MP2K2_HUMAN
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 03-AUG-2022, entry version 235.
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=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 Evidence={ECO:0000269|PubMed:10409742};
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; Evidence={ECO:0000269|PubMed:10409742};
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 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; P05067: APP; NbExp=3; IntAct=EBI-1056930, EBI-77613;
CC P36507; P10398: ARAF; NbExp=9; IntAct=EBI-1056930, EBI-365961;
CC P36507; Q96II5: ARAF; NbExp=4; IntAct=EBI-1056930, EBI-9383168;
CC P36507; P15056: BRAF; NbExp=11; IntAct=EBI-1056930, EBI-365980;
CC P36507; O95273: CCNDBP1; NbExp=3; IntAct=EBI-1056930, EBI-748961;
CC P36507; Q12959: DLG1; NbExp=10; IntAct=EBI-1056930, EBI-357481;
CC P36507; P61978-2: HNRNPK; NbExp=3; IntAct=EBI-1056930, EBI-7060731;
CC P36507; Q8IVT5: KSR1; NbExp=9; IntAct=EBI-1056930, EBI-486984;
CC P36507; P00540: MOS; NbExp=3; IntAct=EBI-1056930, EBI-1757866;
CC P36507; P04049: RAF1; NbExp=6; IntAct=EBI-1056930, EBI-365996;
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_030662.3.
DR PDB; 1S9I; X-ray; 3.20 A; A/B=55-400.
DR PDB; 4H3Q; X-ray; 2.20 A; B=4-16.
DR PDBsum; 1S9I; -.
DR PDBsum; 4H3Q; -.
DR AlphaFoldDB; P36507; -.
DR SMR; P36507; -.
DR BioGRID; 111591; 243.
DR CORUM; P36507; -.
DR DIP; DIP-29119N; -.
DR IntAct; P36507; 135.
DR MINT; P36507; -.
DR STRING; 9606.ENSP00000262948; -.
DR BindingDB; P36507; -.
DR ChEMBL; CHEMBL2964; -.
DR DrugBank; DB11967; Binimetinib.
DR DrugBank; DB06616; Bosutinib.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB11689; Selumetinib.
DR DrugBank; DB08911; Trametinib.
DR DrugCentral; P36507; -.
DR GuidetoPHARMACOLOGY; 2063; -.
DR GlyGen; P36507; 2 sites, 1 O-linked glycan (2 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 EPD; P36507; -.
DR jPOST; P36507; -.
DR MassIVE; P36507; -.
DR MaxQB; P36507; -.
DR PaxDb; P36507; -.
DR PeptideAtlas; P36507; -.
DR PRIDE; P36507; -.
DR ProteomicsDB; 55203; -.
DR Antibodypedia; 3543; 1487 antibodies from 50 providers.
DR CPTC; P36507; 1 antibody.
DR DNASU; 5605; -.
DR Ensembl; ENST00000262948.10; ENSP00000262948.4; ENSG00000126934.15.
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 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 neXtProt; NX_P36507; -.
DR OpenTargets; ENSG00000126934; -.
DR Orphanet; 1340; Cardiofaciocutaneous syndrome.
DR Orphanet; 638; Neurofibromatosis-Noonan syndrome.
DR PharmGKB; PA30587; -.
DR VEuPathDB; HostDB:ENSG00000126934; -.
DR eggNOG; KOG0581; Eukaryota.
DR GeneTree; ENSGT00940000153487; -.
DR InParanoid; P36507; -.
DR OMA; TEPNICI; -.
DR OrthoDB; 688282at2759; -.
DR PhylomeDB; P36507; -.
DR TreeFam; TF105137; -.
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 BioGRID-ORCS; 5605; 24 hits in 1108 CRISPR screens.
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 200 other tissues.
DR ExpressionAtlas; P36507; baseline and differential.
DR Genevisible; P36507; HS.
DR GO; GO:0005911; C:cell-cell junction; IDA:UniProtKB.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:UniProtKB.
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: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: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:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0030165; F:PDZ domain binding; IDA:UniProtKB.
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:0060502; P:epithelial cell proliferation involved in lung morphogenesis; IEA:Ensembl.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IMP:BHF-UCL.
DR GO; GO:0060324; P:face development; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0000165; P:MAPK cascade; IBA:GO_Central.
DR GO; GO:0036289; P:peptidyl-serine autophosphorylation; IDA:UniProtKB.
DR GO; GO:0050772; P:positive regulation of axonogenesis; IEA:Ensembl.
DR GO; GO:2000147; P:positive regulation of cell motility; IEA:Ensembl.
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: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: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; ATP-binding; Cardiomyopathy; Cytoplasm;
KW Direct protein sequencing; Disease variant; Ectodermal dysplasia;
KW Intellectual disability; Kinase; Magnesium; Membrane; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; 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 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 246..262
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 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..386
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
