MK04_MOUSE
ID MK04_MOUSE Reviewed; 583 AA.
AC Q6P5G0;
DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 130.
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;
GN Name=Mapk4; Synonyms=Erk4, Prkm4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
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 [2]
RP FUNCTION IN PHOSPHORYLATION OF MAPKAPK5, SUBCELLULAR LOCATION, INTERACTION
RP WITH MAPKAPK5 AND MAPK6, SUBUNIT, AND MUTAGENESIS OF 49-LYS-LYS-50.
RX PubMed=16973613; DOI=10.1074/jbc.m606693200;
RA Kant S., Schumacher S., Singh M.K., Kispert A., Kotlyarov A., Gaestel M.;
RT "Characterization of the atypical MAPK ERK4 and its activation of the MAPK-
RT activated protein kinase MK5.";
RL J. Biol. Chem. 281:35511-35519(2006).
RN [3]
RP INTERACTION WITH MAPKAPK5, PHOSPHORYLATION AT SER-186, AND MUTAGENESIS OF
RP ASP-168 AND SER-186.
RX PubMed=18248330; DOI=10.1042/bj20071369;
RA Perander M., Aberg E., Johansen B., Dreyer B., Guldvik I.J., Outzen H.,
RA Keyse S.M., Seternes O.M.;
RT "The Ser(186) phospho-acceptor site within ERK4 is essential for its
RT ability to interact with and activate PRAK/MK5.";
RL Biochem. J. 411:613-622(2008).
RN [4]
RP INTERACTION WITH MAPKAPK5, PHOSPHORYLATION AT SER-186, AND MUTAGENESIS OF
RP SER-186.
RX PubMed=18720373; DOI=10.1002/jcp.21560;
RA Deleris P., Rousseau J., Coulombe P., Rodier G., Tanguay P.L., Meloche S.;
RT "Activation loop phosphorylation of the atypical MAP kinases ERK3 and ERK4
RT is required for binding, activation and cytoplasmic relocalization of
RT MK5.";
RL J. Cell. Physiol. 217:778-788(2008).
RN [5]
RP INTERACTION WITH MAPKAPK5, DOMAIN FRIEDE MOTIF, AND MUTAGENESIS OF PHE-328
RP AND ILE-330.
RX PubMed=19473979; DOI=10.1074/jbc.m109.023283;
RA Aberg E., Torgersen K.M., Johansen B., Keyse S.M., Perander M.,
RA Seternes O.M.;
RT "Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel
RT MAPK interaction motif.";
RL J. Biol. Chem. 284:19392-19401(2009).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186 AND SER-430, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Kidney;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
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.
CC {ECO:0000269|PubMed:16973613}.
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. {ECO:0000269|PubMed:16973613,
CC ECO:0000269|PubMed:18248330, ECO:0000269|PubMed:18720373,
CC ECO:0000269|PubMed:19473979}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16973613}. Nucleus
CC {ECO:0000269|PubMed:16973613}. Note=Translocates to the cytoplasm
CC following interaction with MAPKAPK5.
CC -!- DOMAIN: The FRIEDE motif is required for docking MAPKAPK5.
CC {ECO:0000269|PubMed:19473979}.
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. {ECO:0000269|PubMed:19473979}.
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:18248330, ECO:0000269|PubMed:18720373}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. MAP 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; BC058942; AAH58942.1; -; mRNA.
DR EMBL; BC062911; AAH62911.1; -; mRNA.
DR CCDS; CCDS37856.1; -.
DR RefSeq; NP_766220.2; NM_172632.2.
DR RefSeq; XP_006525963.1; XM_006525900.3.
DR RefSeq; XP_006525964.1; XM_006525901.3.
DR AlphaFoldDB; Q6P5G0; -.
DR SMR; Q6P5G0; -.
DR BioGRID; 230421; 1.
DR STRING; 10090.ENSMUSP00000089462; -.
DR iPTMnet; Q6P5G0; -.
DR PhosphoSitePlus; Q6P5G0; -.
DR MaxQB; Q6P5G0; -.
DR PaxDb; Q6P5G0; -.
DR PRIDE; Q6P5G0; -.
DR ProteomicsDB; 295569; -.
DR Antibodypedia; 2079; 396 antibodies from 33 providers.
DR DNASU; 225724; -.
