ID MP2K2_HUMAN Reviewed; 400 AA. AC P36507; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1994, sequence version 1. DT 02-SEP-2026, entry version 254. DE RecName: Full=Dual specificity mitogen-activated protein kinase kinase 2; DE Short=MAP kinase kinase 2; DE Short=MAPKK 2; DE EC=2.7.12.2 {ECO:0000269|PubMed:10409742}; DE AltName: Full=ERK activator kinase 2; DE AltName: Full=MAPK/ERK kinase 2; DE Short=MEK 2; GN Name=MAP2K2; Synonyms=MEK2, MKK2, PRKMK2; 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]. 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Muscle, and Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP PROTEIN SEQUENCE OF 40-51; 53-61; 64-100; 102-112; 164-172; 194-205; RP 265-297; 362-371 AND 389-397, PHOSPHORYLATION AT THR-394, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Colon carcinoma; RA Bienvenut W.V., Zebisch A., Kolch W.; RL Submitted (DEC-2008) to UniProtKB. RN [4] RP PROTEIN SEQUENCE OF 210-231, INACTIVATION BY YERSINIA YOPJ (MICROBIAL RP INFECTION), PHOSPHORYLATION AT SER-222 AND SER-226, ACETYLATION AT SER-222 RP AND SER-226, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=17116858; DOI=10.1073/pnas.0608995103; RA Mittal R., Peak-Chew S.Y., McMahon H.T.; RT "Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by RT YopJ inhibits signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 103:18574-18579(2006). RN [5] RP CLEAVAGE BY ANTHRAX LETHAL FACTOR. 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 PROTEIN SEQUENCE OF 39-49; 52-61 AND 352-361, CATALYTIC ACTIVITY, COFACTOR, RP INTERACTION WITH KSR1, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT RP SER-222. 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 [7] 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 [8] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Platelet; RX PubMed=18088087; DOI=10.1021/pr0704130; RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., RA Schuetz C., Walter U., Gambaryan S., Sickmann A.; RT "Phosphoproteome of resting human platelets."; RL J. Proteome Res. 7:526-534(2008). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-293 AND SER-295, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [12] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). 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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-295 AND THR-394, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [17] 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 [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [19] RP INTERACTION WITH GLS. RX PubMed=22538822; DOI=10.1073/pnas.1116573109; RA Thangavelu K., Pan C.Q., Karlberg T., Balaji G., Uttamchandani M., RA Suresh V., Schuler H., Low B.C., Sivaraman J.; RT "Structural basis for the allosteric inhibitory mechanism of human kidney- RT type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in RT cancer cell metabolism."; RL Proc. Natl. Acad. Sci. U.S.A. 109:7705-7710(2012). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-394 AND THR-396, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-23 AND THR-396, AND 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 [22] RP FUNCTION, AND INTERACTION WITH BRAF AND KSR1. 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 [23] RP VARIANT CFC4 CYS-57. 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 [24] RP VARIANTS CFC4 VAL-57 AND HIS-134. 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 [25] RP VARIANT CFC4 GLN-128, AND CHARACTERIZATION OF VARIANT CFC4 GLN-128. RX PubMed=20358587; DOI=10.1002/ajmg.a.33342; RA Rauen K.A., Tidyman W.E., Estep A.L., Sampath S., Peltier H.M., Bale S.J., RA Lacassie Y.; RT "Molecular and functional analysis of a novel MEK2 mutation in cardio- RT facio-cutaneous syndrome: transmission through four generations."; RL Am. J. Med. Genet. A 152:807-814(2010). CC -!