ID MK09_RAT Reviewed; 423 AA. AC P49186; DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1996, sequence version 1. DT 27-MAR-2024, entry version 188. DE RecName: Full=Mitogen-activated protein kinase 9; DE Short=MAP kinase 9; DE Short=MAPK 9; DE EC=2.7.11.24 {ECO:0000269|PubMed:10856240}; DE AltName: Full=SAPK-alpha; DE AltName: Full=Stress-activated protein kinase JNK2; DE AltName: Full=c-Jun N-terminal kinase 2; DE AltName: Full=p54-alpha; GN Name=Mapk9; Synonyms=Jnk2, Prkm9; 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 [MRNA] (ISOFORMS ALPHA-1 AND ALPHA-2), AND PARTIAL RP PROTEIN SEQUENCE. RC TISSUE=Brain; RX PubMed=8177321; DOI=10.1038/369156a0; RA Kyriakis J.M., Banerjee P., Nikolakaki E., Dai T., Rubie E.A., Ahmad M.F., RA Avruch J., Woodgett J.R.; RT "The stress-activated protein kinase subfamily of c-Jun kinases."; RL Nature 369:156-160(1994). RN [2] RP INTERACTION WITH MECOM, AND CATALYTIC ACTIVITY. RX PubMed=10856240; DOI=10.1093/emboj/19.12.2958; RA Kurokawa M., Mitani K., Yamagata T., Takahashi T., Izutsu K., Ogawa S., RA Moriguchi T., Nishida E., Yazaki Y., Hirai H.; RT "The evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents RT stress-induced cell death."; RL EMBO J. 19:2958-2968(2000). CC -!- FUNCTION: Serine/threonine-protein kinase involved in various processes CC such as cell proliferation, differentiation, migration, transformation CC and programmed cell death. Extracellular stimuli such as pro- CC inflammatory cytokines or physical stress stimulate the stress- CC activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling CC pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and CC MAP2K7/MKK7 phosphorylate and activate MAPK9/JNK2. In turn, MAPK9/JNK2 CC phosphorylates a number of transcription factors, primarily components CC of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional CC activity. In response to oxidative or ribotoxic stresses, inhibits rRNA CC synthesis by phosphorylating and inactivating the RNA polymerase 1- CC specific transcription initiation factor RRN3. Promotes stressed cell CC apoptosis by phosphorylating key regulatory factors including TP53 and CC YAP1. In T-cells, MAPK8 and MAPK9 are required for polarized CC differentiation of T-helper cells into Th1 cells. Upon T-cell receptor CC (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and CC MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in CC the osmotic stress-induced epithelial tight-junctions disruption. When CC activated, promotes beta-catenin/CTNNB1 degradation and inhibits the CC canonical Wnt signaling pathway. Participates also in neurite growth in CC spiral ganglion neurons. Phosphorylates the CLOCK-BMAL1 heterodimer and CC plays a role in the regulation of the circadian clock. Phosphorylates CC POU5F1, which results in the inhibition of POU5F1's transcriptional CC activity and enhances its proteasomal degradation. CC {ECO:0000250|UniProtKB:P45984, ECO:0000250|UniProtKB:Q9WTU6}. 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 Evidence={ECO:0000269|PubMed:10856240}; 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; Evidence={ECO:0000269|PubMed:10856240}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:P45984}; CC -!- ACTIVITY REGULATION: Activated by threonine and tyrosine CC phosphorylation by either of two dual specificity kinases, MAP2K4 and CC MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 CC phosphorylates Tyr-183 preferentially. Inhibited by dual specificity CC phosphatases, such as DUSP1. {ECO:0000250|UniProtKB:P45984}. CC -!