MK15_RAT
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 03-AUG-2022, entry version 159.
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},
GN Erk8 {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}.
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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.ENSRNOP00000012460; -.
DR iPTMnet; Q9Z2A6; -.
DR jPOST; Q9Z2A6; -.
DR PaxDb; Q9Z2A6; -.
DR PRIDE; Q9Z2A6; -.
DR Ensembl; ENSRNOT00000012461; ENSRNOP00000012460; ENSRNOG00000009336.
DR GeneID; 286997; -.
DR KEGG; rno:286997; -.
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 PhylomeDB; Q9Z2A6; -.
DR TreeFam; TF105101; -.
DR PRO; PR:Q9Z2A6; -.
DR Proteomes; UP000002494; Chromosome 7.
DR Bgee; ENSRNOG00000009336; Expressed in testis and 12 other tissues.
DR ExpressionAtlas; Q9Z2A6; baseline and differential.
DR Genevisible; Q9Z2A6; RN.
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:cellular response to DNA damage stimulus; 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:0051973; P:positive regulation of telomerase activity; 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; IMP:RGD.
DR GO; GO:1904491; P:protein localization to ciliary transition zone; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA: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 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 Pfam; PF00069; Pkinase; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS01351; MAPK; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
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