- FUNCTION: Catalyzes the concomitant phosphorylation of a threonine and CC a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. CC Activates the ERK1 and ERK2 MAP kinases (By similarity). Activates BRAF CC in a KSR1 or KSR2-dependent manner; by binding to KSR1 or KSR2 releases CC the inhibitory intramolecular interaction between KSR1 or KSR2 protein CC kinase and N-terminal domains which promotes KSR1 or KSR2-BRAF CC dimerization and BRAF activation (PubMed:29433126). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:29433126}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + CC H(+); 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 Evidence={ECO:0000269|PubMed:10409742}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA- CC COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.12.2; CC Evidence={ECO:0000269|PubMed:10409742}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:20101, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:61978, ChEBI:CHEBI:456216; EC=2.7.12.2; CC Evidence={ECO:0000269|PubMed:10409742}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:10409742}; CC -!- SUBUNIT: Interacts with MORG1 (By similarity). Interacts with SGK1 CC (PubMed:19447520). Interacts with KSR1 (PubMed:10409742). Interacts CC with KSR1 and BRAF; the interaction with KSR1 mediates KSR1-BRAF CC dimerization (PubMed:29433126). Interacts with GLS (PubMed:22538822). CC {ECO:0000250|UniProtKB:Q63932, ECO:0000269|PubMed:10409742, CC ECO:0000269|PubMed:19447520, ECO:0000269|PubMed:22538822, CC ECO:0000269|PubMed:29433126}. CC -!- INTERACTION: CC P36507; Q99767: APBA2; NbExp=2; IntAct=EBI-1056930, EBI-81711; CC P36507; O96018: APBA3; NbExp=3; IntAct=EBI-1056930, EBI-6115839; CC P36507; P05067: APP; NbExp=3; IntAct=EBI-1056930, EBI-77613; CC P36507; P10398: ARAF; NbExp=10; IntAct=EBI-1056930, EBI-365961; CC P36507; Q96II5: ARAF; NbExp=4; IntAct=EBI-1056930, EBI-9383168; CC P36507; P15056: BRAF; NbExp=13; IntAct=EBI-1056930, EBI-365980; CC P36507; O95273: CCNDBP1; NbExp=3; IntAct=EBI-1056930, EBI-748961; CC P36507; Q12959: DLG1; NbExp=12; IntAct=EBI-1056930, EBI-357481; CC P36507; Q15700: DLG2; NbExp=2; IntAct=EBI-1056930, EBI-80426; CC P36507; Q92796: DLG3; NbExp=3; IntAct=EBI-1056930, EBI-80440; CC P36507; P78352: DLG4; NbExp=3; IntAct=EBI-1056930, EBI-80389; CC P36507; Q8TDM6: DLG5; NbExp=2; IntAct=EBI-1056930, EBI-715138; CC P36507; Q68DX3: FRMPD2; NbExp=3; IntAct=EBI-1056930, EBI-53993476; CC P36507; A4D2P6: GRID2IP; NbExp=2; IntAct=EBI-1056930, EBI-15893226; CC P36507; Q9Y3R0: GRIP1; NbExp=7; IntAct=EBI-1056930, EBI-5349621; CC P36507; Q9C0E4: GRIP2; NbExp=7; IntAct=EBI-1056930, EBI-949557; CC P36507; P61978-2: HNRNPK; NbExp=3; IntAct=EBI-1056930, EBI-7060731; CC P36507; Q14005: IL16; NbExp=4; IntAct=EBI-1056930, EBI-2831580; CC P36507; Q8IVT5: KSR1; NbExp=10; IntAct=EBI-1056930, EBI-486984; CC P36507; Q8N448: LNX2; NbExp=3; IntAct=EBI-1056930, EBI-2340947; CC P36507; Q96QZ7: MAGI1; NbExp=6; IntAct=EBI-1056930, EBI-924464; CC P36507; Q86UL8: MAGI2; NbExp=2; IntAct=EBI-1056930, EBI-311035; CC P36507; Q5TCQ9: MAGI3; NbExp=5; IntAct=EBI-1056930, EBI-310506; CC P36507; P00540: MOS; NbExp=3; IntAct=EBI-1056930, EBI-1757866; CC P36507; O75970: MPDZ; NbExp=12; IntAct=EBI-1056930, EBI-821405; CC P36507; Q15599: NHERF2; NbExp=2; IntAct=EBI-1056930, EBI-1149760; CC P36507; Q86UT5: NHERF4; NbExp=3; IntAct=EBI-1056930, EBI-8744528; CC P36507; Q8TEW0: PARD3; NbExp=2; IntAct=EBI-1056930, EBI-81968; CC P36507; Q8TEW8: PARD3B; NbExp=3; IntAct=EBI-1056930, EBI-2861929; CC P36507; Q8NI35: PATJ; NbExp=9; IntAct=EBI-1056930, EBI-724390; CC P36507; O15018: PDZD2; NbExp=5; IntAct=EBI-1056930, EBI-310669; CC P36507; Q9H5P4: PDZD7; NbExp=3; IntAct=EBI-1056930, EBI-20859318; CC P36507; Q5T2W1: PDZK1; NbExp=4; IntAct=EBI-1056930, EBI-349819; CC P36507; Q9UPQ7: PDZRN3; NbExp=2; IntAct=EBI-1056930, EBI-11329693; CC P36507; Q6ZMN7: PDZRN4; NbExp=2; IntAct=EBI-1056930, EBI-1222628; CC P36507; Q70Z35: PREX2; NbExp=2; IntAct=EBI-1056930, EBI-1790593; CC P36507; Q12923: PTPN13; NbExp=4; IntAct=EBI-1056930, EBI-355227; CC P36507; P04049: RAF1; NbExp=7; IntAct=EBI-1056930, EBI-365996; CC