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 27-MAR-2024, entry version 239. 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] RP INTERACTION WITH MOS. RX PubMed=34779126; DOI=10.15252/emmm.202114887; RA Zhang Y.L., Zheng W., Ren P., Hu H., Tong X., Zhang S.P., Li X., Wang H., RA Jiang J.C., Jin J., Yang W., Cao L., He Y., Ma Y., Zhang Y., Gu Y., Hu L., RA Luo K., Gong F., Lu G.X., Lin G., Fan H.Y., Zhang S.; RT "Biallelic mutations in MOS cause female infertility characterized by human RT early embryonic arrest and fragmentation."; RL EMBO Mol. Med. 13:e14887-e14887(2021). RN [27] RP INTERACTION WITH MOS. RX PubMed=35670744; DOI=10.1093/humrep/deac120; RA Zhang Y.L., Zheng W., Ren P., Jin J., Hu Z., Liu Q., Fan H.Y., Gong F., RA Lu G.X., Lin G., Zhang S., Tong X.; RT "Biallelic variants in MOS cause large polar body in oocyte and human RT female infertility."; RL Hum. Reprod. 37:1932-1944(2022). RN [28] {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 [29] {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 [30] {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 [31] {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 [32] {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 [33] {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 [34] {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 [35] {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 [36] {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 [37] 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 [38] 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 [39] 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). Interacts with MOS CC (PubMed:34779126, PubMed:35670744). {ECO:0000250|UniProtKB:P29678, CC ECO:0000250|UniProtKB:P31938, ECO:0000250|UniProtKB:Q01986, CC ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:17101779, CC ECO:0000269|PubMed:18329369, ECO:0000269|PubMed:19447520, CC ECO:0000269|PubMed:20679487, ECO:0000269|PubMed:20956560, CC ECO:0000269|PubMed:26195727, ECO:0000269|PubMed:29433126, CC ECO:0000269|PubMed:32721402, ECO:0000269|PubMed:34779126, CC ECO:0000269|PubMed:35670744}. 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 --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 7F2X; X-ray; 2.01 A; A=45-392. 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 PDB; 7UMB; X-ray; 3.23 A; C=35-393. DR PDB; 7XLP; X-ray; 2.10 A; A=37-383. DR PDB; 7XNC; X-ray; 2.10 A; A=37-383. DR PDB; 8DGS; EM; 4.30 A; B=1-392. DR PDB; 8DGT; EM; 3.90 A; B=1-392. 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; 7F2X; -. 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 PDBsum; 7UMB; -. DR PDBsum; 7XLP; -. DR PDBsum; 7XNC; -. DR PDBsum; 8DGS; -. DR PDBsum; 8DGT; -. DR AlphaFoldDB; Q02750; -. DR EMDB; EMD-0541; -. DR EMDB; EMD-20550; -. DR EMDB; EMD-20552; -. DR EMDB; EMD-23813; -. DR EMDB; EMD-27428; -. DR EMDB; EMD-27429; -. DR SMR; Q02750; -. DR BioGRID; 111590; 282. DR CORUM; Q02750; -. DR DIP; DIP-201N; -. DR ELM; Q02750; -. DR IntAct; Q02750; 133. 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; DB07101; Mirdametinib. 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; DB14904; Pimasertib. DR DrugBank; DB11689; Selumetinib. DR DrugBank; DB08911; Trametinib. DR DrugCentral; Q02750; -. DR GuidetoPHARMACOLOGY; 2062; -. DR CarbonylDB; Q02750; -. DR GlyGen; Q02750; 1 site, 1 O-linked glycan (1 site). 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-2939; -. DR CPTAC; CPTAC-2940; -. DR CPTAC; CPTAC-5745; -. DR CPTAC; CPTAC-808; -. DR CPTAC; CPTAC-809; -. DR CPTAC; non-CPTAC-5410; -. DR CPTAC; non-CPTAC-5411; -. DR CPTAC; non-CPTAC-5557; -. DR CPTAC; non-CPTAC-5704; -. DR EPD; Q02750; -. DR jPOST; Q02750; -. DR MassIVE; Q02750; -. DR MaxQB; Q02750; -. DR PaxDb; 9606-ENSP00000302486; -. DR PeptideAtlas; Q02750; -. DR ProteomicsDB; 58119; -. [Q02750-1] DR ProteomicsDB; 58120; -. [Q02750-2] DR Pumba; Q02750; -. DR Antibodypedia; 3542; 3873 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 AGR; HGNC:6840; -. 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; LTPYDWH; -. DR OrthoDB; 2900742at2759; -. 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; 39 hits in 1212 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 207 other cell types or tissues. DR ExpressionAtlas; Q02750; baseline and differential. DR GO; GO:0005813; C:centrosome; IEA:UniProtKB-SubCell. 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: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:0030295; F:protein kinase activator activity; IDA:GO_Central. DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc. 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:0038133; P:ERBB2-ERBB3 signaling pathway; 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:0048009; P:insulin-like growth factor receptor signaling pathway; 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:0042552; P:myelination; IEA:Ensembl. 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:0045893; P:positive regulation of DNA-templated transcription; IMP:BHF-UCL. 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:0071902; P:positive regulation of protein serine/threonine kinase activity; IDA:UniProtKB. 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:0014044; P:Schwann cell development; IEA:Ensembl. 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 GO; GO:0044342; P:type B pancreatic cell proliferation; IEA:Ensembl. DR CDD; cd06650; PKc_MEK1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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 PANTHER; PTHR47448; DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE DSOR1-LIKE PROTEIN; 1. DR PANTHER; PTHR47448:SF2; MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q02750; HS. 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:rs121908596)" 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 FT BRAF-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 FT BRAF-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 FT BRAF-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 //