DR Ensembl; ENSMUST00000091851; ENSMUSP00000089462; ENSMUSG00000024558.
DR GeneID; 225724; -.
DR KEGG; mmu:225724; -.
DR UCSC; uc008fpa.2; mouse.
DR CTD; 5596; -.
DR MGI; MGI:2444559; Mapk4.
DR VEuPathDB; HostDB:ENSMUSG00000024558; -.
DR eggNOG; KOG0660; Eukaryota.
DR GeneTree; ENSGT00940000159850; -.
DR HOGENOM; CLU_000288_181_15_1; -.
DR InParanoid; Q6P5G0; -.
DR OMA; CISEHPS; -.
DR OrthoDB; 741207at2759; -.
DR PhylomeDB; Q6P5G0; -.
DR TreeFam; TF105098; -.
DR Reactome; R-MMU-5687128; MAPK6/MAPK4 signaling.
DR BioGRID-ORCS; 225724; 4 hits in 75 CRISPR screens.
DR ChiTaRS; Mapk4; mouse.
DR PRO; PR:Q6P5G0; -.
DR Proteomes; UP000000589; Chromosome 18.
DR RNAct; Q6P5G0; protein.
DR Bgee; ENSMUSG00000024558; Expressed in caudate-putamen and 131 other tissues.
DR ExpressionAtlas; Q6P5G0; baseline and differential.
DR Genevisible; Q6P5G0; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA: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; IPI:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IPI: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; IEA:InterPro.
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..583
FT /note="Mitogen-activated protein kinase 4"
FT /id="PRO_0000186255"
FT DOMAIN 20..312
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 366..410
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 495..531
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 389..410
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 505..519
FT /note="Pro 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:18248330,
FT ECO:0000269|PubMed:18720373, ECO:0007744|PubMed:21183079"
FT MOD_RES 430
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MUTAGEN 49..50
FT /note="KK->AA: ATP-binding site mutant; unable to activate
FT MAPKAPK5."
FT /evidence="ECO:0000269|PubMed:16973613"
FT MUTAGEN 168
FT /note="D->A: Kinase defective mutant, abolishes activity."
FT /evidence="ECO:0000269|PubMed:18248330"
FT MUTAGEN 186
FT /note="S->A,D: Unable to activate MAPKAPK5 promote MAPKAPK5
FT localization to the cytoplasm."
FT /evidence="ECO:0000269|PubMed:18248330,
FT ECO:0000269|PubMed:18720373"
FT MUTAGEN 328
FT /note="F->A,Y: Impairs binding to MAPKAPK5."
FT /evidence="ECO:0000269|PubMed:19473979"
FT MUTAGEN 330
FT /note="I->K: Abolishes binding to MAPKAPK5."
FT /evidence="ECO:0000269|PubMed:19473979"
SQ SEQUENCE 583 AA; 65574 MW; 7CE7B2D5359CB52A CRC64;
MAEKGDCIAS VYGYDLGGRF IDFQPLGFGV NGLVLSATDS RACRKVAVKK IVLSDARSMK
HALREIKIIR RLDHDNIVKV YEVLGPKGSD LQGELFKFSV AYIVQEYMET DLACLLEQGT
LTEDHAKLFM YQLLRGLKYI HSANVLHRDL KPANIFISTE DLVLKIGDFG LARIVDQHYS
HKGYLSEGLV TKWYRSPRLL LSPNNYTKAI DMWAAGCILA EMLTGKMLFA GAHELEQMQL
ILDTIPVVRE EDKEELLRVM PSFVSSTWEV KRPLRKLLPD VNSEAIDFLE KILTFNPMDR
LTAEMGLQHP YMSPYSCPED EPTSQHPFRI EDEIDDIVLM AASQSQLSNW DRYPVSLSSD
LEWRPDRCQD ASEVQRDPRA GSTPLAEDVQ VDPRKDSQSS SERFLEQSHS SMERAFEADY
GRSCDYKVGS PSYLDKLLWR DNKPHHYSEP KLILDLSHWK QAASAPPRAA VAADPVSRED
EPASLFLEIA QWVKSTQSGS ERASPPPDAP EPRLSASPPG HPTPIDGGAS PQFDLDVFIS
RALKLCTKPE DLPENKLGDL NGACISEHPG DLVQTEAFSK ERW
