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Protein

Mitogen-activated protein kinase 15

Gene

MAPK15

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Atypical MAPK protein that regulates several process such as autophagy, ciliogenesis, protein trafficking/secretion and genome integrity, in a kinase activity-dependent manner (PubMed:22948227, PubMed:24618899, PubMed:29021280, PubMed:21847093, PubMed:20733054). Controls both, basal and starvation-induced autophagy throught its interaction with GABARAP, MAP1LC3B and GABARAPL1 leading to autophagosome formation, SQSTM1 degradation and reduced MAP1LC3B inhibitory phosphorylation (PubMed:22948227). Regulates primary cilium formation and the localization of ciliary proteins involved in cilium structure, transport, and signaling (PubMed:29021280). Prevents the relocation of the sugar-adding enzymes from the Golgi to the endoplasmic reticulum, thereby restricting the production of sugar-coated proteins (PubMed:24618899). Upon amino-acid starvation, mediates transitional endoplasmic reticulum site disassembly and inhibition of secretion (PubMed:21847093). Binds to chromatin leading to MAPK15 activation and interaction with PCNA, that which protects genomic integrity by inhibiting MDM2-mediated degradation of PCNA (PubMed:20733054). Regulates DA transporter (DAT) activity and protein expression via activation of RhoA (PubMed:28842414). In response to H2O2 treatment phosphorylates ELAVL1, thus preventing it from binding to the PDCD4 3'UTR and rendering the PDCD4 mRNA accessible to miR-21 and leading to its degradation and loss of protein expression (PubMed:26595526). Also functions in a kinase activity-independent manner as a negative regulator of growth (By similarity). Phosphorylates in vitro FOS and MBP (PubMed:11875070, PubMed:16484222, PubMed:20638370, PubMed:19166846). During oocyte maturation, plays a key role in the microtubule organization and meiotic cell cycle progression in oocytes, fertilized eggs, and early embryos (By similarity). Interacts with ESRRA promoting its re-localization from the nucleus to the cytoplasm and then prevents its transcriptional activity (PubMed:21190936).By similarity12 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Activated by threonine and tyrosine phosphorylation (PubMed:11875070, PubMed:16336213, PubMed:19166846). Inhibited by dual specificity phosphatases, such as DUSP1 (By similarity). Phosphorylation and activation in response to DNA damaging agents, serum stimulation (PubMed:11875070, PubMed:16336213, PubMed:19166846). Constitutively actived when phosphorylated on Tyr-177. Activity depends on the relative rates of MAPK15 autophosphorylation and dephosphorylation by PTPN1 (PubMed:16336213).By similarity3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei42ATPPROSITE-ProRule annotation1
Active sitei137Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi19 – 27ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • chromatin binding Source: UniProtKB
  • kinase activity Source: UniProtKB
  • MAP kinase activity Source: UniProtKB
  • protein kinase activity Source: UniProtKB
  • SH3 domain binding Source: UniProtKB

GO - Biological processi

  • cellular response to DNA damage stimulus Source: UniProtKB
  • dopamine uptake Source: UniProtKB
  • endoplasmic reticulum organization Source: UniProtKB
  • negative regulation of cell migration Source: UniProtKB
  • positive regulation of cell proliferation Source: UniProtKB
  • positive regulation of metaphase/anaphase transition of meiosis I Source: Ensembl
  • positive regulation of spindle assembly Source: Ensembl
  • positive regulation of telomerase activity Source: BHF-UCL
  • positive regulation of telomere capping Source: BHF-UCL
  • positive regulation of telomere maintenance via telomerase Source: BHF-UCL
  • protein autophosphorylation Source: UniProtKB
  • protein localization to ciliary transition zone Source: UniProtKB
  • regulation of autophagy Source: UniProtKB
  • regulation of cilium assembly Source: UniProtKB
  • regulation of COPII vesicle coating Source: UniProtKB
  • regulation of gene expression Source: GO_Central