P36507; Q14160: SCRIB; NbExp=4; IntAct=EBI-1056930, EBI-357345; CC P36507; O00560: SDCBP; NbExp=2; IntAct=EBI-1056930, EBI-727004; CC P36507; Q9H190: SDCBP2; NbExp=2; IntAct=EBI-1056930, EBI-742426; CC P36507; Q07157: TJP1; NbExp=3; IntAct=EBI-1056930, EBI-79553; CC P36507; Q9UDY2: TJP2; NbExp=2; IntAct=EBI-1056930, EBI-1042602; CC P36507; O95049: TJP3; NbExp=2; IntAct=EBI-1056930, EBI-1171427; CC P36507; Q9Y6N9: USH1C; NbExp=3; IntAct=EBI-1056930, EBI-954308; CC P36507; Q9P202: WHRN; NbExp=3; IntAct=EBI-1056930, EBI-310886; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10409742}. Membrane CC {ECO:0000269|PubMed:10409742}; Peripheral membrane protein CC {ECO:0000269|PubMed:10409742}. Note=Membrane localization is probably CC regulated by its interaction with KSR1. {ECO:0000269|PubMed:10409742}. CC -!- PTM: MAPKK is itself dependent on Ser/Thr phosphorylation for activity CC catalyzed by MAP kinase kinase kinases (RAF or MEKK1). Phosphorylated CC by MAP2K1/MEK1 (By similarity). {ECO:0000250}. CC -!- PTM: (Microbial infection) Acetylation of Ser-222 and Ser-226 by CC Yersinia YopJ prevents phosphorylation and activation, thus blocking CC the MAPK signaling pathway. {ECO:0000269|PubMed:17116858, CC ECO:0000269|Ref.3}. CC -!- DISEASE: Cardiofaciocutaneous syndrome 4 (CFC4) [MIM:615280]: 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 {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:18042262, CC ECO:0000269|PubMed:20358587}. 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; L11285; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; BC000471; AAH00471.1; -; mRNA. DR EMBL; BC018645; AAH18645.1; -; mRNA. DR CCDS; CCDS12120.1; -. DR PIR; A46723; A46723. DR RefSeq; NP_109587.1; NM_030662.4. DR PDB; 1S9I; X-ray; 3.20 A; A/B=55-400. DR PDB; 4H3Q; X-ray; 2.20 A; B=4-16. DR AlphaFoldDB; P36507; -. DR MDRepo; P36507; -. DR SMR; P36507; -. DR BioGRID; 111591; 348. DR CORUM; P36507; -. DR DIP; DIP-29119N; -. DR FunCoup; P36507; 3936. DR IntAct; P36507; 371. DR MINT; P36507; -. DR NDEx; IQUERY-CP-MAP2K2; 132 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000262948; -. DR BindingDB; P36507; -. DR ChEMBL; CHEMBL2964; -. DR DrugBank; DB11967; Binimetinib. DR DrugBank; DB06616; Bosutinib. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB07101; Mirdametinib. DR DrugBank; DB17042; PD-98059. DR DrugBank; DB14904; Pimasertib. DR DrugBank; DB11689; Selumetinib. DR DrugBank; DB08911; Trametinib. DR DrugCentral; P36507; -. DR GuidetoPHARMACOLOGY; 2063; -. DR GlyCosmos; P36507; 2 sites, 1 glycan. DR GlyGen; P36507; 6 sites, 1 O-linked glycan (5 sites). DR iPTMnet; P36507; -. DR MetOSite; P36507; -. DR PhosphoSitePlus; P36507; -. DR SwissPalm; P36507; -. DR BioMuta; MAP2K2; -. DR DMDM; 547915; -. DR REPRODUCTION-2DPAGE; IPI00003783; -. DR CPTAC; CPTAC-1045; -. DR CPTAC; CPTAC-1543; -. DR CPTAC; CPTAC-811; -. DR CPTAC; CPTAC-812; -. DR CPTAC; CPTAC-813; -. DR jPOST; P36507; -. DR MassIVE; P36507; -. DR PaxDb; 9606-ENSP00000262948; -. DR PeptideAtlas; P36507; -. DR ProteomicsDB; 55203; -. DR Pumba; P36507; -. DR Antibodypedia; 3543; 1475 antibodies from 53 providers. DR CPTC; P36507; 1 antibody. DR DNASU; 5605; -. DR Ensembl; ENST00000262948.10; ENSP00000262948.4; ENSG00000126934.16. DR GeneID; 5605; -. DR KEGG; hsa:5605; -. DR MANE-Select; ENST00000262948.10; ENSP00000262948.4; NM_030662.4; NP_109587.1. DR UCSC; uc002lzk.4; human. DR AGR; HGNC:6842; -. DR CIViC; 5605; 11 evidence items across 10 molecular profiles. DR ClinPGx; PA30587; -. DR CTD; 5605; -. DR DisGeNET; 5605; -. DR GeneCards; MAP2K2; -. DR GeneReviews; MAP2K2; -. DR HGNC; HGNC:6842; MAP2K2. DR HPA; ENSG00000126934; Low tissue specificity. DR MalaCards; MAP2K2; -. DR MIM; 601263; gene. DR MIM; 615280; phenotype. DR OpenTargets; ENSG00000126934; -. DR Orphanet; 1340; Cardiofaciocutaneous syndrome. DR Orphanet; 638; Neurofibromatosis-Noonan syndrome. DR VEuPathDB; HostDB:ENSG00000126934; -. DR eggNOG; KOG0581; Eukaryota. DR GeneTree; ENSGT00940000153487; -. DR InParanoid; P36507; -. DR OMA; QMTLTEP; -. DR OrthoDB; 10252354at2759; -. DR PAN-GO; P36507; 2 GO annotations based on evolutionary models. DR PhylomeDB; P36507; -. DR BRENDA; 2.7.12.2; 2681. DR PathwayCommons; P36507; -. DR Reactome; R-HSA-112411; MAPK1 (ERK2) 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-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; P36507; -. DR SIGNOR; P36507; -. DR Agora; ENSG00000126934; -. DR BioGRID-ORCS; 5605; 27 hits in 1195 CRISPR screens. DR CD-CODE; 8C2F96ED; Centrosome. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; MAP2K2; human. DR EvolutionaryTrace; P36507; -. DR GeneWiki; MAP2K2; -. DR GenomeRNAi; 5605; -. DR Pharos; P36507; Tclin. DR PRO; PR:P36507; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P36507; protein. DR Bgee; ENSG00000126934; Expressed in mucosa of transverse colon and 202 other cell types or tissues. DR ExpressionAtlas; P36507; baseline and differential. DR GO; GO:0005911; C:cell-cell junction; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; EXP:UniProtKB. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:UniProtKB. 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:UniProtKB. DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB. DR GO; GO:0005925; C:focal adhesion; TAS:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; TAS:UniProtKB. DR GO; GO:0016020; C:membrane; EXP:UniProtKB. DR GO; GO:0005874; C:microtubule; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; TAS:UniProtKB. DR GO; GO:0005634; C:nucleus; TAS:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005778; C:peroxisomal membrane; HDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:InterPro. 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:0030165; F:PDZ domain binding; IDA:UniProtKB. DR GO; GO:0106310; F:protein serine kinase activity; EXP:UniProtKB. DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB. DR GO; GO:0004674; F:protein serine/threonine kinase activity; TAS:Reactome. DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; TAS:UniProtKB. DR GO; GO:0004713; F:protein tyrosine kinase activity; EXP:UniProtKB. DR GO; GO:0097110; F:scaffold protein binding; IPI:UniProtKB. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IMP:BHF-UCL. DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central. DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:BHF-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:BHF-UCL. DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:2000641; P:regulation of early endosome to late endosome transport; TAS:UniProtKB. DR GO; GO:0090170; P:regulation of Golgi inheritance; TAS:UniProtKB. DR GO; GO:0032872; P:regulation of stress-activated MAPK cascade; TAS:UniProtKB. DR CDD; cd06649; PKc_MEK2; 1. DR FunFam; 1.10.510.10:FF:000115; Dual specificity mitogen-activated protein kinase kinase 1; 1. DR FunFam; 3.30.200.20:FF:000100; Dual specificity mitogen-activated protein kinase kinase 1; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR050915; MAP_kinase_kinase. 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:SF3; MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2; 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 PDBsum; 1S9I; -. DR PDBsum; 4H3Q; -. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; ATP-binding; Cardiomyopathy; Cytoplasm; KW Direct protein sequencing; Disease variant; Ectodermal dysplasia; KW Intellectual disability; Kinase; Magnesium; Membrane; Metal-binding; KW Nucleotide-binding; Phosphoprotein; Proteomics identification; KW Reference proteome; Serine/threonine-protein kinase; Transferase; KW Tyrosine-protein kinase. FT CHAIN 1..400 FT /note="Dual specificity mitogen-activated protein kinase FT kinase 2" FT /id="PRO_0000086372" FT DOMAIN 72..369 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 286..310 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 194 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 78..86 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 