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Protein

MAP kinase-activated protein kinase 5

Gene

Mapkapk5

Organism
Mus musculus (Mouse)
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.6 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

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 sitei51ATPCurated1
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
  • mitogen-activated protein kinase binding Source: UniProtKB
  • p53 binding Source: UniProtKB
  • protein kinase activity Source: MGI
  • 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 dendritic spine development Source: MGI
  • positive regulation of telomerase activity Source: MGI
  • positive regulation of telomere capping Source: MGI
  • positive regulation of telomere maintenance via telomerase Source: MGI
  • protein autophosphorylation Source: UniProtKB
  • Ras protein signal transduction Source: UniProtKB
  • regulation of translation Source: UniProtKB
  • 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

ReactomeiR-MMU-2559580. Oxidative Stress Induced Senescence.
R-MMU-5687128. MAPK6/MAPK4 signaling.
R-MMU-6804756. Regulation of TP53 Activity through Phosphorylation.

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:
MAPKAPK-5
Gene namesi
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 5

Organism-specific databases

MGIiMGI:1333110. 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

  • cytoplasm Source: UniProtKB
  • nucleoplasm Source: MGI
  • nucleus Source: UniProtKB
  • protein complex Source: MGI
  • septin cytoskeleton Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Phenotypes are different depending on reports. According to a first report, mice are viable and fertile and do not show changes in tissue morphology and behavior: they exhibit the same susceptibility to LPS-induced endotoxic shock as wild-type animals and do not show the defects in LPS-induced biosynthesis of inflammatory cytokines known to occur with Mapkapk2-deficient animals (PubMed:14560018). According to another report, both homozygous and heterozygous mutant mice are highly susceptible to skin carcinogenesis induced by DMBA (PubMed:17254968). According to a third report, mutant show embryonic lethality around E11 in a C57BL/6 background (PubMed:15538386).3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi51K → E: No p38-alpha/MAPK14-, p38-beta/MAPK11-, ERK3/MAPK6-, ERK4/MAPK4-induced activation. 4 Publications1
Mutagenesisi51K → R or M: Kinase defective mutant, abolishes activity. 4 Publications1
Mutagenesisi115S → A: Impairs shuttling to the cytoplasm. 1 Publication1
Mutagenesisi115S → D: Mimicks phosphorylation state, lesding to localization to the cytoplasm. 1 Publication1
Mutagenesisi182T → A: Impairs protein kinase activity and shuttling to the cytoplasm. 4 Publications1
Mutagenesisi337L → A: Constitutive active mutant. In a knockin model, mouse display increased amounts of head dips and open arm time on the maze, compared to littermate controls. In addition, they also explore further into the open arm on the elevated plus maze and are less active in the closed arm compared to littermate controls. Male knockin mice display no differences in anxiety, but their locomotor activity increases compared to non-transgenic littermates. 1 Publication1

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862971 – 473MAP kinase-activated protein kinase 5Add BLAST473

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei115Phosphoserine; by PKA1 Publication1
Modified residuei182Phosphothreonine; by MAPK11, MAPK14, MAPK4, MAPK6 and PKA2 Publications1
Modified residuei212PhosphoserineBy similarity1
Modified residuei354PhosphoserineBy similarity1

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.4 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiO54992.
PaxDbiO54992.
PeptideAtlasiO54992.
PRIDEiO54992.

PTM databases

iPTMnetiO54992.
PhosphoSitePlusiO54992.

Expressioni

Tissue specificityi

Expressed ubiquitously.1 Publication

Gene expression databases

BgeeiENSMUSG00000029454.
CleanExiMM_MAPKAPK5.
ExpressionAtlasiO54992. baseline and differential.
GenevisibleiO54992. MM.

Interactioni

Subunit structurei

Interacts with SQSTM1 (By similarity). Interacts with ERK3/MAPK6 and ERK4/MAPK4 (via FRIEDE motif); the interaction is direct. Interacts with YWHAE; the interaction prevents phosphorylation of HSP27/HSPB1 leading to disrupt F-actin polymerization.By similarity6 Publications

GO - Molecular functioni

  • calmodulin binding Source: GO_Central
  • mitogen-activated protein kinase binding Source: UniProtKB
  • p53 binding Source: UniProtKB

Protein-protein interaction databases

BioGridi201309. 2 interactors.
IntActiO54992. 2 interactors.
STRINGi10090.ENSMUSP00000031410.

