MK04_HUMAN
ID MK04_HUMAN Reviewed; 587 AA.
AC P31152; A1A4C4; Q0VG04;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 25-NOV-2008, sequence version 2.
DT 03-AUG-2022, entry version 191.
DE RecName: Full=Mitogen-activated protein kinase 4;
DE Short=MAP kinase 4;
DE Short=MAPK 4;
DE EC=2.7.11.24;
DE AltName: Full=Extracellular signal-regulated kinase 4;
DE Short=ERK-4;
DE AltName: Full=MAP kinase isoform p63;
DE Short=p63-MAPK;
GN Name=MAPK4; Synonyms=ERK4, PRKM4;
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=1319925; DOI=10.1016/0014-5793(92)80612-k;
RA Gonzalez F.A., Raden D.L., Rigby M.R., Davis R.J.;
RT "Heterogeneous expression of four MAP kinase isoforms in human tissues.";
RL FEBS Lett. 304:170-178(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D.,
RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J.,
RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L.,
RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A.,
RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C.,
RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-38.
RC TISSUE=Brain, and Cerebellum;
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 [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186, AND IDENTIFICATION BY
RP 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 [7]
RP PHOSPHORYLATION AT SER-186.
RX PubMed=21177870; DOI=10.1074/jbc.m110.181529;
RA Deleris P., Trost M., Topisirovic I., Tanguay P.L., Borden K.L.,
RA Thibault P., Meloche S.;
RT "Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated
RT kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5
RT signaling pathway.";
RL J. Biol. Chem. 286:6470-6478(2011).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-434, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
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 [9]
RP VARIANTS [LARGE SCALE ANALYSIS] MET-38 AND PRO-371.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Atypical MAPK protein. Phosphorylates microtubule-associated
CC protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed
CC with MAPKAPK5 is still unclear, but the complex follows a complex set
CC of phosphorylation events: upon interaction with atypical MAPKAPK5,
CC ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates
CC phosphorylation and activation of MAPKAPK5, which in turn
CC phosphorylates ERK4/MAPK4. May promote entry in the cell cycle (By
CC similarity). {ECO:0000250}.
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=2.7.11.24;
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=2.7.11.24;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation at Ser-186.
CC -!- SUBUNIT: Homodimer. Heterodimer with ERK3/MAPK6. Interacts with (via
CC FRIEDE motif) MAPKAPK5 (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC P31152; P08238: HSP90AB1; NbExp=3; IntAct=EBI-3906061, EBI-352572;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC Note=Translocates to the cytoplasm following interaction with MAPKAPK5.
CC {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: High expression in heart and brain.
CC -!- DOMAIN: The FRIEDE motif is required for docking MAPKAPK5.
CC {ECO:0000250}.
CC -!- DOMAIN: In contrast to classical MAPKs, the TXY motif within the
CC activation loop is replaced by the SEG motif, whose phosphorylation
CC activates the MAP kinases.
CC -!- PTM: Phosphorylated at Ser-186 by PAK1, PAK2 and PAK3 resulting in
CC catalytic activation. Phosphorylated by MAPKAPK5 at other sites.
CC {ECO:0000269|PubMed:21177870}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. MAP kinase subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA42411.1; Type=Frameshift; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MAPK4ID41293ch18q21.html";
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DR EMBL; X59727; CAA42411.1; ALT_FRAME; mRNA.
DR EMBL; AK295058; BAG58107.1; -; mRNA.
DR EMBL; AC012433; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC090395; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471096; EAW62976.1; -; Genomic_DNA.
DR EMBL; CH471096; EAW62977.1; -; Genomic_DNA.
DR EMBL; BC050299; AAH50299.1; -; mRNA.
DR EMBL; BC117216; AAI17217.1; -; mRNA.
DR CCDS; CCDS42437.1; -.
DR PIR; S23429; S23429.
DR RefSeq; NP_001278968.1; NM_001292039.1.
DR RefSeq; NP_001278969.1; NM_001292040.1.
DR RefSeq; NP_002738.2; NM_002747.3.
DR RefSeq; XP_005258356.1; XM_005258299.3.
DR RefSeq; XP_011524376.1; XM_011526074.2.
DR RefSeq; XP_011524377.1; XM_011526075.2.
DR RefSeq; XP_011524378.1; XM_011526076.2.
DR RefSeq; XP_016881328.1; XM_017025839.1.
DR AlphaFoldDB; P31152; -.
DR SMR; P31152; -.
DR BioGRID; 111582; 39.
DR IntAct; P31152; 45.
DR STRING; 9606.ENSP00000383234; -.
DR BindingDB; P31152; -.
DR ChEMBL; CHEMBL5759; -.
DR DrugBank; DB00945; Acetylsalicylic acid.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB01017; Minocycline.
DR DrugCentral; P31152; -.
DR iPTMnet; P31152; -.
DR PhosphoSitePlus; P31152; -.
DR BioMuta; MAPK4; -.
DR DMDM; 215274102; -.
DR CPTAC; CPTAC-883; -.
DR CPTAC; CPTAC-884; -.
