ID MK15_RAT Reviewed; 547 AA. AC Q9Z2A6; DT 18-APR-2006, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2002, sequence version 2. DT 24-JAN-2024, entry version 165. DE RecName: Full=Mitogen-activated protein kinase 15 {ECO:0000305}; DE Short=MAP kinase 15; DE Short=MAPK 15; DE EC=2.7.11.24; DE AltName: Full=Extracellular signal-regulated kinase 7; DE Short=ERK-7; DE AltName: Full=Extracellular signal-regulated kinase 8; DE Short=ERK-8; GN Name=Mapk15; GN Synonyms=Erk7 {ECO:0000303|PubMed:9891064}, Erk8 GN {ECO:0000303|PubMed:11875070}; 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], FUNCTION, DOMAIN, TISSUE SPECIFICITY, RP SUBCELLULAR LOCATION, CHARACTERIZATION, PHOSPHORYLATION AT THR-176 AND RP TYR-178, MUTAGENESIS OF LYS-43; THR-176; TYR-178 AND 176-THR--TYR-178, AND RP ACTIVITY REGULATION. RC STRAIN=Sprague-Dawley; TISSUE=Testis; RX PubMed=9891064; DOI=10.1128/mcb.19.2.1301; RA Abe M.K., Kuo W.-L., Hershenson M.B., Rosner M.R.; RT "Extracellular signal-regulated kinase 7 (ERK7), a novel ERK with a C- RT terminal domain that regulates its activity, its cellular localization, and RT cell growth."; RL Mol. Cell. Biol. 19:1301-1312(1999). RN [2] RP PROTEIN SEQUENCE OF 154-161, AND IDENTIFICATION BY MASS SPECTROMETRY. RC STRAIN=Sprague-Dawley; TISSUE=Brain; RA Lubec G., Kang S.U.; RL Submitted (JUL-2007) to UniProtKB. RN [3] RP INTERACTION WITH CLIC3, AND SUBCELLULAR LOCATION. RX PubMed=9880541; DOI=10.1074/jbc.274.3.1621; RA Qian Z., Okuhara D., Abe M.K., Rosner M.R.; RT "Molecular cloning and characterization of a mitogen-activated protein RT kinase-associated intracellular chloride channel."; RL J. Biol. Chem. 274:1621-1627(1999). RN [4] RP DOMAIN, AND CHARACTERIZATION. RX PubMed=11287416; DOI=10.1074/jbc.m100026200; RA Abe M.K., Kahle K.T., Saelzler M.P., Orth K., Dixon J.E., Rosner M.R.; RT "ERK7 is an autoactivated member of the MAPK family."; RL J. Biol. Chem. 276:21272-21279(2001). RN [5] RP FUNCTION. RX PubMed=11875070; DOI=10.1074/jbc.m112483200; RA Abe M.K., Saelzler M.P., Espinosa R. III, Kahle K.T., Hershenson M.B., RA Le Beau M.M., Rosner M.R.; RT "ERK8, a new member of the mitogen-activated protein kinase family."; RL J. Biol. Chem. 277:16733-16743(2002). RN [6] RP UBIQUITINATION, AND TISSUE SPECIFICITY. RX PubMed=15033983; DOI=10.1074/jbc.m313696200; RA Kuo W.-L., Duke C.J., Abe M.K., Kaplan E.L., Gomes S., Rosner M.R.; RT "ERK7 expression and kinase activity is regulated by the ubiquitin- RT proteosome pathway."; RL J. Biol. Chem. 279:23073-23081(2004). CC -!- FUNCTION: Atypical MAPK protein that regulates several process such as CC autophagy, ciliogenesis, protein trafficking/secretion and genome CC integrity, in a kinase activity-dependent manner. Controls both, basal CC and starvation-induced autophagy throught its interaction with GABARAP, CC MAP1LC3B and GABARAPL1 leading to autophagosome formation, SQSTM1 CC degradation and reduced MAP1LC3B inhibitory phosphorylation. Regulates CC primary cilium formation and the localization of ciliary proteins CC involved in cilium structure, transport, and signaling. Prevents the CC relocation of the sugar-adding enzymes from the Golgi to the CC endoplasmic reticulum, thereby restricting the production of sugar- CC coated proteins. Upon amino-acid starvation, mediates transitional CC endoplasmic reticulum site disassembly and inhibition of secretion. CC Binds to chromatin leading to MAPK15 activation and interaction with CC PCNA, that which protects genomic integrity by inhibiting MDM2-mediated CC degradation of PCNA. Regulates DA transporter (DAT) activity and CC protein expression via activation of RhoA. In response to H(2)O(2) CC treatment phosphorylates ELAVL1, thus preventing it from binding to