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Protein

MAP kinase-activated protein kinase 5

Gene

MAPKAPK5

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Tumor suppressor serine/threonine-protein kinase involved in mTORC1 signaling and post-transcriptional regulation. Phosphorylates FOXO3, ERK3/MAPK6, ERK4/MAPK4, HSP27/HSPB1, p53/TP53 and RHEB. Acts as a tumor suppressor by mediating Ras-induced senescence and phosphorylating p53/TP53. Involved in post-transcriptional regulation of MYC by mediating phosphorylation of FOXO3: phosphorylation of FOXO3 leads to promote nuclear localization of FOXO3, enabling expression of miR-34b and miR-34c, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent MYC translation. Acts as a negative regulator of mTORC1 signaling by mediating phosphorylation and inhibition of RHEB. Part of the atypical MAPK signaling via its interaction with ERK3/MAPK6 or ERK4/MAPK4: the precise role of the complex formed with ERK3/MAPK6 or ERK4/MAPK4 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPK (ERK3/MAPK6 or ERK4/MAPK4), ERK3/MAPK6 (or ERK4/MAPK4) is phosphorylated and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6 (or ERK4/MAPK4). Mediates phosphorylation of HSP27/HSPB1 in response to PKA/PRKACA stimulation, inducing F-actin rearrangement.5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Activated following phosphorylation at Thr-182 by p38-alpha/MAPK14, p38-beta/MAPK11, ERK2/MAPK1, ERK3/MAPK6, and ERK4/MAPK4. Activated by stress-related extracellular stimuli; such as H2O2, arsenite, anisomycin TNF alpha and also PMA and the calcium ionophore A23187; but to a lesser extent. In vitro, activated by SQSTM1. Inhibited by diterpenoid alkaloid noroxoaconitine.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei51ATPPROSITE-ProRule annotation1
Active sitei148Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi28 – 36ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • calcium-dependent protein serine/threonine kinase activity Source: GO_Central
  • calmodulin binding Source: GO_Central
  • calmodulin-dependent protein kinase activity Source: GO_Central
  • MAP kinase kinase activity Source: ProtInc
  • p53 binding Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • negative regulation of TOR signaling Source: UniProtKB
  • peptidyl-serine phosphorylation Source: GO_Central
  • 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
  • Ras protein signal transduction Source: UniProtKB
  • regulation of signal transduction by p53 class mediator Source: Reactome
  • regulation of translation Source: UniProtKB
  • signal transduction Source: ProtInc
  • stress-induced premature senescence Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS01625-MONOMER.
ReactomeiR-HSA-2559580. Oxidative Stress Induced Senescence.
R-HSA-5687128. MAPK6/MAPK4 signaling.
R-HSA-6804756. Regulation of TP53 Activity through Phosphorylation.
SignaLinkiQ8IW41.
SIGNORiQ8IW41.

Names & Taxonomyi

Protein namesi
Recommended name:
MAP kinase-activated protein kinase 5 (EC:2.7.11.1)
Short name:
MAPK-activated protein kinase 5
Short name:
MAPKAP kinase 5
Short name:
MAPKAP-K5
Short name:
MAPKAPK-5
Short name:
MK-5
Short name:
MK5
Alternative name(s):
p38-regulated/activated protein kinase
Short name:
PRAK
Gene namesi
Name:MAPKAPK5
Synonyms:PRAK
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:6889. MAPKAPK5.

Subcellular locationi

  • Cytoplasm
  • Nucleus

  • Note: Translocates to the cytoplasm following phosphorylation and activation. Interaction with ERK3/MAPK6 or ERK4/MAPK4 and phosphorylation at Thr-182, activates the protein kinase activity, followed by translocation to the cytoplasm. Phosphorylation by PKA/PRKACA at Ser-115 also induces nuclear export.

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi51K → M: Kinase defective mutant, abolishes activity. 1 Publication1
Mutagenesisi182T → A: No p38-beta/MAPK11-induced activation. 3 Publications1
Mutagenesisi182T → D: Mimicks phosphorylation state and induces constitutive protein kinase activity. 3 Publications1
Mutagenesisi212S → D: Mimicks phosphorylation state and displays a slightly higher protein kinase activity. 1 Publication1
Mutagenesisi337L → G: Induces constitutive protein kinase activity. 1 Publication1

Keywords - Diseasei

Tumor suppressor

Organism-specific databases

DisGeNETi8550.
OpenTargetsiENSG00000089022.
PharmGKBiPA30633.

Chemistry databases

ChEMBLiCHEMBL3094.
GuidetoPHARMACOLOGYi2096.

Polymorphism and mutation databases

DMDMi52000829.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862961 – 473MAP kinase-activated protein kinase 5Add BLAST473

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei115Phosphoserine; by PKABy similarity1
Modified residuei182Phosphothreonine; by MAPK11, MAPK14, MAPK4, MAPK6 and PKACombined sources1 Publication1
Modified residuei212Phosphoserine1 Publication1
Modified residuei354PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated on Thr-182 ERK3/MAPK6 or ERK4/MAPK4; which is the regulatory phosphorylation site and is located on the T-loop/loop 12, leading to activation. Phosphorylation at Thr-182 by p38-alpha/MAPK14, p38-beta/MAPK11 is subject to debate. Phosphorylated at Ser-115 by PKA/PRKACA, leading to localization to the cytoplasm. Autophosphorylated (By similarity).By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ8IW41.
PaxDbiQ8IW41.
PeptideAtlasiQ8IW41.
PRIDEiQ8IW41.

