR RefSeq; NP_002746.1; NM_002755.3. [Q02750-1]
DR RefSeq; XP_016877900.1; XM_017022411.1. [Q02750-2]
DR PDB; 1S9J; X-ray; 2.40 A; A=62-393.
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=45-263, A/B=308-383.
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; 3W8Q; X-ray; 2.20 A; A=39-382.
DR PDB; 3WIG; X-ray; 2.70 A; A=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 PDB; 4MNE; X-ray; 2.85 A; A/D/E/H=62-393.
DR PDB; 4U7Z; X-ray; 2.80 A; A=62-393.
DR PDB; 4U80; X-ray; 2.80 A; A=62-393.
DR PDB; 4U81; X-ray; 2.70 A; A=62-393.
DR PDB; 5BX0; X-ray; 2.93 A; A=37-383.
DR PDB; 5EYM; X-ray; 2.70 A; A/B=35-393.
DR PDB; 5HZE; X-ray; 2.40 A; A=37-383.
DR PDB; 5YT3; X-ray; 2.90 A; A/B/C/D=39-382.
DR PDB; 6NYB; EM; 4.10 A; B=1-393.
DR PDB; 6PP9; X-ray; 2.59 A; B=1-393.
DR PDB; 6Q0J; EM; 4.90 A; C/D=1-393.
DR PDB; 6Q0T; EM; 5.70 A; C=1-392.
DR PDB; 6U2G; X-ray; 2.89 A; A=2-393.
DR PDB; 6V2W; X-ray; 3.12 A; B=1-393.
DR PDB; 6X2P; X-ray; 2.40 A; D=28-44.
DR PDB; 6X2S; X-ray; 2.50 A; D=29-44.
DR PDB; 6X2X; X-ray; 2.46 A; D=29-44.
DR PDB; 7B3M; X-ray; 2.30 A; A/B=37-263, A/B=308-383.
DR PDB; 7B7R; X-ray; 1.70 A; A/B=37-263, A/B=308-383.
DR PDB; 7B94; X-ray; 2.00 A; A/B=37-263, A/B=308-383.
DR PDB; 7B9L; X-ray; 1.70 A; A/B=37-263, A/B=308-383.
DR PDB; 7M0T; X-ray; 3.19 A; B=1-393.
DR PDB; 7M0U; X-ray; 3.09 A; B=1-393.
DR PDB; 7M0V; X-ray; 3.16 A; B=1-393.
DR PDB; 7M0W; X-ray; 3.09 A; B=1-393.
DR PDB; 7M0X; X-ray; 2.47 A; B=1-393.
DR PDB; 7M0Y; X-ray; 3.45 A; B=1-393.
DR PDB; 7M0Z; X-ray; 3.12 A; B=1-393.
DR PDB; 7MFD; EM; 3.66 A; B=1-393.
DR PDB; 7PQV; X-ray; 2.13 A; A=39-382.
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; 3W8Q; -.
DR PDBsum; 3WIG; -.
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 PDBsum; 4MNE; -.
DR PDBsum; 4U7Z; -.
DR PDBsum; 4U80; -.
DR PDBsum; 4U81; -.
DR PDBsum; 5BX0; -.
DR PDBsum; 5EYM; -.
DR PDBsum; 5HZE; -.
DR PDBsum; 5YT3; -.
DR PDBsum; 6NYB; -.
DR PDBsum; 6PP9; -.
DR PDBsum; 6Q0J; -.
DR PDBsum; 6Q0T; -.
DR PDBsum; 6U2G; -.
DR PDBsum; 6V2W; -.
DR PDBsum; 6X2P; -.
DR PDBsum; 6X2S; -.
DR PDBsum; 6X2X; -.
DR PDBsum; 7B3M; -.
DR PDBsum; 7B7R; -.
DR PDBsum; 7B94; -.
DR PDBsum; 7B9L; -.
DR PDBsum; 7M0T; -.
DR PDBsum; 7M0U; -.
DR PDBsum; 7M0V; -.
DR PDBsum; 7M0W; -.
DR PDBsum; 7M0X; -.
DR PDBsum; 7M0Y; -.
DR PDBsum; 7M0Z; -.
DR PDBsum; 7MFD; -.
DR PDBsum; 7PQV; -.
DR AlphaFoldDB; Q02750; -.
DR SMR; Q02750; -.
DR BioGRID; 111590; 255.
DR CORUM; Q02750; -.
DR DIP; DIP-201N; -.
DR ELM; Q02750; -.
DR IntAct; Q02750; 132.
DR MINT; Q02750; -.