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

SignaLinkiQ8TD08
SIGNORiQ8TD08

Names & Taxonomyi

Protein namesi
Recommended name:
Mitogen-activated protein kinase 15Curated (EC:2.7.11.24)
Short name:
MAP kinase 15
Short name:
MAPK 15
Alternative name(s):
Extracellular signal-regulated kinase 7
Short name:
ERK-7
Extracellular signal-regulated kinase 8
Short name:
ERK-8
Gene namesi
Name:MAPK15Imported
Synonyms:ERK7By similarity, ERK82 Publications
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

EuPathDBiHostDB:ENSG00000181085.14
HGNCiHGNC:24667 MAPK15
neXtProtiNX_Q8TD08

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell junction, Cell projection, Cytoplasm, Cytoplasmic vesicle, Cytoskeleton, Golgi apparatus, Nucleus, Tight junction

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi42K → A: Not phosphorylated at Thr-175 and Tyr-177. 1 Publication1
Mutagenesisi42K → R: Loss of autophosphorylation and activity. Does not increase dopamine transporter activity. Impairs kinase activity. Does not rescue cilium assembly in MAPK15-depleted cells. 3 Publications1
Mutagenesisi59R → Q: Does not increase dopamine transporter activity. Impairs kinase activity. 1 Publication1
Mutagenesisi155D → A: Unable to induce the formation of autophagosomal structures. Is able to bind to MAP1LC3B and to colocalize with this protein to autophagosomal structures. Does not induce phosphorylation by methyl methanesulfonate. Loas of phosphorylation. Dominant negative mutant. Not phosphorylated at Thr-175 and Tyr-177. 3 Publications1
Mutagenesisi175T → A: Loss of autophosphorylation and activity. Still heavily phosphorylated at Tyr-177. Does not rescues inhibition of O-glycosylation in MAPK15-depleted cells; when associated with F-177. 3 Publications1
Mutagenesisi177Y → A: Loss of autophosphorylation and activity. Heavily phosphorylated at Thr-175. 2 Publications1
Mutagenesisi177Y → F: Does not rescues inhibition of O-glycosylation in MAPK15-depleted cells; when associated with A-175. 1 Publication1
Mutagenesisi265 – 269LDALL → ADAAA: Markedly decreases interaction with ESRRA. Impairs interaction with ESRRA; when associated with A-281 and 284-A--A-285. Loses the ability to re-localize ESRRA to the cytoplasm. Does not affect subcellular location in cytoplasm in presence of ESRRA. Loses the ability to repress ESRRA transcriptional activity. 1 Publication5
Mutagenesisi281 – 285LRRLL → ARRAA: Markedly decreases interaction with ESRRA. Impairs interaction with ESRRA; when associated with A-265 and 268-A--A-269. Loses the ability to re-localize ESRRA to the cytoplasm. Does not affect subcellular location in cytoplasm in presence of ESRRA.Loses the ability to repress ESRRA transcriptional activity. 1 Publication5
Mutagenesisi300Q → A: Impairs interaction with PCNA. Associates with chromatin. 1 Publication1
Mutagenesisi340 – 343YQMI → AQMA: Impairs interaction with GABARAP and MAP1LC3B. Affects subcellular localization in autophagosome. Does not induce autophagy. 1 Publication4
Mutagenesisi390P → A: Impairs chromatin binding; when associated with A-398. Increases kinase activity; when associated with A-398. 1 Publication1
Mutagenesisi398P → A: Impairs chromatin binding; when associated with A-390. Increases kinase activity; when associated with A-390. 1 Publication1

Organism-specific databases

DisGeNETi225689
OpenTargetsiENSG00000181085
PharmGKBiPA142671478

Chemistry databases

ChEMBLiCHEMBL5198
GuidetoPHARMACOLOGYi2090

Polymorphism and mutation databases

BioMutaiMAPK15
DMDMi74760462

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002326371 – 544Mitogen-activated protein kinase 15Add BLAST544

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei175Phosphothreonine3 Publications1
Modified residuei177Phosphotyrosine3 Publications1
Modified residuei449Omega-N-methylarginineCombined sources1