Structurei

3D structure databases

ProteinModelPortaliO54992.
SMRiO54992.
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.
InParanoidiO54992.
KOiK04442.
OMAiIHDRENG.
OrthoDBiEOG091G14PL.
PhylomeDBiO54992.
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 (5)i

Sequence statusi: Complete.

This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O54992-1) [UniParc]FASTAAdd to basket
Also known as: MK-5 type 1

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
MSEDSDMEKA IKETSILEEY SINWTQKLGA GISGPVRVCV KKSTQERFAL
60 70 80 90 100
KILLDRPKAR NEVRLHMMCA THPNIVQIIE VFANSVQFPH ESSPRARLLI
110 120 130 140 150
VMEMMEGGEL FHRISQHRHF TEKQASQVTK QIALALQHCH LLNIAHRDLK
160 170 180 190 200
PENLLFKDNS LDAPVKLCDF GFAKVDQGDL MTPQFTPYYV APQVLEAQRR
210 220 230 240 250
HQKEKSGIIP TSPTPYTYNK SCDLWSLGVI IYVMLCGYPP FYSKHHSRTI
260 270 280 290 300
PKDMRKKIMT GSFEFPEEEW SQISEMAKDV VRKLLKVKPE ERLTIEGVLD
310 320 330 340 350
HPWLNSTEAL DNVLPSAQLM MDKAVVAGIQ QAHAEQLANM RIQDLKVSLK
360 370 380 390 400
PLHSVNNPIL RKRKLLGTKP KDGIYIHDHE NGTEDSNVAL EKLRDVIAQC
410 420 430 440 450
ILPQAGKGEN EDEKLNEVMQ EAWKYNRECK LLRDALQSFS WNGRGFTDKV
460 470
DRLKLAEVVK QVIEEQTLPH EPQ
Length:473
Mass (Da):54,152
Last modified:June 1, 1998 - v1
Checksum:i45441A735075B247
GO
Isoform 2 (identifier: O54992-2) [UniParc]FASTAAdd to basket
Also known as: MK-5 type 3

The sequence of this isoform differs from the canonical sequence as follows:
     344-408: DLKVSLKPLHSVNNPILRKRKLLGTKPKDGIYIHDHENGTEDSNVALEKLRDVIAQCILPQAGKG → E

Show »
Length:409
Mass (Da):47,103
Checksum:i7EEAF061669A3F61
GO
Isoform 3 (identifier: O54992-3) [UniParc]FASTAAdd to basket
Also known as: MK-5 type 4

The sequence of this isoform differs from the canonical sequence as follows:
     13-161: Missing.

Show »
Length:324
Mass (Da):37,042
Checksum:i25BF2CB86528174D
GO
Isoform 4 (identifier: O54992-4) [UniParc]FASTAAdd to basket
Also known as: MK-5 type 5

The sequence of this isoform differs from the canonical sequence as follows:
     13-161: Missing.
     407-408: Missing.

Show »
Length:322
Mass (Da):36,856
Checksum:iBADC2B6FEB4AEA4A
GO
Isoform 5 (identifier: O54992-5) [UniParc]FASTAAdd to basket
Also known as: MK-5 type 2

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

Show »
Length:471
Mass (Da):53,967
Checksum:iAC171E324E40A3D4
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_01159913 – 161Missing in isoform 3 and isoform 4. 1 PublicationAdd BLAST149
Alternative sequenceiVSP_011600344 – 408DLKVS…QAGKG → E in isoform 2. 1 PublicationAdd BLAST65
Alternative sequenceiVSP_011598407 – 408Missing in isoform 4 and isoform 5. 1 Publication2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF039840 mRNA. Translation: AAC40047.1.
AY533679 mRNA. Translation: AAS22330.1.
AY533680 mRNA. Translation: AAS22331.2.
AY533681 mRNA. Translation: AAS22332.1.
AY533682 mRNA. Translation: AAS22333.1.
AC155316 Genomic DNA. No translation available.
BC019184 mRNA. Translation: AAH19184.1.
CCDSiCCDS39248.1. [O54992-1]
PIRiJC5952.
RefSeqiNP_034895.1. NM_010765.2. [O54992-1]
UniGeneiMm.272206.