PTM databases

iPTMnetiQ8IW41.
PhosphoSitePlusiQ8IW41.

Expressioni

Tissue specificityi

Expressed ubiquitously.1 Publication

Inductioni

Directly regulated by MYC: expression is activated by MYC, suggesting the existence of a feedback regulatory loop.1 Publication

Gene expression databases

BgeeiENSG00000089022.
CleanExiHS_MAPKAPK5.
ExpressionAtlasiQ8IW41. baseline and differential.
GenevisibleiQ8IW41. HS.

Organism-specific databases

HPAiCAB004546.
HPA015515.

Interactioni

Subunit structurei

Interacts with ERK3/MAPK6 and ERK4/MAPK4 (via FRIEDE motif); the interaction is direct (By similarity). Interacts with YWHAE; the interaction prevents phosphorylation of HSP27/HSPB1 leading to disrupt F-actin polymerization. Interacts with SQSTM1.By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
HSPB1P047922EBI-1201460,EBI-352682
MAPK6Q166597EBI-1201460,EBI-1384105
TP53P046372EBI-1201460,EBI-366083

GO - Molecular functioni

  • calmodulin binding Source: GO_Central
  • p53 binding Source: UniProtKB

Protein-protein interaction databases

BioGridi114120. 19 interactors.
IntActiQ8IW41. 18 interactors.
MINTiMINT-4711647.
STRINGi9606.ENSP00000202788.

Chemistry databases

BindingDBiQ8IW41.

Structurei

3D structure databases

ProteinModelPortaliQ8IW41.
SMRiQ8IW41.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini22 – 304Protein kinasePROSITE-ProRule annotationAdd BLAST283

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili409 – 440Sequence analysisAdd BLAST32

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG0604. Eukaryota.
ENOG410XP8F. LUCA.
GeneTreeiENSGT00830000128274.
HOGENOMiHOG000233031.
HOVERGENiHBG106948.
InParanoidiQ8IW41.
KOiK04442.
OMAiIHDRENG.
OrthoDBiEOG091G14PL.
PhylomeDBiQ8IW41.
TreeFamiTF312891.

Family and domain databases

Gene3Di4.10.1170.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR027442. MAPKAPK_C.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8IW41-1) [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
MSEESDMDKA IKETSILEEY SINWTQKLGA GISGPVRVCV KKSTQERFAL
60 70 80 90 100
KILLDRPKAR NEVRLHMMCA THPNIVQIIE VFANSVQFPH ESSPRARLLI
110 120 130 140 150
VMEMMEGGEL FHRISQHRHF TEKQASQVTK QIALALRHCH LLNIAHRDLK
160 170 180 190 200
PENLLFKDNS LDAPVKLCDF GFAKIDQGDL MTPQFTPYYV APQVLEAQRR
210 220 230 240 250
HQKEKSGIIP TSPTPYTYNK SCDLWSLGVI IYVMLCGYPP FYSKHHSRTI
260 270 280 290 300
PKDMRRKIMT GSFEFPEEEW SQISEMAKDV VRKLLKVKPE ERLTIEGVLD
310 320 330 340 350
HPWLNSTEAL DNVLPSAQLM MDKAVVAGIQ QAHAEQLANM RIQDLKVSLK
360 370 380 390 400
PLHSVNNPIL RKRKLLGTKP KDSVYIHDHE NGAEDSNVAL EKLRDVIAQC
410 420 430 440 450
ILPQAGKGEN EDEKLNEVMQ EAWKYNRECK LLRDTLQSFS WNGRGFTDKV
460 470
DRLKLAEIVK QVIEEQTTSH ESQ
Note: No experimental confirmation available.
Length:473
Mass (Da):54,220
Last modified:September 13, 2004 - v2
Checksum:iF3D9DDC83CC0C49D
GO
Isoform 2 (identifier: Q8IW41-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     407-408: Missing.

Show »
Length:471
Mass (Da):54,035
Checksum:i176FA041A7F28570
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti273I → T in CAB53747 (PubMed:17974005).Curated1
Sequence conflicti291E → R in AAC39863 (PubMed:9628874).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04075867M → I.1 PublicationCorresponds to variant rs34132040dbSNPEnsembl.1
Natural variantiVAR_040759282R → K.1 PublicationCorresponds to variant rs34843470dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_011597407 – 408Missing in isoform 2. 3 Publications2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF032437 Genomic DNA. Translation: AAC39863.1.
AK122767 mRNA. Translation: BAG53717.1.
CH471054 Genomic DNA. Translation: EAW97981.1.
BC000833 mRNA. Translation: AAH00833.1.
BC041049 mRNA. Translation: AAH41049.1.
BC047284 mRNA. Translation: AAH47284.2.
AL110301 mRNA. Translation: CAB53747.1.
CCDSiCCDS44975.1. [Q8IW41-1]
CCDS44976.1. [Q8IW41-2]
PIRiT34519.
RefSeqiNP_003659.2. NM_003668.3. [Q8IW41-2]
NP_620777.1. NM_139078.2. [Q8IW41-1]
UniGeneiHs.333120.
Hs.413901.