DR STRING; 9606.ENSP00000302486; -.
DR BindingDB; Q02750; -.
DR ChEMBL; CHEMBL3587; -.
DR DrugBank; DB06892; (5S)-4,5-difluoro-6-[(2-fluoro-4-iodophenyl)imino]-N-(2-hydroxyethoxy)cyclohexa-1,3-diene-1-carboxamide.
DR DrugBank; DB07046; 2-[(2-chloro-4-iodophenyl)amino]-N-{[(2R)-2,3-dihydroxypropyl]oxy}-3,4-difluorobenzamide.
DR DrugBank; DB08208; 2-[(4-ETHYNYL-2-FLUOROPHENYL)AMINO]-3,4-DIFLUORO-N-(2-HYDROXYETHOXY)BENZAMIDE.
DR DrugBank; DB03115; 5-Bromo-N-[(2S)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzamide.
DR DrugBank; DB06616; Bosutinib.
DR DrugBank; DB05239; Cobimetinib.
DR DrugBank; DB02152; K-252a.
DR DrugBank; DB08130; N-(5-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}-1,3,4-oxadiazol-2-yl)ethane-1,2-diamine.
DR DrugBank; DB07101; PD-0325901.
DR DrugBank; DB11689; Selumetinib.
DR DrugBank; DB08911; Trametinib.
DR DrugCentral; Q02750; -.
DR GuidetoPHARMACOLOGY; 2062; -.
DR CarbonylDB; Q02750; -.
DR iPTMnet; Q02750; -.
DR PhosphoSitePlus; Q02750; -.
DR SwissPalm; Q02750; -.
DR BioMuta; MAP2K1; -.
DR DMDM; 400274; -.
DR CPTAC; CPTAC-1544; -.
DR CPTAC; CPTAC-1545; -.
DR CPTAC; CPTAC-808; -.
DR CPTAC; CPTAC-809; -.
DR EPD; Q02750; -.
DR jPOST; Q02750; -.
DR MassIVE; Q02750; -.
DR MaxQB; Q02750; -.
DR PaxDb; Q02750; -.
DR PeptideAtlas; Q02750; -.
DR PRIDE; Q02750; -.
DR ProteomicsDB; 58119; -. [Q02750-1]
DR ProteomicsDB; 58120; -. [Q02750-2]
DR Antibodypedia; 3542; 3527 antibodies from 51 providers.
DR CPTC; Q02750; 2 antibodies.
DR DNASU; 5604; -.
DR Ensembl; ENST00000307102.10; ENSP00000302486.5; ENSG00000169032.11. [Q02750-1]
DR GeneID; 5604; -.
DR KEGG; hsa:5604; -.
DR MANE-Select; ENST00000307102.10; ENSP00000302486.5; NM_002755.4; NP_002746.1.
DR UCSC; uc010bhq.4; human. [Q02750-1]
DR CTD; 5604; -.
DR DisGeNET; 5604; -.
DR GeneCards; MAP2K1; -.
DR GeneReviews; MAP2K1; -.
DR HGNC; HGNC:6840; MAP2K1.
DR HPA; ENSG00000169032; Low tissue specificity.
DR MalaCards; MAP2K1; -.
DR MIM; 155950; phenotype.
DR MIM; 176872; gene.
DR MIM; 615279; phenotype.
DR neXtProt; NX_Q02750; -.
DR OpenTargets; ENSG00000169032; -.
DR Orphanet; 1340; Cardiofaciocutaneous syndrome.
DR Orphanet; 389; Langerhans cell histiocytosis.
DR PharmGKB; PA30584; -.
DR VEuPathDB; HostDB:ENSG00000169032; -.
DR eggNOG; KOG0581; Eukaryota.
DR GeneTree; ENSGT00940000153487; -.
DR InParanoid; Q02750; -.
DR OMA; EAWASTF; -.
DR PhylomeDB; Q02750; -.
DR TreeFam; TF105137; -.
DR BRENDA; 2.7.12.2; 2681.
DR PathwayCommons; Q02750; -.
DR Reactome; R-HSA-110056; MAPK3 (ERK1) activation.
DR Reactome; R-HSA-170968; Frs2-mediated activation.
DR Reactome; R-HSA-445144; Signal transduction by L1.
DR Reactome; R-HSA-5210891; Uptake and function of anthrax toxins.
DR Reactome; R-HSA-5673000; RAF activation.
DR Reactome; R-HSA-5674135; MAP2K and MAPK activation.
DR Reactome; R-HSA-5674499; Negative feedback regulation of MAPK pathway.
