ID   MAPK3_RAT               Reviewed;         384 AA.
AC   Q66H84;
DT   06-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT   11-OCT-2004, sequence version 1.
DT   24-JAN-2024, entry version 145.
DE   RecName: Full=MAP kinase-activated protein kinase 3;
DE            Short=MAPK-activated protein kinase 3;
DE            Short=MAPKAP kinase 3;
DE            Short=MAPKAP-K3;
DE            Short=MAPKAPK-3;
DE            Short=MK-3;
DE            EC=2.7.11.1;
GN   Name=Mapkapk3;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Kidney;
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).
CC   -!- FUNCTION: Stress-activated serine/threonine-protein kinase involved in
CC       cytokines production, endocytosis, cell migration, chromatin remodeling
CC       and transcriptional regulation. Following stress, it is phosphorylated
CC       and activated by MAP kinase p38-alpha/MAPK14, leading to
CC       phosphorylation of substrates. Phosphorylates serine in the peptide
CC       sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue.
CC       MAPKAPK2 and MAPKAPK3, share the same function and substrate
CC       specificity, but MAPKAPK3 kinase activity and level in protein
CC       expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1,
CC       KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates
CC       phosphorylation of HSP27/HSPB1 in response to stress, leading to
CC       dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps)
CC       oligomers and impair their chaperone activities and ability to protect
CC       against oxidative stress effectively. Involved in inflammatory response
CC       by regulating tumor necrosis factor (TNF) and IL6 production post-
CC       transcriptionally: acts by phosphorylating AU-rich elements (AREs)-
CC       binding proteins, such as TTP/ZFP36, leading to regulate the stability
CC       and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a
CC       major post-transcriptional regulator of TNF, promotes its binding to
CC       14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition
CC       of dependent degradation of ARE-containing transcript. Involved in
CC       toll-like receptor signaling pathway (TLR) in dendritic cells: required
CC       for acute TLR-induced macropinocytosis by phosphorylating and
CC       activating RPS6KA3. Also acts as a modulator of Polycomb-mediated
CC       repression (By 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=2.7.11.1;
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=2.7.11.1;
CC   -!- ACTIVITY REGULATION: Activated following phosphorylation by p38-
CC       alpha/MAPK14 following various stresses. Inhibited by ligand 5B (2'-[2-
CC       (1,3-benzodioxol-5-yl)pyrimidin-4-yl]-5',6'-
CC       dihydrospiro[piperidine-4,7'-pyrrolo[3,2-c]pyridin]- 4'(1'h)-one) and
CC       ligand P4O (2-[2-(2-fluorophenyl)pyridin-4-yl]-1,5,6,7-tetrahydro- 4h-
CC       pyrrolo[3,2-c]pyridin-4-one), 2 ATP-competitive inhibitors (By
CC       similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Heterodimer with p38-alpha/MAPK14. The heterodimer with p38-
CC       alpha/MAPK14 forms a stable complex: molecules are positioned 'face to
CC       face' so that the ATP-binding sites of both kinases are at the
CC       heterodimer interface. Interacts with TCF3 and with polycomb proteins,
CC       such as PCH2 and BMI1/PCGF4 (By similarity). {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}.
CC       Note=Predominantly located in the nucleus, when activated it
CC       translocates to the cytoplasm. {ECO:0000250}.
CC   -!- PTM: Phosphorylated and activated by MAPK1/ERK2 and MAPK3/ERK1.
CC       Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-203,
CC       Ser-253 and Thr-315. {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC       protein kinase family. {ECO:0000305}.
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DR   EMBL; BC081974; AAH81974.1; -; mRNA.
DR   RefSeq; NP_001012127.1; NM_001012127.1.
DR   RefSeq; XP_006243838.1; XM_006243776.3.
DR   RefSeq; XP_008764753.1; XM_008766531.2.
DR   AlphaFoldDB; Q66H84; -.
DR   SMR; Q66H84; -.
DR   STRING; 10116.ENSRNOP00000020065; -.
DR   iPTMnet; Q66H84; -.
DR   PhosphoSitePlus; Q66H84; -.
DR   PaxDb; 10116-ENSRNOP00000020065; -.
DR   Ensembl; ENSRNOT00000020065.6; ENSRNOP00000020065.3; ENSRNOG00000014832.7.
DR   Ensembl; ENSRNOT00055021044; ENSRNOP00055017012; ENSRNOG00055012357.
DR   Ensembl; ENSRNOT00060042850; ENSRNOP00060035489; ENSRNOG00060024691.
DR   Ensembl; ENSRNOT00065012942; ENSRNOP00065009527; ENSRNOG00065008167.
DR   GeneID; 315994; -.
DR   KEGG; rno:315994; -.
DR   UCSC; RGD:1304980; rat.
DR   AGR; RGD:1304980; -.
DR   CTD; 7867; -.