Genome annotation databases

EnsembliENSMUST00000031410; ENSMUSP00000031410; ENSMUSG00000029454. [O54992-1]
ENSMUST00000111782; ENSMUSP00000107412; ENSMUSG00000029454. [O54992-4]
ENSMUST00000111783; ENSMUSP00000107413; ENSMUSG00000029454. [O54992-5]
ENSMUST00000111786; ENSMUSP00000107416; ENSMUSG00000029454. [O54992-3]
ENSMUST00000200170; ENSMUSP00000143668; ENSMUSG00000105340. [O54992-5]
GeneIDi17165.
KEGGimmu:17165.
UCSCiuc008zjq.1. mouse. [O54992-1]
uc008zjr.1. mouse. [O54992-3]
uc008zjs.1. mouse. [O54992-4]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF039840 mRNA. Translation: AAC40047.1.
AY533679 mRNA. Translation: AAS22330.1.
AY533680 mRNA. Translation: AAS22331.2.
AY533681 mRNA. Translation: AAS22332.1.
AY533682 mRNA. Translation: AAS22333.1.
AC155316 Genomic DNA. No translation available.
BC019184 mRNA. Translation: AAH19184.1.
CCDSiCCDS39248.1. [O54992-1]
PIRiJC5952.
RefSeqiNP_034895.1. NM_010765.2. [O54992-1]
UniGeneiMm.272206.

3D structure databases

ProteinModelPortaliO54992.
SMRiO54992.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi201309. 2 interactors.
IntActiO54992. 2 interactors.
STRINGi10090.ENSMUSP00000031410.

PTM databases

iPTMnetiO54992.
PhosphoSitePlusiO54992.

Proteomic databases

MaxQBiO54992.
PaxDbiO54992.
PeptideAtlasiO54992.
PRIDEiO54992.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000031410; ENSMUSP00000031410; ENSMUSG00000029454. [O54992-1]
ENSMUST00000111782; ENSMUSP00000107412; ENSMUSG00000029454. [O54992-4]
ENSMUST00000111783; ENSMUSP00000107413; ENSMUSG00000029454. [O54992-5]
ENSMUST00000111786; ENSMUSP00000107416; ENSMUSG00000029454. [O54992-3]
ENSMUST00000200170; ENSMUSP00000143668; ENSMUSG00000105340. [O54992-5]
GeneIDi17165.
KEGGimmu:17165.
UCSCiuc008zjq.1. mouse. [O54992-1]
uc008zjr.1. mouse. [O54992-3]
uc008zjs.1. mouse. [O54992-4]

Organism-specific databases

CTDi8550.
MGIiMGI:1333110. Mapkapk5.

Phylogenomic databases

eggNOGiKOG0604. Eukaryota.
ENOG410XP8F. LUCA.
GeneTreeiENSGT00830000128274.
HOGENOMiHOG000233031.
HOVERGENiHBG106948.
InParanoidiO54992.
KOiK04442.
OMAiIHDRENG.
OrthoDBiEOG091G14PL.
PhylomeDBiO54992.
TreeFamiTF312891.

Enzyme and pathway databases

ReactomeiR-MMU-2559580. Oxidative Stress Induced Senescence.
R-MMU-5687128. MAPK6/MAPK4 signaling.
R-MMU-6804756. Regulation of TP53 Activity through Phosphorylation.

Miscellaneous databases

ChiTaRSiMapkapk5. mouse.
PROiO54992.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000029454.
CleanExiMM_MAPKAPK5.
ExpressionAtlasiO54992. baseline and differential.
GenevisibleiO54992. MM.

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_MOUSE
AccessioniPrimary (citable) accession number: O54992
Secondary accession number(s): E9QQ45
, Q6QME4, Q6QME5, Q6QME6, Q6QME7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 13, 2004
Last sequence update: June 1, 1998
Last modified: November 2, 2016
This is version 145 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

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:9480836). According to other reports, it is not activated by p38-alpha/MAPK14 and p38-beta/MAPK11 (PubMed:14560018). An explanation for these discrepancies, might be that the interaction with p38 MAPK kinases is weak and occurs only under specific conditions.2 Publications

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. 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.