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   24-JAN-2024, entry version 138.
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}.
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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   SwissPalm; Q6P5G0; -.
DR   MaxQB; Q6P5G0; -.
DR   PaxDb; 10090-ENSMUSP00000089462; -.
DR   ProteomicsDB; 295569; -.
DR   Antibodypedia; 2079; 463 antibodies from 33 providers.
DR   DNASU; 225724; -.
DR   Ensembl; ENSMUST00000091851.10; ENSMUSP00000089462.4; ENSMUSG00000024558.13.
DR   GeneID; 225724; -.
DR   KEGG; mmu:225724; -.
DR   UCSC; uc008fpa.2; mouse.
DR   AGR; MGI:2444559; -.
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; QGPLFYP; -.
DR   OrthoDB; 5344491at2759; -.
DR   PhylomeDB; Q6P5G0; -.
DR   TreeFam; TF105098; -.
DR   Reactome; R-MMU-5687128; MAPK6/MAPK4 signaling.
DR   BioGRID-ORCS; 225724; 4 hits in 80 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 132 other cell types or tissues.
DR   ExpressionAtlas; Q6P5G0; baseline and differential.
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; IEA:UniProtKB-EC.
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:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   CDD; cd07854; STKc_MAPK4_6; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
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   PANTHER; PTHR24055; MITOGEN-ACTIVATED PROTEIN KINASE; 1.
DR   PANTHER; PTHR24055:SF25; MITOGEN-ACTIVATED PROTEIN KINASE 4; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   PRINTS; PR01771; ERK3ERK4MAPK.
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; Q6P5G0; MM.
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
//