- SUBUNIT: Interacts with MECOM (PubMed:10856240). Binds to at least four CC scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK8IP3/JIP- CC 3/JSAP1 and SPAG9/MAPK8IP4/JIP-4. These proteins also bind other CC components of the JNK signaling pathway (By similarity). Interacts with CC NFATC4 (By similarity). Interacts with ATF7; the interaction does not CC phosphorylate ATF7 but acts as a docking site for ATF7-associated CC partners such as JUN (By similarity). Interacts with BCL10 (By CC similarity). Interacts with CTNNB1 and GSK3B (By similarity). Interacts CC with DCLK2 (By similarity). Interacts with MAPKBP1 (By similarity). CC Interacts with POU5F1; phosphorylates POU5F1 at 'Ser-347'. Found in a CC complex with SH3RF1, RAC2, MAP3K7/TAK1, MAP2K7/MKK7, MAPK8IP1/JIP1 and CC MAPK8/JNK1 (By similarity). {ECO:0000250|UniProtKB:P45984, CC ECO:0000250|UniProtKB:Q9WTU6, ECO:0000269|PubMed:10856240}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P45984}. Nucleus CC {ECO:0000250|UniProtKB:Q9WTU6}. Note=Colocalizes with POU5F1 in the CC nucleus. {ECO:0000250|UniProtKB:Q9WTU6}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=Alpha-2; CC IsoId=P49186-1; Sequence=Displayed; CC Name=Alpha-1; CC IsoId=P49186-2; Sequence=VSP_004838; CC -!- DOMAIN: The TXY motif contains the threonine and tyrosine residues CC whose phosphorylation activates the MAP kinases. CC -!- PTM: Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, CC which activates the enzyme. Autophosphorylated in vitro. CC {ECO:0000250|UniProtKB:P45984}. 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; L27112; AAA42109.1; -; mRNA. DR EMBL; L27111; AAA42108.1; -; mRNA. DR PIR; S43968; S43968. DR RefSeq; NP_001257473.1; NM_001270544.1. DR RefSeq; NP_059018.1; NM_017322.2. [P49186-1] DR AlphaFoldDB; P49186; -. DR SMR; P49186; -. DR BioGRID; 248408; 1. DR IntAct; P49186; 2. DR MINT; P49186; -. DR STRING; 10116.ENSRNOP00000004010; -. DR iPTMnet; P49186; -. DR PhosphoSitePlus; P49186; -. DR jPOST; P49186; -. DR PaxDb; 10116-ENSRNOP00000003987; -. DR GeneID; 50658; -. DR KEGG; rno:50658; -. DR UCSC; RGD:628847; rat. [P49186-1] DR AGR; RGD:628847; -. DR CTD; 5601; -. DR RGD; 628847; Mapk9. DR eggNOG; KOG0665; Eukaryota. DR InParanoid; P49186; -. DR OrthoDB; 158564at2759; -. DR PhylomeDB; P49186; -. DR BRENDA; 2.7.11.24; 5301. DR Reactome; R-RNO-2559580; Oxidative Stress Induced Senescence. DR Reactome; R-RNO-2871796; FCERI mediated MAPK activation. DR Reactome; R-RNO-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1. DR Reactome; R-RNO-450341; Activation of the AP-1 family of transcription factors. DR PRO; PR:P49186; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0005737; C:cytoplasm; ISO:RGD. DR GO; GO:0005829; C:cytosol; IDA:MGI. DR GO; GO:0005739; C:mitochondrion; ISO:RGD. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0043204; C:perikaryon; IDA:RGD. DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; ISO:RGD. DR GO; GO:0005524; F:ATP binding; IDA:RGD. DR GO; GO:0008656; F:cysteine-type endopeptidase activator activity involved in apoptotic process; IMP:RGD. DR GO; GO:0004705; F:JUN kinase activity; IDA:RGD. DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; IPI:RGD. DR GO; GO:0004672; F:protein kinase activity; ISO:RGD. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:RGD. DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; ISO:RGD. DR GO; GO:0097190; P:apoptotic signaling pathway; ISO:RGD. DR GO; GO:0071474; P:cellular hyperosmotic response; IEP:RGD. DR GO; GO:1904646; P:cellular response to amyloid-beta; IEP:RGD. DR GO; GO:0071276; P:cellular response to cadmium ion; ISO:RGD. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEP:RGD. DR GO; GO:0071347; P:cellular response to interleukin-1; IEP:RGD. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEP:RGD. DR GO; GO:0034614; P:cellular response to reactive oxygen species; ISO:RGD. DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IEP:RGD. DR GO; GO:0034644; P:cellular response to UV; IMP:RGD. DR GO; GO:0090594; P:inflammatory response to wounding; ISO:RGD. DR GO; GO:0007254; P:JNK cascade; IDA:RGD. DR GO; GO:0050804; P:modulation of chemical synaptic transmission; ISO:RGD. DR GO; GO:0048666; P:neuron development; IEP:RGD. DR GO; GO:0031175; P:neuron projection development; IMP:RGD. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:RGD. DR GO; GO:2001235; P:positive regulation of apoptotic signaling pathway; ISO:RGD. DR GO; GO:0045597; P:positive regulation of cell differentiation; IMP:RGD. DR GO; GO:0032722; P:positive regulation of chemokine production; IMP:RGD. DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; ISO:RGD. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:RGD. DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD. DR GO; GO:0010744; P:positive regulation of macrophage derived foam cell differentiation; ISO:RGD. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IMP:RGD. DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IMP:RGD. DR GO; GO:0071803; P:positive regulation of podosome assembly; ISO:RGD. DR GO; GO:0031394; P:positive regulation of prostaglandin biosynthetic process; IMP:RGD. DR GO; GO:0032308; P:positive regulation of prostaglandin secretion; IMP:RGD. DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISO:RGD. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:RGD. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISO:RGD. DR GO; GO:0061833; P:protein localization to tricellular tight junction; ISO:RGD. DR GO; GO:0006626; P:protein targeting to mitochondrion; IEP:RGD. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0046328; P:regulation of JNK cascade; IMP:RGD. DR GO; GO:0031396; P:regulation of protein ubiquitination; IMP:RGD. DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IMP:RGD. DR GO; GO:0014075; P:response to amine; IEP:RGD. DR GO; GO:0046686; P:response to cadmium ion; ISO:RGD. DR GO; GO:0009612; P:response to mechanical stimulus; IEP:RGD. DR GO; GO:1990089; P:response to nerve growth factor; IEP:RGD. DR GO; GO:0010033; P:response to organic substance; IEP:RGD. DR GO; GO:0009636; P:response to toxic substance; IEP:RGD. DR GO; GO:0009410; P:response to xenobiotic stimulus; IMP:RGD. DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW. DR CDD; cd07850; STKc_JNK; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR003527; MAP_kinase_CS. DR InterPro; IPR008351; MAPK_JNK. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24055; MITOGEN-ACTIVATED PROTEIN KINASE; 1. DR PANTHER; PTHR24055:SF172; MITOGEN-ACTIVATED PROTEIN KINASE 9; 1. DR Pfam; PF00069; Pkinase; 1. DR PRINTS; PR01772; JNKMAPKINASE. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS01351; MAPK; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; P49186; RN. PE 1: Evidence at protein level; KW Alternative splicing; ATP-binding; Biological rhythms; Cytoplasm; KW Direct protein sequencing; Kinase; Nucleotide-binding; Nucleus; KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase; KW Transferase. FT CHAIN 1..423 FT /note="Mitogen-activated protein kinase 9" FT /id="PRO_0000186275" FT DOMAIN 26..321 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 366..423 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 183..185 FT /note="TXY" FT COMPBIAS 374..415 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 151 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 32..40 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 55 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 183 FT /note="Phosphothreonine; by MAP2K7" FT /evidence="ECO:0000250|UniProtKB:P45984" FT MOD_RES 185 FT /note="Phosphotyrosine; by MAP2K4" FT /evidence="ECO:0000250|UniProtKB:P45984" FT VAR_SEQ 216..230 FT /note="GELVKGCVIFQGTDH -> AEMVLHKSCSPGRDY (in isoform FT Alpha-1)" FT /evidence="ECO:0000303|PubMed:8177321" FT /id="VSP_004838" SQ SEQUENCE 423 AA; 48017 MW; EE549B9F4F12F421 CRC64; MSDSKSDGQF YSVQVADSTF TVLKRYQQLK PIGSGAQGIV CAAFDTVLGI NVAVKKLSRP FQNQTHAKRA YRELVLLKCV NHKNIISLLN VFTPQKTLEE FQDVYLVMEL MDANLCQVIH MELDHERMSY LLYQMLCGIK HLHSAGIIHR DLKPSNIVVK SDCTLKILDF GLARTACTNF MMTPYVVTRY YRAPEVILGM GYKENVDIWS VGCIMGELVK GCVIFQGTDH IDQWNKVIEQ LGTPSAEFMK KLQPTVRNYV ENRPKYPGIK FEELFPDWIF PSESERDKIK TSQARDLLSK MLVIDPDKRI SVDEALRHPY ITVWYDPAEA EAPPPQIYDA QLEEREHAIE EWKELIYKEV MDWEERSKNG VKDQPSDAAV SSKATPSQSS SINDISSMST EHTLASDTDS SLDASTGPLE GCR //