Post-translational modificationi

Autophosphorylated on Thr-175 and Tyr-177; activates the enzyme.3 Publications
Ubiquitinated (PubMed:19166846). Ubiquitination may allow its tight kinase activity regulation and rapid turnover. May be ubiquitinated by a SCF E3 ligase (By similarity).By similarity1 Publication

Keywords - PTMi

Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ8TD08
MaxQBiQ8TD08
PaxDbiQ8TD08
PeptideAtlasiQ8TD08
PRIDEiQ8TD08
ProteomicsDBi74209
74210 [Q8TD08-2]
74211 [Q8TD08-3]

PTM databases

iPTMnetiQ8TD08
PhosphoSitePlusiQ8TD08

Expressioni

Tissue specificityi

Widely expressed with a maximal expression in lung and kidney.2 Publications

Gene expression databases

BgeeiENSG00000181085
CleanExiHS_MAPK15
GenevisibleiQ8TD08 HS

Organism-specific databases

HPAiHPA002704

Interactioni

Subunit structurei

Interacts with CSK/c-Src, ABL1, RET and TGFB1I1 (PubMed:11875070, PubMed:16484222, PubMed:16624805). Interacts with GABARAP, MAP1LC3B and GABARAPL1; controls, in a kinase-dependent fashion, both basal and starvation-induced autophagy (PubMed:22948227). Interacts with ESRRA; promotes re-localization of ESRRA to the cytoplasm through a XPO1-dependent mechanism then inhibits ESRRA transcriptional activity (PubMed:21190936). Interacts with PCNA; the interaction is chromatin binding- and kinase activity-dependent and prevents MDM2-mediated PCNA destruction by inhibiting the association of PCNA with MDM2 (PubMed:20733054). Interacts with DVL2 (By similarity). Interacts with CLIC3; MAPK15 does not phosphorylates CLIC3 (By similarity).By similarity6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
CDK2P249414EBI-1383794,EBI-375096

GO - Molecular functioni

  • SH3 domain binding Source: UniProtKB

Protein-protein interaction databases

BioGridi128827, 22 interactors
IntActiQ8TD08, 9 interactors
STRINGi9606.ENSP00000337691

Chemistry databases

BindingDBiQ8TD08

Structurei

3D structure databases

ProteinModelPortaliQ8TD08
SMRiQ8TD08
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini13 – 304Protein kinasePROSITE-ProRule annotationAdd BLAST292
Repeati371 – 375PXXXP motif1 Publication5
Repeati378 – 382PXXXP motif1 Publication5
Repeati386 – 390PXXXP motif; regulates binding with chromatin and interaction with PCNA1 Publication5
Repeati394 – 398PXXXP motif; regulates binding with chromatin and interaction with PCNA1 Publication5

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni265 – 285Necessary to interact with ESRRA, to regulate its subcellular localization and to inhibit its transcriptional activity1 PublicationAdd BLAST21
Regioni300 – 373Requires for interaction with GABARAP, MAP1LC3B AND GABARAPL11 PublicationAdd BLAST74

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi175 – 177TXY3

Domaini

The N-terminal region (1-20) is the minimal region necessary for ubiquitination and further proteasomal degradation.By similarity
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

Sequence similaritiesi

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0660 Eukaryota
ENOG410XNY0 LUCA
GeneTreeiENSGT00910000144035
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiQ8TD08
KOiK19603
OMAiIRGDWNR
OrthoDBiEOG091G08QL
PhylomeDBiQ8TD08
TreeFamiTF105101