the CC PDCD4 3'UTR and rendering the PDCD4 mRNA accessible to miR-21 and CC leading to its degradation and loss of protein expression (By CC similarity). Also functions in a kinase activity-independent manner as CC a negative regulator of growth (PubMed:9891064). Phosphorylates in CC vitro FOS and MBP (PubMed:11875070). During oocyte maturation, plays a CC key role in the microtubule organization and mei- otic cell cycle CC progression in oocytes, fertilized eggs, and early embryos (By CC similarity). Interacts with ESRRA promoting its re-localization from CC the nucleus to the cytoplasm and then prevents its transcriptional CC activity (By similarity). {ECO:0000250|UniProtKB:Q80Y86, CC ECO:0000250|UniProtKB:Q8TD08, ECO:0000269|PubMed:11875070, CC ECO:0000269|PubMed:9891064}. 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 -!- ACTIVITY REGULATION: Activated by threonine and tyrosine CC phosphorylation. Inhibited by dual specificity phosphatases, such as CC DUSP1 (By similarity). Phosphorylation and activation in response to CC DNA damaging agents, serum stimulation. Constitutively activated when CC phosphorylated on Tyr-178. Activity depends on the relative rates of CC MAPK15 autophosphorylation and dephosphorylation by PTPN1 (By CC similarity). {ECO:0000250|UniProtKB:Q8TD08, CC ECO:0000269|PubMed:9891064}. CC -!- SUBUNIT: Interacts with CSK/c-Src, ABL1, RET and TGFB1I1. Interacts CC with GABARAP, MAP1LC3B and GABARAPL1; controls, in a kinase-dependent CC fashion, both basal and starvation-induced autophagy. Interacts with CC ESRRA; promotes re-localization of ESRRA to the cytoplasm through a CC XPO1-dependent mechanism then inhibits ESRRA transcriptional activity. CC Interacts with PCNA; the interaction is chromatin binding- and kinase CC activity-dependent and prevents MDM2-mediated PCNA destruction by CC inhibiting the association of PCNA with MDM2 (By similarity). Interacts CC with DVL2 (By similarity). Interacts with CLIC3; MAPK15 does not CC phosphorylates CLIC3 (PubMed:9880541). {ECO:0000250|UniProtKB:Q80Y86, CC ECO:0000250|UniProtKB:Q8TD08, ECO:0000269|PubMed:9880541}. CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, cilium basal body CC {ECO:0000250|UniProtKB:Q8TD08}. Cell junction, tight junction CC {ECO:0000250|UniProtKB:Q8TD08}. Cytoplasm, cytoskeleton, microtubule CC organizing center, centrosome, centriole CC {ECO:0000250|UniProtKB:Q8TD08}. Cytoplasmic vesicle, autophagosome CC {ECO:0000250|UniProtKB:Q8TD08}. Golgi apparatus CC {ECO:0000250|UniProtKB:Q8TD08}. Nucleus {ECO:0000269|PubMed:9880541, CC ECO:0000269|PubMed:9891064}. Cytoplasm {ECO:0000250|UniProtKB:Q8TD08}. CC Cytoplasm, cytoskeleton, spindle {ECO:0000250|UniProtKB:Q80Y86}. CC Note=Co-localizes to the cytoplasm only in presence of ESRRA. CC Translocates to the nucleus upon activation (By similarity). At CC prometaphase I, metaphase I (MI), anaphase I, telophase I, and CC metaphase II (MII) stages, is stably detected at the spindle (By CC similarity). {ECO:0000250|UniProtKB:Q80Y86, CC ECO:0000250|UniProtKB:Q8TD08}. CC -!- TISSUE SPECIFICITY: Ubiquitously expressed at a weak level. Highest CC expression is found in testis and to a lower extent in lung. CC {ECO:0000269|PubMed:15033983, ECO:0000269|PubMed:9891064}. CC -!- DOMAIN: C-terminal domain, rather than the kinase activity, is required CC for the full function of the enzyme. This region may be a protein CC interaction domain that regulates kinase localization, activation and CC transcriptional activity. When C-terminally truncated, the enzyme shows CC a reduction in the Thr-Glu-Tyr (TEY) phosphorylation level, in the in CC vitro kinase activity, in its nuclear localization and in its CC inhibitory effect on cell growth. CC -!