DR Reactome; R-HSA-5684264; MAP3K8 (TPL2)-dependent MAPK1/3 activation.
DR Reactome; R-HSA-6802946; Signaling by moderate kinase activity BRAF mutants.
DR Reactome; R-HSA-6802948; Signaling by high-kinase activity BRAF mutants.
DR Reactome; R-HSA-6802952; Signaling by BRAF and RAF1 fusions.
DR Reactome; R-HSA-6802955; Paradoxical activation of RAF signaling by kinase inactive BRAF.
DR Reactome; R-HSA-9649948; Signaling downstream of RAS mutants.
DR Reactome; R-HSA-9652169; Signaling by MAP2K mutants.
DR Reactome; R-HSA-9656223; Signaling by RAF1 mutants.
DR SignaLink; Q02750; -.
DR SIGNOR; Q02750; -.
DR BioGRID-ORCS; 5604; 37 hits in 1122 CRISPR screens.
DR ChiTaRS; MAP2K1; human.
DR EvolutionaryTrace; Q02750; -.
DR GeneWiki; MAP2K1; -.
DR GenomeRNAi; 5604; -.
DR Pharos; Q02750; Tclin.
DR PRO; PR:Q02750; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q02750; protein.
DR Bgee; ENSG00000169032; Expressed in secondary oocyte and 206 other tissues.
DR ExpressionAtlas; Q02750; baseline and differential.
DR Genevisible; Q02750; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005769; C:early endosome; TAS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
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:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; TAS:UniProtKB.
DR GO; GO:0005634; C:nucleus; TAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004708; F:MAP kinase kinase activity; IDA:UniProtKB.
DR GO; GO:0005078; F:MAP-kinase scaffold activity; IMP:UniProtKB.
DR GO; GO:0008022; F:protein C-terminus binding; IDA:MGI.
DR GO; GO:0030295; F:protein kinase activator activity; IDA:GO_Central.
DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR GO; GO:0047485; F:protein N-terminus binding; IDA:MGI.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
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:0004712; F:protein serine/threonine/tyrosine kinase activity; TAS:UniProtKB.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0097110; F:scaffold protein binding; IPI:UniProtKB.
DR GO; GO:0060020; P:Bergmann glial cell differentiation; IEA:Ensembl.
DR GO; GO:0048870; P:cell motility; IEA:Ensembl.
DR GO; GO:0090398; P:cellular senescence; IMP:BHF-UCL.
DR GO; GO:0021697; P:cerebellar cortex formation; IEA:Ensembl.
DR GO; GO:0006935; P:chemotaxis; TAS:ProtInc.
DR GO; GO:0035987; P:endodermal cell differentiation; IEA:Ensembl.
DR GO; GO:0060502; P:epithelial cell proliferation involved in lung morphogenesis; IEA:Ensembl.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; TAS:Reactome.
DR GO; GO:0060324; P:face development; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0030216; P:keratinocyte differentiation; IEA:Ensembl.
DR GO; GO:0060711; P:labyrinthine layer development; IEA:Ensembl.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:BHF-UCL.
DR GO; GO:0030182; P:neuron differentiation; IBA:GO_Central.
DR GO; GO:0060674; P:placenta blood vessel development; IEA:Ensembl.
DR GO; GO:0050772; P:positive regulation of axonogenesis; IEA:Ensembl.
DR GO; GO:1903226; P:positive regulation of endodermal cell differentiation; IEA:Ensembl.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:BHF-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
DR GO; GO:1903800; P:positive regulation of miRNA maturation; IMP:BHF-UCL.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:BHF-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IDA:FlyBase.
DR GO; GO:0048679; P:regulation of axon regeneration; IEA:Ensembl.
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:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0048538; P:thymus development; IEA:Ensembl.
DR GO; GO:0030878; P:thyroid gland development; IEA:Ensembl.
DR GO; GO:0060440; P:trachea formation; IEA:Ensembl.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
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; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Disease variant; Ectodermal dysplasia; Intellectual disability; Kinase;
KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Tyrosine-protein kinase.