101 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT SITE 10..11 FT /note="Cleavage; by anthrax lethal factor" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:19413330" FT MOD_RES 23 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 222 FT /note="(Microbial infection) O-acetylserine; by Yersinia FT YopJ; alternate" FT /evidence="ECO:0000269|PubMed:17116858" FT MOD_RES 222 FT /note="Phosphoserine; by RAF; alternate" FT /evidence="ECO:0000269|PubMed:10409742, FT ECO:0000269|PubMed:17116858" FT MOD_RES 226 FT /note="(Microbial infection) O-acetylserine; by Yersinia FT YopJ; alternate" FT /evidence="ECO:0000269|PubMed:17116858" FT MOD_RES 226 FT /note="Phosphoserine; alternate" FT /evidence="ECO:0000269|PubMed:17116858" FT MOD_RES 293 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976" FT MOD_RES 295 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:20068231" FT MOD_RES 306 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q02750" FT MOD_RES 394 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|Ref.3, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 396 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT VARIANT 57 FT /note="F -> C (in CFC4; dbSNP:rs121434497)" FT /evidence="ECO:0000269|PubMed:16439621" FT /id="VAR_035095" FT VARIANT 57 FT /note="F -> V (in CFC4; dbSNP:rs121434498)" FT /evidence="ECO:0000269|PubMed:18042262" FT /id="VAR_069781" FT VARIANT 128 FT /note="P -> Q (in CFC4; results in increased kinase FT activity; dbSNP:rs267607230)" FT /evidence="ECO:0000269|PubMed:20358587" FT /id="VAR_069782" FT VARIANT 134 FT /note="Y -> H (in CFC4; dbSNP:rs121434499)" FT /evidence="ECO:0000269|PubMed:18042262" FT /id="VAR_069783" FT CONFLICT 56 FT /note="A -> R (in Ref. 6; AA sequence)" FT /evidence="ECO:0000305" FT HELIX 10..12 FT /evidence="ECO:0007829|PDB:4H3Q" FT HELIX 69..71 FT /evidence="ECO:0007829|PDB:1S9I" FT STRAND 72..80 FT /evidence="ECO:0007829|PDB:1S9I" FT STRAND 85..91 FT /evidence="ECO:0007829|PDB:1S9I" FT TURN 92..94 FT /evidence="ECO:0007829|PDB:1S9I" FT STRAND 97..103 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 110..119 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 120..122 FT /evidence="ECO:0007829|PDB:1S9I" FT STRAND 133..148 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 155..161 FT /evidence="ECO:0007829|PDB:1S9I" FT STRAND 162..164 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 167..186 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 197..199 FT /evidence="ECO:0007829|PDB:1S9I" FT STRAND 200..202 FT /evidence="ECO:0007829|PDB:1S9I" FT STRAND 208..210 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 217..222 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 236..239 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 242..244 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 246..262 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 269..271 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 272..279 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 318..327 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 329..331 FT /evidence="ECO:0007829|PDB:1S9I" FT TURN 335..337 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 340..349 FT /evidence="ECO:0007829|PDB:1S9I" FT TURN 354..356 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 360..364 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 367..374 FT /evidence="ECO:0007829|PDB:1S9I" FT HELIX 379..387 FT /evidence="ECO:0007829|PDB:1S9I" SQ SEQUENCE 400 AA; 44424 MW; 3401D522515C30A5 CRC64; MLARRKPVLP ALTINPTIAE GPSPTSEGAS EANLVDLQKK LEELELDEQQ KKRLEAFLTQ KAKVGELKDD DFERISELGA GNGGVVTKVQ HRPSGLIMAR KLIHLEIKPA IRNQIIRELQ VLHECNSPYI VGFYGAFYSD GEISICMEHM DGGSLDQVLK EAKRIPEEIL GKVSIAVLRG LAYLREKHQI MHRDVKPSNI LVNSRGEIKL CDFGVSGQLI DSMANSFVGT RSYMAPERLQ GTHYSVQSDI WSMGLSLVEL AVGRYPIPPP DAKELEAIFG RPVVDGEEGE PHSISPRPRP PGRPVSGHGM DSRPAMAIFE LLDYIVNEPP PKLPNGVFTP DFQEFVNKCL IKNPAERADL KMLTNHTFIK RSEVEEVDFA GWLCKTLRLN QPGTPTRTAV //