- DOMAIN: The N-terminal region (1-20) is the minimal region necessary CC for ubiquitination and further proteasomal degradation. CC -!- DOMAIN: The TXY motif contains the threonine and tyrosine residues CC whose phosphorylation activates the MAP kinases. CC -!- PTM: Autophosphorylated on Thr-176 and Tyr-178; activates the enzyme. CC {ECO:0000269|PubMed:9891064}. CC -!- PTM: Dephosphorylated by PTPN1. {ECO:0000250|UniProtKB:Q8TD08}. CC -!- PTM: Ubiquitinated. Ubiquitination may allow its tight kinase activity CC regulation and rapid turnover. May be ubiquitinated by a SCF E3 ligase. CC {ECO:0000269|PubMed:15033983}. 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; AF078798; AAD12719.2; -; mRNA. DR RefSeq; NP_775453.1; NM_173331.2. DR RefSeq; XP_006241841.1; XM_006241779.3. DR AlphaFoldDB; Q9Z2A6; -. DR SMR; Q9Z2A6; -. DR IntAct; Q9Z2A6; 1. DR MINT; Q9Z2A6; -. DR STRING; 10116.ENSRNOP00000075332; -. DR iPTMnet; Q9Z2A6; -. DR PhosphoSitePlus; Q9Z2A6; -. DR jPOST; Q9Z2A6; -. DR PaxDb; 10116-ENSRNOP00000012460; -. DR Ensembl; ENSRNOT00000012461.5; ENSRNOP00000012460.3; ENSRNOG00000009336.6. DR Ensembl; ENSRNOT00060036494; ENSRNOP00060030033; ENSRNOG00060021050. DR Ensembl; ENSRNOT00065015061; ENSRNOP00065011266; ENSRNOG00065009415. DR GeneID; 286997; -. DR KEGG; rno:286997; -. DR AGR; RGD:628675; -. DR CTD; 225689; -. DR RGD; 628675; Mapk15. DR eggNOG; KOG0660; Eukaryota. DR GeneTree; ENSGT00940000159758; -. DR HOGENOM; CLU_000288_181_14_1; -. DR InParanoid; Q9Z2A6; -. DR OrthoDB; 117891at2759; -. DR PhylomeDB; Q9Z2A6; -. DR TreeFam; TF105101; -. DR PRO; PR:Q9Z2A6; -. DR Proteomes; UP000002494; Chromosome 7. DR Bgee; ENSRNOG00000009336; Expressed in testis and 12 other cell types or tissues. DR ExpressionAtlas; Q9Z2A6; baseline and differential. DR GO; GO:0005776; C:autophagosome; ISS:UniProtKB. DR GO; GO:0005923; C:bicellular tight junction; IEA:UniProtKB-SubCell. DR GO; GO:0005911; C:cell-cell junction; ISS:UniProtKB. DR GO; GO:0005814; C:centriole; ISS:UniProtKB. DR GO; GO:0036064; C:ciliary basal body; ISS:UniProtKB. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0072687; C:meiotic spindle; ISO:RGD. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB. DR GO; GO:0016301; F:kinase activity; ISS:UniProtKB. DR GO; GO:0004707; F:MAP kinase activity; ISS:UniProtKB. DR GO; GO:0004672; F:protein kinase activity; ISS: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:0006974; P:DNA damage response; ISO:RGD. DR GO; GO:0090494; P:dopamine uptake; ISS:UniProtKB. DR GO; GO:0007029; P:endoplasmic reticulum organization; ISS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central. DR GO; GO:0030336; P:negative regulation of cell migration; ISS:UniProtKB. DR GO; GO:0008156; P:negative regulation of DNA replication; IMP:RGD. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:RGD. DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB. DR GO; GO:1905188; P:positive regulation of metaphase/anaphase transition of meiosis I; ISO:RGD. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IMP:RGD. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:RGD. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IMP:RGD. DR GO; GO:1905832; P:positive regulation of spindle assembly; ISO:RGD. DR GO; GO:1904355; P:positive regulation of telomere capping; ISO:RGD. DR GO; GO:0032212; P:positive regulation of telomere maintenance via telomerase; ISO:RGD. DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB. DR GO; GO:1904491; P:protein localization to ciliary transition zone; ISO:RGD. DR GO; GO:0010506; P:regulation of autophagy; ISS:UniProtKB. DR GO; GO:1902017; P:regulation of cilium assembly; ISS:UniProtKB. DR GO; GO:0003400; P:regulation of COPII vesicle coating; ISS:UniProtKB. DR