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR003527 MAP_kinase_CS
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS01351 MAPK, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8TD08-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MCTVVDPRIV RRYLLRRQLG QGAYGIVWKA VDRRTGEVVA IKKIFDAFRD
60 70 80 90 100
KTDAQRTFRE ITLLQEFGDH PNIISLLDVI RAENDRDIYL VFEFMDTDLN
110 120 130 140 150
AVIRKGGLLQ DVHVRSIFYQ LLRATRFLHS GHVVHRDQKP SNVLLDANCT
160 170 180 190 200
VKLCDFGLAR SLGDLPEGPE DQAVTEYVAT RWYRAPEVLL SSHRYTLGVD
210 220 230 240 250
MWSLGCILGE MLRGRPLFPG TSTLHQLELI LETIPPPSEE DLLALGSGCR
260 270 280 290 300
ASVLHQLGSR PRQTLDALLP PDTSPEALDL LRRLLVFAPD KRLSATQALQ
310 320 330 340 350
HPYVQRFHCP SDEWAREADV RPRAHEGVQL SVPEYRSRVY QMILECGGSS
360 370 380 390 400
GTSREKGPEG VSPSQAHLHK PRADPQLPSR TPVQGPRPRP QSSPGHDPAE
410 420 430 440 450
HESPRAAKNV PRQNSAPLLQ TALLGNGERP PGAKEAPPLT LSLVKPSGRG
460 470 480 490 500
AAPSLTSQAA AQVANQALIR GDWNRGGGVR VASVQQVPPR LPPEARPGRR
510 520 530 540
MFSTSALQGA QGGARALLGG YSQAYGTVCH SALGHLPLLE GHHV
Length:544
Mass (Da):59,832
Last modified:June 1, 2002 - v1
Checksum:i758E0E3B9654AAC5
GO
Isoform 2 (identifier: Q8TD08-2) [UniParc]FASTAAdd to basket
Also known as: Erk8 delta

The sequence of this isoform differs from the canonical sequence as follows:
     241-254: DLLALGSGCRASVL → GAQTACRSGTGAST
     255-544: Missing.

Note: Appears not to be a CSK- and RET-dependent activated kinase.
Show »
Length:254
Mass (Da):28,696
Checksum:i88FC081FFB15644A
GO
Isoform 3 (identifier: Q8TD08-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     95-95: M → MGCPPSPPPPTAVRTLSA
     261-544: Missing.

Note: No experimental confirmation available.
Show »
Length:277
Mass (Da):31,112
Checksum:i07B9D39A696701D0
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti113H → R in AAY44299 (PubMed:16484222).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_061535221T → K. Corresponds to variant dbSNP:rs60732298Ensembl.1
Natural variantiVAR_061536505S → P. Corresponds to variant dbSNP:rs56038219Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_01791895M → MGCPPSPPPPTAVRTLSA in isoform 3. 1 Publication1
Alternative sequenceiVSP_017919241 – 254DLLAL…RASVL → GAQTACRSGTGAST in isoform 2. 1 PublicationAdd BLAST14
Alternative sequenceiVSP_017920255 – 544Missing in isoform 2. 1 PublicationAdd BLAST290
Alternative sequenceiVSP_017921261 – 544Missing in isoform 3. 1 PublicationAdd BLAST284

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY065978 mRNA Translation: AAL40897.1
AY994058 mRNA Translation: AAY44299.1
BC028034 mRNA Translation: AAH28034.1
CCDSiCCDS6409.2 [Q8TD08-1]
RefSeqiNP_620590.2, NM_139021.2 [Q8TD08-1]
UniGeneiHs.493169

Genome annotation databases

EnsembliENST00000338033; ENSP00000337691; ENSG00000181085 [Q8TD08-1]
ENST00000395107; ENSP00000378539; ENSG00000181085 [Q8TD08-3]
ENST00000395108; ENSP00000378540; ENSG00000181085 [Q8TD08-2]
ENST00000615253; ENSP00000483093; ENSG00000274205 [Q8TD08-1]
GeneIDi225689
KEGGihsa:225689
UCSCiuc003yzj.4 human [Q8TD08-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiMK15_HUMAN
AccessioniPrimary (citable) accession number: Q8TD08
Secondary accession number(s): Q2TCF9, Q8N362
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 18, 2006
Last sequence update: June 1, 2002
Last modified: July 18, 2018
This is version 140 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 8
    Human chromosome 8: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  5. SIMILARITY comments
    Index of protein domains and families

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