DR EPD; P31152; -.
DR jPOST; P31152; -.
DR MassIVE; P31152; -.
DR PaxDb; P31152; -.
DR PeptideAtlas; P31152; -.
DR PRIDE; P31152; -.
DR ProteomicsDB; 54762; -.
DR Antibodypedia; 2079; 396 antibodies from 33 providers.
DR DNASU; 5596; -.
DR Ensembl; ENST00000400384.7; ENSP00000383234.1; ENSG00000141639.12.
DR GeneID; 5596; -.
DR KEGG; hsa:5596; -.
DR MANE-Select; ENST00000400384.7; ENSP00000383234.1; NM_002747.4; NP_002738.2.
DR UCSC; uc002lev.4; human.
DR CTD; 5596; -.
DR DisGeNET; 5596; -.
DR GeneCards; MAPK4; -.
DR HGNC; HGNC:6878; MAPK4.
DR HPA; ENSG00000141639; Tissue enhanced (brain, parathyroid gland).
DR MIM; 176949; gene.
DR neXtProt; NX_P31152; -.
DR OpenTargets; ENSG00000141639; -.
DR PharmGKB; PA30623; -.
DR VEuPathDB; HostDB:ENSG00000141639; -.
DR eggNOG; KOG0660; Eukaryota.
DR GeneTree; ENSGT00940000159850; -.
DR HOGENOM; CLU_000288_181_15_1; -.
DR InParanoid; P31152; -.
DR OMA; CISEHPS; -.
DR OrthoDB; 741207at2759; -.
DR PhylomeDB; P31152; -.
DR TreeFam; TF105098; -.
DR BRENDA; 2.7.11.24; 2681.
DR PathwayCommons; P31152; -.
DR Reactome; R-HSA-5687128; MAPK6/MAPK4 signaling.
DR SignaLink; P31152; -.
DR SIGNOR; P31152; -.
DR BioGRID-ORCS; 5596; 8 hits in 1077 CRISPR screens.
DR ChiTaRS; MAPK4; human.
DR GeneWiki; MAPK4; -.
DR GenomeRNAi; 5596; -.
DR Pharos; P31152; Tbio.
DR PRO; PR:P31152; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; P31152; protein.
DR Bgee; ENSG00000141639; Expressed in caudate nucleus and 87 other tissues.
DR ExpressionAtlas; P31152; baseline and differential.
DR Genevisible; P31152; HS.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004707; F:MAP kinase activity; IBA:GO_Central.
DR GO; GO:0046982; F:protein heterodimerization activity; IEA:Ensembl.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR008350; MAPK_ERK3/4.
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 PRINTS; PR01771; ERK3ERK4MAPK.
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 ATP-binding; Cell cycle; Cytoplasm; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT CHAIN 1..587
FT /note="Mitogen-activated protein kinase 4"
FT /id="PRO_0000186254"
FT DOMAIN 20..312
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 373..413
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 499..534
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 186..188
FT /note="SEG motif"
FT MOTIF 328..333
FT /note="FRIEDE motif"
FT COMPBIAS 393..413
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 149
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 26..34
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 49
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 186
FT /note="Phosphoserine; by PAK1, PAK2 and PAK3"
FT /evidence="ECO:0000269|PubMed:21177870,
FT ECO:0007744|PubMed:18669648"
FT MOD_RES 434
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VARIANT 38
FT /note="V -> M (in dbSNP:rs3752087)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_042254"
FT VARIANT 371
FT /note="R -> P (in dbSNP:rs3752089)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042255"
FT CONFLICT 220
FT /note="A -> S (in Ref. 5; AAH50299)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 587 AA; 65922 MW; 71DB32D1E63EF8EE CRC64;
MAEKGDCIAS VYGYDLGGRF VDFQPLGFGV NGLVLSAVDS RACRKVAVKK IALSDARSMK
HALREIKIIR RLDHDNIVKV YEVLGPKGTD LQGELFKFSV AYIVQEYMET DLARLLEQGT
LAEEHAKLFM YQLLRGLKYI HSANVLHRDL KPANIFISTE DLVLKIGDFG LARIVDQHYS
HKGYLSEGLV TKWYRSPRLL LSPNNYTKAI DMWAAGCILA EMLTGRMLFA GAHELEQMQL
ILETIPVIRE EDKDELLRVM PSFVSSTWEV KRPLRKLLPE VNSEAIDFLE KILTFNPMDR
LTAEMGLQHP YMSPYSCPED EPTSQHPFRI EDEIDDIVLM AANQSQLSNW DTCSSRYPVS
LSSDLEWRPD RCQDASEVQR DPRAGSAPLA EDVQVDPRKD SHSSSERFLE QSHSSMERAF
EADYGRSCDY KVGSPSYLDK LLWRDNKPHH YSEPKLILDL SHWKQAAGAP PTATGLADTG
AREDEPASLF LEIAQWVKST QGGPEHASPP ADDPERRLSA SPPGRPAPVD GGASPQFDLD
VFISRALKLC TKPEDLPDNK LGDLNGACIP EHPGDLVQTE AFSKERW