FT CHAIN 1..393
FT /note="Dual specificity mitogen-activated protein kinase
FT kinase 1"
FT /id="PRO_0000086365"
FT DOMAIN 68..361
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..27
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 270..307
FT /note="RAF1-binding"
FT /evidence="ECO:0000269|PubMed:20956560"
FT ACT_SITE 190
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 74..82
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:15543157, ECO:0000269|PubMed:17880056,
FT ECO:0000269|PubMed:18951019, ECO:0000269|PubMed:19019675,
FT ECO:0000269|PubMed:19706763, ECO:0000269|PubMed:21310613"
FT BINDING 97
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:15543157, ECO:0000269|PubMed:17880056,
FT ECO:0000269|PubMed:18951019, ECO:0000269|PubMed:19019675,
FT ECO:0000269|PubMed:19706763, ECO:0000269|PubMed:21310613"
FT BINDING 97
FT /ligand="U0126"
FT /ligand_id="ChEBI:CHEBI:90693"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:19161339,
FT ECO:0007744|PDB:3EQH"
FT BINDING 143..146
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:15543157, ECO:0000269|PubMed:17880056,
FT ECO:0000269|PubMed:18951019, ECO:0000269|PubMed:19019675,
FT ECO:0000269|PubMed:19706763, ECO:0000269|PubMed:21310613"
FT BINDING 144..146
FT /ligand="K-252a"
FT /ligand_id="ChEBI:CHEBI:43616"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:19161339,
FT ECO:0007744|PDB:3EQF"
FT BINDING 150..153
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:15543157, ECO:0000269|PubMed:17880056,
FT ECO:0000269|PubMed:18951019, ECO:0000269|PubMed:19019675,
FT ECO:0000269|PubMed:19706763, ECO:0000269|PubMed:21310613"
FT BINDING 192..195
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:15543157, ECO:0000269|PubMed:17880056,
FT ECO:0000269|PubMed:18951019, ECO:0000269|PubMed:19019675,
FT ECO:0000269|PubMed:19706763, ECO:0000269|PubMed:21310613"
FT BINDING 194
FT /ligand="K-252a"
FT /ligand_id="ChEBI:CHEBI:43616"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:19161339,
FT ECO:0007744|PDB:3EQF"
FT BINDING 208..211
FT /ligand="U0126"
FT /ligand_id="ChEBI:CHEBI:90693"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:19161339,
FT ECO:0007744|PDB:3EQH"
FT BINDING 208
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000269|PubMed:15543157, ECO:0000269|PubMed:17880056,
FT ECO:0000269|PubMed:18951019, ECO:0000269|PubMed:19019675,
FT ECO:0000269|PubMed:19706763, ECO:0000269|PubMed:21310613"
FT SITE 8..9
FT /note="Cleavage; by anthrax lethal factor"
FT MOD_RES 218
FT /note="Phosphoserine; by BRAF and RAF1"
FT /evidence="ECO:0000269|PubMed:10409742,
FT ECO:0000269|PubMed:20956560, ECO:0000269|PubMed:29433126,
FT ECO:0000269|PubMed:8131746"
FT MOD_RES 222
FT /note="Phosphoserine; by BRAF and RAF1"
FT /evidence="ECO:0000269|PubMed:20956560,
FT ECO:0000269|PubMed:29433126, ECO:0000269|PubMed:8131746"
FT MOD_RES 286
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18691976"
FT MOD_RES 292
FT /note="Phosphothreonine; by MAPK1"
FT /evidence="ECO:0000250|UniProtKB:Q01986"
FT MOD_RES 298
FT /note="Phosphoserine; by PAK"
FT /evidence="ECO:0000269|PubMed:16129686"
FT VAR_SEQ 147..172
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:1281467"
FT /id="VSP_040500"
FT VARIANT 53
FT /note="F -> S (in CFC3; dbSNP:rs121908594)"
FT /evidence="ECO:0000269|PubMed:16439621"
FT /id="VAR_035093"
FT VARIANT 56
FT /note="Q -> P (in MEL; somatic mutation;
FT dbSNP:rs1057519729)"
FT /evidence="ECO:0000269|PubMed:29643386"
FT /id="VAR_084452"
FT VARIANT 57
FT /note="K -> E (in MEL; somatic mutation;
FT dbSNP:rs397516790)"
FT /evidence="ECO:0000269|PubMed:29643386"
FT /id="VAR_084453"
FT VARIANT 57
FT /note="K -> N (in MEL; somatic mutation; results in
FT increased MAPK signal transduction; dbSNP:rs869025608)"
FT /evidence="ECO:0000269|PubMed:29643386"
FT /id="VAR_084454"
FT VARIANT 128
FT /note="G -> V (in CFC3; dbSNP:rs730880508)"
FT /evidence="ECO:0000269|PubMed:18042262"
FT /id="VAR_069780"
FT VARIANT 130
FT /note="Y -> C (in CFC3; dbSNP:rs121908595)"
FT /evidence="ECO:0000269|PubMed:16439621"
FT /id="VAR_035094"
FT MUTAGEN 97
FT /note="K->A: Loss of catalytic activity. Strongly reduces
FT phosphorylation upon UV irradiation."