DR   RGD; 1304980; Mapkapk3.
DR   eggNOG; KOG0604; Eukaryota.
DR   GeneTree; ENSGT00940000154089; -.
DR   HOGENOM; CLU_000288_63_0_1; -.
DR   InParanoid; Q66H84; -.
DR   OMA; HIMREIC; -.
DR   OrthoDB; 1121238at2759; -.
DR   PhylomeDB; Q66H84; -.
DR   TreeFam; TF312891; -.
DR   Reactome; R-RNO-171007; p38MAPK events.
DR   Reactome; R-RNO-2559580; Oxidative Stress Induced Senescence.
DR   Reactome; R-RNO-4420097; VEGFA-VEGFR2 Pathway.
DR   Reactome; R-RNO-450302; activated TAK1 mediates p38 MAPK activation.
DR   PRO; PR:Q66H84; -.
DR   Proteomes; UP000002494; Chromosome 8.
DR   Bgee; ENSRNOG00000014832; Expressed in ovary and 20 other cell types or tissues.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0009931; F:calcium-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR   GO; GO:0005516; F:calmodulin binding; IBA:GO_Central.
DR   GO; GO:0004683; F:calmodulin-dependent protein kinase activity; IBA:GO_Central.
DR   GO; GO:0051019; F:mitogen-activated protein kinase binding; IBA:GO_Central.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR   GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR   GO; GO:0044351; P:macropinocytosis; ISS:UniProtKB.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   GO; GO:0034097; P:response to cytokine; ISS:UniProtKB.
DR   GO; GO:0032496; P:response to lipopolysaccharide; ISS:UniProtKB.
DR   GO; GO:0002224; P:toll-like receptor signaling pathway; ISS:UniProtKB.
DR   CDD; cd14172; STKc_MAPKAPK3; 1.
DR   Gene3D; 4.10.1170.10; MAP kinase activated protein kinase 2; 1.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR   InterPro; IPR011009; Kinase-like_dom_sf.
DR   InterPro; IPR027442; MAPKAPK_C.
DR   InterPro; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   PANTHER; PTHR24349:SF64; MAP KINASE-ACTIVATED PROTEIN KINASE 3; 1.
DR   PANTHER; PTHR24349; SERINE/THREONINE-PROTEIN KINASE; 1.
DR   Pfam; PF00069; Pkinase; 1.
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; Q66H84; RN.
PE   2: Evidence at transcript level;
KW   Acetylation; ATP-binding; Cytoplasm; Kinase; Nucleotide-binding; Nucleus;
KW   Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW   Transferase.
FT   CHAIN           1..384
FT                   /note="MAP kinase-activated protein kinase 3"
FT                   /id="PRO_0000086295"
FT   DOMAIN          46..306
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          1..33
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          309..345
FT                   /note="Autoinhibitory helix"
FT                   /evidence="ECO:0000250"
FT   REGION          347..371
FT                   /note="p38 MAPK-binding site"
FT                   /evidence="ECO:0000250"
FT   REGION          359..384
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           337..346
FT                   /note="Nuclear export signal (NES)"
FT                   /evidence="ECO:0000250"
FT   MOTIF           352..355
FT                   /note="Bipartite nuclear localization signal 1"
FT                   /evidence="ECO:0000250"
FT   MOTIF           366..370
FT                   /note="Bipartite nuclear localization signal 2"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        370..384
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        168
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         52..60
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   BINDING         75
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16644"
FT   MOD_RES         203
FT                   /note="Phosphothreonine; by MAPK14"
FT                   /evidence="ECO:0000250|UniProtKB:Q3UMW7"
FT   MOD_RES         253
FT                   /note="Phosphoserine; by MAPK14"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         309
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         315
FT                   /note="Phosphothreonine; by MAPK14"
FT                   /evidence="ECO:0000250"
SQ   SEQUENCE   384 AA;  43222 MW;  E094358C901F7E70 CRC64;
     MDGETAGEKG SLVPQPGALG APALGGAPAP GVRREPKKYA VTDDYQLSKQ VLGLGVNGKV
     LECYHRRSGQ KCALKLLYDS PKARQEVDHH WQASGGPHIV RILDVYENMH HGKRCLLIVM
     ECMEGGELFS RIQERGDQAF TEREAAEIMR DIGTAIQFLH SQNIAHRDVK PENLLYTSKE
     KDAVLKLTDF GFAKETTQNA LQTPCYTPYY VAPEVLGPEK YDKSCDMWSL GVIMYILLCG
     FPPFYSNTGQ AISPGMKRRI RLGQYGFPKP EWADVSEDAK QLIRLLLKTD PTERLTIMQF
     MNHPWINQSM EVPQTPLHTA RVLEEDKDHW DDVKEEMTSA LATMRVDYDQ VKIKDLKTSN
     NRLLNKRRKK QGGSSSASPG CNNQ
//