ID   MK06_MOUSE              Reviewed;         720 AA.
AC   Q61532; Q497T9; Q6YKB0; Q7TT30; Q80XH5; Q922U4; Q9JLU6;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   13-SEP-2004, sequence version 3.
DT   24-JAN-2024, entry version 178.
DE   RecName: Full=Mitogen-activated protein kinase 6;
DE            Short=MAP kinase 6;
DE            Short=MAPK 6;
DE            EC=2.7.11.24;
DE   AltName: Full=Extracellular signal-regulated kinase 3;
DE            Short=ERK-3;
GN   Name=Mapk6; Synonyms=Erk3, Prkm4, Prkm6;
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 [MRNA], AND DEVELOPMENTAL STAGE.
RC   TISSUE=Pituitary;
RX   PubMed=10657254; DOI=10.1042/bj3460169;
RA   Turgeon B., Saba-El-Leil M.K., Meloche S.;
RT   "Cloning and characterization of mouse extracellular-signal-regulated
RT   protein kinase 3 as a unique gene product of 100 kDa.";
RL   Biochem. J. 346:169-175(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=129/Sv;
RX   PubMed=12504858; DOI=10.1006/geno.2002.7013;
RA   Turgeon B., Lang B.F., Meloche S.;
RT   "The protein kinase ERK3 is encoded by a single functional gene: genomic
RT   analysis of the ERK3 gene family.";
RL   Genomics 80:673-680(2002).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J, and Czech II;
RC   TISSUE=Embryonic brain, Embryonic germ cell, Mammary tumor, and
RC   Olfactory epithelium;
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   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 156-195.
RC   STRAIN=CBA/J; TISSUE=Hematopoietic;
RX   PubMed=8444355; DOI=10.1016/0378-1119(93)90411-u;
RA   Ershler M.A., Nagorskaya T.V., Visser J.W.M., Belyavsky A.V.;
RT   "Novel CDC2-related protein kinases produced in murine hematopoietic stem
RT   cells.";
RL   Gene 124:305-306(1993).
RN   [5]
RP   FUNCTION IN PHOSPHORYLATION OF MAPKAPK5, SUBCELLULAR LOCATION, AND
RP   INTERACTION WITH MAPKAPK5.
RX   PubMed=15538386; DOI=10.1038/sj.emboj.7600467;
RA   Schumacher S., Laass K., Kant S., Shi Y., Visel A., Gruber A.D.,
RA   Kotlyarov A., Gaestel M.;
RT   "Scaffolding by ERK3 regulates MK5 in development.";
RL   EMBO J. 23:4770-4779(2004).
RN   [6]
RP   FUNCTION IN PHOSPHORYLATION OF MAPKAPK5, SUBCELLULAR LOCATION, INTERACTION
RP   WITH MAPKAPK5, AND MUTAGENESIS OF ASP-171 AND SER-189.
RX   PubMed=15577943; DOI=10.1038/sj.emboj.7600489;
RA   Seternes O.M., Mikalsen T., Johansen B., Michaelsen E., Armstrong C.G.,
RA   Morrice N.A., Turgeon B., Meloche S., Moens U., Keyse S.M.;
RT   "Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel
RT   signal transduction pathway.";
RL   EMBO J. 23:4780-4791(2004).
RN   [7]
RP   INTERACTION WITH MAPK4.
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   [8]
RP   INTERACTION WITH MAPKAPK5, PHOSPHORYLATION AT SER-189, AND MUTAGENESIS OF
RP   SER-189.
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   [9]
RP   INTERACTION WITH MAPKAPK5, DOMAIN FRIEDE MOTIF, AND MUTAGENESIS OF ILE-334.
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).
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       ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates
CC       phosphorylation and activation of MAPKAPK5, which in turn
CC       phosphorylates ERK3/MAPK6. May promote entry in the cell cycle.
CC       {ECO:0000269|PubMed:15538386, ECO:0000269|PubMed:15577943}.
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-189.
CC   -!- SUBUNIT: Heterodimer with ERK4/MAPK4. Interacts with (via FRIEDE motif)
CC       MAPKAPK5. Interacts with UBE3A; this interaction may be indirect and
CC       mediated by HERC2, possibly via HERC2 interaction with NEURL4 (By
CC       similarity). {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocates to the
CC       cytoplasm following interaction with MAPKAPK5.