Genome annotation databases

EnsembliENST00000550735; ENSP00000449667; ENSG00000089022. [Q8IW41-2]
ENST00000551404; ENSP00000449381; ENSG00000089022. [Q8IW41-1]
GeneIDi8550.
KEGGihsa:8550.
UCSCiuc001tta.5. human. [Q8IW41-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF032437 Genomic DNA. Translation: AAC39863.1.
AK122767 mRNA. Translation: BAG53717.1.
CH471054 Genomic DNA. Translation: EAW97981.1.
BC000833 mRNA. Translation: AAH00833.1.
BC041049 mRNA. Translation: AAH41049.1.
BC047284 mRNA. Translation: AAH47284.2.
AL110301 mRNA. Translation: CAB53747.1.
CCDSiCCDS44975.1. [Q8IW41-1]
CCDS44976.1. [Q8IW41-2]
PIRiT34519.
RefSeqiNP_003659.2. NM_003668.3. [Q8IW41-2]
NP_620777.1. NM_139078.2. [Q8IW41-1]
UniGeneiHs.333120.
Hs.413901.

3D structure databases

ProteinModelPortaliQ8IW41.
SMRiQ8IW41.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114120. 19 interactors.
IntActiQ8IW41. 18 interactors.
MINTiMINT-4711647.
STRINGi9606.ENSP00000202788.

Chemistry databases

BindingDBiQ8IW41.
ChEMBLiCHEMBL3094.
GuidetoPHARMACOLOGYi2096.

PTM databases

iPTMnetiQ8IW41.
PhosphoSitePlusiQ8IW41.

Polymorphism and mutation databases

DMDMi52000829.

Proteomic databases

MaxQBiQ8IW41.
PaxDbiQ8IW41.
PeptideAtlasiQ8IW41.
PRIDEiQ8IW41.

Protocols and materials databases

DNASUi8550.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000550735; ENSP00000449667; ENSG00000089022. [Q8IW41-2]
ENST00000551404; ENSP00000449381; ENSG00000089022. [Q8IW41-1]
GeneIDi8550.
KEGGihsa:8550.
UCSCiuc001tta.5. human. [Q8IW41-1]

Organism-specific databases

CTDi8550.
DisGeNETi8550.
GeneCardsiMAPKAPK5.
HGNCiHGNC:6889. MAPKAPK5.
HPAiCAB004546.
HPA015515.
MIMi606723. gene.
neXtProtiNX_Q8IW41.
OpenTargetsiENSG00000089022.
PharmGKBiPA30633.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0604. Eukaryota.
ENOG410XP8F. LUCA.
GeneTreeiENSGT00830000128274.
HOGENOMiHOG000233031.
HOVERGENiHBG106948.
InParanoidiQ8IW41.
KOiK04442.
OMAiIHDRENG.
OrthoDBiEOG091G14PL.
PhylomeDBiQ8IW41.
TreeFamiTF312891.

Enzyme and pathway databases

BioCyciZFISH:HS01625-MONOMER.
ReactomeiR-HSA-2559580. Oxidative Stress Induced Senescence.
R-HSA-5687128. MAPK6/MAPK4 signaling.
R-HSA-6804756. Regulation of TP53 Activity through Phosphorylation.
SignaLinkiQ8IW41.
SIGNORiQ8IW41.

Miscellaneous databases

ChiTaRSiMAPKAPK5. human.
GeneWikiiMAPKAPK5.
GenomeRNAii8550.
PROiQ8IW41.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000089022.
CleanExiHS_MAPKAPK5.
ExpressionAtlasiQ8IW41. baseline and differential.
GenevisibleiQ8IW41. HS.

Family and domain databases

Gene3Di4.10.1170.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR027442. MAPKAPK_C.
IPR000719. Prot_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMAPK5_HUMAN
AccessioniPrimary (citable) accession number: Q8IW41
Secondary accession number(s): B3KVA5
, O60491, Q86X46, Q9BVX9, Q9UG86
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 13, 2004
Last sequence update: September 13, 2004
Last modified: November 30, 2016
This is version 145 of the entry and version 2 of the sequence. [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

Caution

The role of p38 MAPK kinases is unclear in phosphorylation and activation of MAPKAPK5. According to some reports, it interacts and is phosphorylated by p38-alpha/MAPK14 and p38-beta/MAPK11 (PubMed:9628874 and PubMed:12808055). According to other reports, it is not activated by p38-alpha/MAPK14 and p38-beta/MAPK11. An explanation for these discrepancies, might be that the interaction with p38 MAPK kinases is weak and occurs only under specific conditions.Curated

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: 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. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.