GO; GO:0032355; P:response to estradiol; IMP:RGD. DR CDD; cd07852; STKc_MAPK15-like; 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; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR PANTHER; PTHR24055; MITOGEN-ACTIVATED PROTEIN KINASE; 1. DR PANTHER; PTHR24055:SF79; MITOGEN-ACTIVATED PROTEIN KINASE 15; 1. DR Pfam; PF00069; Pkinase; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS01351; MAPK; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR Genevisible; Q9Z2A6; RN. PE 1: Evidence at protein level; KW ATP-binding; Cell junction; Cell projection; Cytoplasm; KW Cytoplasmic vesicle; Cytoskeleton; Direct protein sequencing; KW Golgi apparatus; Kinase; Methylation; Nucleotide-binding; Nucleus; KW Phosphoprotein; Reference proteome; Repeat; KW Serine/threonine-protein kinase; Tight junction; Transferase; KW Ubl conjugation. FT CHAIN 1..547 FT /note="Mitogen-activated protein kinase 15" FT /id="PRO_0000232639" FT DOMAIN 14..305 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REPEAT 378..382 FT /note="PXXXP motif" FT /evidence="ECO:0000250|UniProtKB:Q8TD08" FT REPEAT 385..389 FT /note="PXXXP motif" FT /evidence="ECO:0000250|UniProtKB:Q8TD08" FT REPEAT 393..397 FT /note="PXXXP motif; regulates binding with chromatin and FT interaction with PCNA" FT /evidence="ECO:0000250|UniProtKB:Q8TD08" FT REPEAT 401..405 FT /note="PXXXP motif; regulates binding with chromatin and FT interaction with PCNA" FT /evidence="ECO:0000250|UniProtKB:Q8TD08" FT REGION 1..20 FT /note="Ubiquitin-conjugating" FT REGION 266..286 FT /note="Necessary to interact with ESRRA, to regulate its FT subcellular localization and to inhibit its transcriptional FT activity" FT /evidence="ECO:0000250|UniProtKB:Q8TD08" FT REGION 301..380 FT /note="Requires for interaction with GABARAP, MAP1LC3B AND FT GABARAPL1" FT /evidence="ECO:0000250|UniProtKB:Q8TD08" FT REGION 370..503 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 176..178 FT /note="TXY" FT COMPBIAS 397..413 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 423..437 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 451..465 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 138 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 20..28 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 43 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 176 FT /note="Phosphothreonine" FT /evidence="ECO:0000269|PubMed:9891064" FT MOD_RES 178 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:9891064" FT MOD_RES 449 FT /note="Omega-N-methylarginine" FT /evidence="ECO:0000250|UniProtKB:Q8TD08" FT MUTAGEN 43 FT /note="K->R: Loss of autophosphorylation and activity." FT /evidence="ECO:0000269|PubMed:9891064" FT MUTAGEN 176 FT /note="T->A: Loss of autophosphorylation and activity. Loss FT of autophosphorylation and activity; when associated with FT F-178." FT /evidence="ECO:0000269|PubMed:9891064" FT MUTAGEN 178 FT /note="Y->F: Loss of autophosphorylation and activity. Loss FT of autophosphorylation and activity; when associated with FT A-176." FT /evidence="ECO:0000269|PubMed:9891064" SQ SEQUENCE 547 AA; 60724 MW; D8B7D9955B06862F CRC64; MCAAEVDRHV SQRYLIKRRL GKGAYGIVWK AMDRRTGEVV AIKKIFDAFR DQTDAQRTFR EIMLLREFGG HPNIIRLLDV IPAKNDRDIY LVFESMDTDL NAVIQKGRLL EDIHKRCIFY QLLRATKFIH SGRVIHRDQK PANVLLDAAC RVKLCDFGLA RSLSDFPEGP GGQALTEYVA TRWYRAPEVL LSSRWYTPGV DMWSLGCILG EMLRGQPLFP GTSTFHQLEL ILETIPLPSM EELQGLGSDY SALILQNLGS RPRQTLDALL PPDTPPEALD LLKRLLAFAP DKRLSAEQAL QHPYVQRFHC PDREWTRGSD VRLPVHEGDQ LSAPEYRNRL YQMILERRRN SRSPREEDLG VVASRAELRA SQRQSLKPGV LPQVLAETPA RKRGPKPQNG HGHDPEHVEV RRQSSDPLYQ LPPPGSGERP PGATGEPPSA PSGVKTHVRA VAPSLTSQAA AQAANQPLIR SDPARGGGPR AVGARRVPSR LPREAPEPRP GRRMFGISVS QGAQGAARAA LGGYSQAYGT VCRSALGRLP LLPGPRA //