CC   -!- DEVELOPMENTAL STAGE: Expression increases markedly from days 9 to 11 in
CC       the developing embryo, followed by a gradual decrease up to birth.
CC       {ECO:0000269|PubMed:10657254}.
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-189 by PAK1, PAK2 and PAK3 resulting in
CC       catalytic activation. Phosphorylated by MAPKAPK5 at other sites.
CC       {ECO:0000269|PubMed:18720373}.
CC   -!- PTM: Ubiquitination at Met-1 leads to degradation by the proteasome
CC       pathway. {ECO:0000250}.
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; AF132850; AAF61348.1; -; mRNA.
DR   EMBL; AY134883; AAN64588.1; -; Genomic_DNA.
DR   EMBL; AY134660; AAN64588.1; JOINED; Genomic_DNA.
DR   EMBL; AY134880; AAN64588.1; JOINED; Genomic_DNA.
DR   EMBL; AY134881; AAN64588.1; JOINED; Genomic_DNA.
DR   EMBL; AY134882; AAN64588.1; JOINED; Genomic_DNA.
DR   EMBL; BC006778; AAH06778.1; -; mRNA.
DR   EMBL; BC048779; AAH48779.1; -; mRNA.
DR   EMBL; BC052420; AAH52420.2; -; mRNA.
DR   EMBL; BC100385; AAI00386.1; -; mRNA.
DR   EMBL; X64607; CAA45891.1; -; mRNA.
DR   CCDS; CCDS23342.1; -.
DR   PIR; PN0481; PN0481.
DR   RefSeq; NP_056621.4; NM_015806.5.
DR   RefSeq; NP_081694.1; NM_027418.2.
DR   RefSeq; XP_011241069.1; XM_011242767.2.
DR   AlphaFoldDB; Q61532; -.
DR   SMR; Q61532; -.
DR   BioGRID; 206104; 10.
DR   STRING; 10090.ENSMUSP00000129024; -.
DR   iPTMnet; Q61532; -.
DR   PhosphoSitePlus; Q61532; -.
DR   EPD; Q61532; -.
DR   jPOST; Q61532; -.
DR   MaxQB; Q61532; -.
DR   PaxDb; 10090-ENSMUSP00000040315; -.
DR   PeptideAtlas; Q61532; -.
DR   ProteomicsDB; 252571; -.
DR   Antibodypedia; 3920; 645 antibodies from 39 providers.
DR   DNASU; 50772; -.
DR   Ensembl; ENSMUST00000049355.11; ENSMUSP00000040315.11; ENSMUSG00000042688.17.
DR   Ensembl; ENSMUST00000168937.8; ENSMUSP00000129024.2; ENSMUSG00000042688.17.
DR   GeneID; 50772; -.
DR   KEGG; mmu:50772; -.
DR   UCSC; uc009qsd.2; mouse.
DR   AGR; MGI:1354946; -.
DR   CTD; 5597; -.
DR   MGI; MGI:1354946; Mapk6.
DR   VEuPathDB; HostDB:ENSMUSG00000042688; -.
DR   eggNOG; KOG0660; Eukaryota.
DR   GeneTree; ENSGT00940000154351; -.
DR   HOGENOM; CLU_000288_181_15_1; -.
DR   InParanoid; Q61532; -.
DR   OMA; EADWQLH; -.
DR   OrthoDB; 5344491at2759; -.
DR   PhylomeDB; Q61532; -.
DR   TreeFam; TF105098; -.
DR   BRENDA; 2.7.11.24; 3474.
DR   Reactome; R-MMU-5687128; MAPK6/MAPK4 signaling.
DR   BioGRID-ORCS; 50772; 0 hits in 81 CRISPR screens.
DR   ChiTaRS; Mapk6; mouse.
DR   PRO; PR:Q61532; -.
DR   Proteomes; UP000000589; Chromosome 9.
DR   RNAct; Q61532; Protein.
DR   Bgee; ENSMUSG00000042688; Expressed in spermatocyte and 269 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0032991; C:protein-containing complex; IDA:MGI.
DR   GO; GO:0032156; C:septin cytoskeleton; IDA:MGI.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004707; F:MAP kinase activity; IDA:UniProtKB.
DR   GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB.
DR   GO; GO:0004672; F:protein kinase activity; IDA:MGI.