FT /evidence="ECO:0000269|PubMed:20956560"
FT MUTAGEN 97
FT /note="K->R: Loss of catalytic activity. No effect on BRAF-
FT KSR1 or BRAF-KSR2 dimerization."
FT /evidence="ECO:0000269|PubMed:29433126,
FT ECO:0000269|PubMed:8131746"
FT MUTAGEN 150
FT /note="S->A: No loss of activity."
FT /evidence="ECO:0000269|PubMed:8131746"
FT MUTAGEN 212
FT /note="S->A: No loss of activity."
FT /evidence="ECO:0000269|PubMed:8131746"
FT MUTAGEN 218
FT /note="S->A: Loss of catalytic activity. No effect on BRAF-
FT KSR1 dimerization; when associated with A-222."
FT /evidence="ECO:0000269|PubMed:29433126,
FT ECO:0000269|PubMed:8131746"
FT MUTAGEN 218
FT /note="S->D: No effect on BRAF-KSR1 dimerization; when
FT associated with D-222."
FT /evidence="ECO:0000269|PubMed:29433126"
FT MUTAGEN 219
FT /note="M->V: Increases interaction with KSR1 and BRAF."
FT /evidence="ECO:0000269|PubMed:29433126"
FT MUTAGEN 219
FT /note="M->W: Increases interaction with KSR1 and BRAF; when
FT associated with L-220."
FT /evidence="ECO:0000269|PubMed:29433126"
FT MUTAGEN 220
FT /note="A->L: Increases interaction with KSR1 and BRAF; when
FT associated with w-219."
FT /evidence="ECO:0000269|PubMed:29433126"
FT MUTAGEN 221
FT /note="N->Y: Increases interaction with KSR1 and BRAF."
FT /evidence="ECO:0000269|PubMed:29433126"
FT MUTAGEN 222
FT /note="S->A: Loss of catalytic activity. No effect on BRAF-
FT KSR1 dimerization; when associated with A-218."
FT /evidence="ECO:0000269|PubMed:29433126,
FT ECO:0000269|PubMed:8131746"
FT MUTAGEN 222
FT /note="S->D: No effect on BRAF-KSR1 dimerization; when
FT associated with D-218."
FT /evidence="ECO:0000269|PubMed:29433126"
FT MUTAGEN 311
FT /note="F->S: Loss of interaction with BRAF and KSR1. Loss
FT of BRAF-KSR1 dimerization."
FT /evidence="ECO:0000269|PubMed:29433126"
FT CONFLICT 52
FT /note="A -> R (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 180
FT /note="Missing (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 38..40
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 44..57
FT /evidence="ECO:0007829|PDB:7B7R"
FT TURN 58..60
FT /evidence="ECO:0007829|PDB:3ZLY"
FT HELIX 65..67
FT /evidence="ECO:0007829|PDB:7B7R"
FT STRAND 68..76
FT /evidence="ECO:0007829|PDB:7B7R"
FT STRAND 78..87
FT /evidence="ECO:0007829|PDB:7B7R"
FT TURN 88..91
FT /evidence="ECO:0007829|PDB:7B7R"
FT STRAND 92..100
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 105..115
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 116..120
FT /evidence="ECO:0007829|PDB:7B7R"
FT STRAND 129..135
FT /evidence="ECO:0007829|PDB:7B7R"
FT STRAND 138..144
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 151..158
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 163..184
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 193..195
FT /evidence="ECO:0007829|PDB:7B7R"
FT STRAND 196..198
FT /evidence="ECO:0007829|PDB:7B7R"
FT TURN 200..202
FT /evidence="ECO:0007829|PDB:3DY7"
FT STRAND 204..206
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 213..218
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 221..223
FT /evidence="ECO:0007829|PDB:3VVH"
FT HELIX 227..229
FT /evidence="ECO:0007829|PDB:4AN3"
FT HELIX 232..236
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 242..258
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 268..275
FT /evidence="ECO:0007829|PDB:3EQC"
FT HELIX 310..319
FT /evidence="ECO:0007829|PDB:7B7R"
FT TURN 327..329
FT /evidence="ECO:0007829|PDB:7B9L"
FT HELIX 332..341
FT /evidence="ECO:0007829|PDB:7B7R"
FT TURN 346..348
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 352..356
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 359..366
FT /evidence="ECO:0007829|PDB:7B7R"
FT HELIX 371..379
FT /evidence="ECO:0007829|PDB:7B7R"
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