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:0060999; P:positive regulation of dendritic spine development; IGI:MGI.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
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:SF171; MITOGEN-ACTIVATED PROTEIN KINASE 6; 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; Q61532; 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; Ubl conjugation.
FT   CHAIN           1..720
FT                   /note="Mitogen-activated protein kinase 6"
FT                   /id="PRO_0000186258"
FT   DOMAIN          20..316
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          638..657
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          700..720
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           189..191
FT                   /note="SEG motif"
FT   MOTIF           332..337
FT                   /note="FRIEDE motif"
FT   ACT_SITE        152
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         189
FT                   /note="Phosphoserine; by PAK1, PAK2 and PAK3"
FT                   /evidence="ECO:0000305|PubMed:18720373"
FT   MOD_RES         386
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16659"
FT   MOD_RES         554
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16659"
FT   MOD_RES         556
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16659"
FT   MOD_RES         683
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16659"
FT   CROSSLNK        1
FT                   /note="Peptide (Met-Gly) (interchain with G-Cter in
FT                   ubiquitin)"
FT                   /evidence="ECO:0000250"
FT   MUTAGEN         171
FT                   /note="D->A: Kinase defective mutant, abolishes activity."
FT                   /evidence="ECO:0000269|PubMed:15577943"
FT   MUTAGEN         189
FT                   /note="S->A: Unable to activate MAPKAPK5 promote MAPKAPK5
FT                   localization to the cytoplasm."
FT                   /evidence="ECO:0000269|PubMed:15577943,
FT                   ECO:0000269|PubMed:18720373"
FT   MUTAGEN         189
FT                   /note="S->E: Mimicks phosphorylation state and induces
FT                   constitutive protein kinase activity."
FT                   /evidence="ECO:0000269|PubMed:15577943,
FT                   ECO:0000269|PubMed:18720373"
FT   MUTAGEN         334
FT                   /note="I->K: Abolishes binding to MAPKAPK5."
FT                   /evidence="ECO:0000269|PubMed:19473979"
FT   CONFLICT        19
FT                   /note="R -> T (in Ref. 2; AAN64588)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        40..41
FT                   /note="ND -> KY (in Ref. 2; AAN64588)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        63
FT                   /note="L -> P (in Ref. 3; AAI00386)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        123
FT                   /note="P -> S (in Ref. 1; AAF61348)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        574
FT                   /note="E -> K (in Ref. 2; AAN64588)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   720 AA;  82199 MW;  D8BC667DEF6F62E2 CRC64;
     MAEKFESLMN IHGFDLGSRY MDLKPLGCGG NGLVFSAVDN DCDKRVAIKK IVLTDPQSVK
     HALREIKIIR RLDHDNIVKV FEILGPSGSQ LTDDVGSLTE LNSVYIVQEY METDLANVLE
     QGPLLEEHAR LFMYQLLRGL KYIHSANVLH RDLKPANLFI NTEDLVLKIG DFGLARIMDP
     HYSHKGHLSE GLVTKWYRSP RLLLSPNNYT KAIDMWAAGC IFAEMLTGKT LFAGAHELEQ
     MQLILDSIPV VHEEDRQELL SVIPVYIRND MTEPHRPLTQ LLPGISREAL DFLEQILTFS
     PMDRLTAEEA LSHPYMSIYS FPTDEPISSH PFHIEDEVDD ILLMDETHSH IYNWERYHDC
     QFSEHDWPIH NNFDIDEVQL DPRALSDVTD EEEVQVDPRK YLDGDREKYL EDPAFDTSYS
     AEPCWQYPDH HENKYCDLEC SHTCNYKTRS SPYLDNLVWR ESEVNHYYEP KLIIDLSNWK
     EQSKEKSDKR GKSKCERNGL VKAQIALEEA SQQLAERERG QGFDFDSFIA GTIQLSAQHQ
     SADVVDKLND LNSSVSQLEL KSLISKSVSR EKQEKGRANL AQLGALYQSS WDSQFVSGGE
     ECFLISQFCC EVRKDEHAEK ENTYTSYLDK FFSRKEDSEM LETEPVEEGK RGERGREAGL
     LSGGGEFLLS KQLESIGTPQ FHSPVGSPLK SIQATLTPSA MKSSPQIPHK TYSSILKHLN
//