Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

O54992 (MAPK5_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 117. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
MAP kinase-activated protein kinase 5

Short name=MAPK-activated protein kinase 5
Short name=MAPKAP kinase 5
Short name=MAPKAPK-5
EC=2.7.11.1
Gene names
Name:Mapkapk5
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length473 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.6 Ref.7 Ref.8 Ref.10 Ref.18 Ref.19

Catalytic activity

ATP + a protein = ADP + a phosphoprotein. Ref.16

Enzyme regulation

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. Ref.1 Ref.16

Subunit structure

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. Ref.6 Ref.7 Ref.8 Ref.12 Ref.14 Ref.15

Subcellular location

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. Ref.6 Ref.7 Ref.8 Ref.11 Ref.13 Ref.16 Ref.17

Tissue specificity

Expressed ubiquitously. Ref.1

Post-translational modification

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. Ref.1 Ref.6 Ref.7 Ref.17

Disruption phenotype

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 (Ref.5). According to another report, both homozygous and heterozygous mutant mice are highly susceptible to skin carcinogenesis induced by DMBA (Ref.10). According to a third report, mutant show embryonic lethality around E11 in a C57BL/6 background (Ref.6). Ref.5 Ref.6 Ref.10

Sequence similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.

Contains 1 protein kinase domain.

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 (Ref.1). According to other reports, it is not activated by p38-alpha/MAPK14 and p38-beta/MAPK11 (Ref.5). An explanation for these discrepancies, might be that the interaction with p38 MAPK kinases is weak and occurs only under specific conditions.

Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O54992-1)

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.
Isoform 2 (identifier: O54992-2)

Also known as: MK-5 type 3;

The sequence of this isoform differs from the canonical sequence as follows:
     344-408: DLKVSLKPLHSVNNPILRKRKLLGTKPKDGIYIHDHENGTEDSNVALEKLRDVIAQCILPQAGKG → E
Isoform 3 (identifier: O54992-3)

Also known as: MK-5 type 4;

The sequence of this isoform differs from the canonical sequence as follows:
     13-161: Missing.
Isoform 4 (identifier: O54992-4)

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.
Isoform 5 (identifier: O54992-5)

Also known as: MK-5 type 2;

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 473473MAP kinase-activated protein kinase 5
PRO_0000086297

Regions

Domain22 – 304283Protein kinase
Nucleotide binding28 – 369ATP By similarity
Coiled coil409 – 44032 Potential

Sites

Active site1481Proton acceptor By similarity
Binding site511ATP Probable

Amino acid modifications

Modified residue1151Phosphoserine; by PKA Ref.17
Modified residue1821Phosphothreonine; by MAPK11, MAPK14, MAPK4, MAPK6 and PKA Ref.6 Ref.7
Modified residue2121Phosphoserine By similarity

Natural variations

Alternative sequence13 – 161149Missing in isoform 3 and isoform 4.
VSP_011599
Alternative sequence344 – 40865DLKVS…QAGKG → E in isoform 2.
VSP_011600
Alternative sequence407 – 4082Missing in isoform 4 and isoform 5.
VSP_011598

Experimental info

Mutagenesis511K → E: No p38-alpha/MAPK14-, p38-beta/MAPK11-, ERK3/MAPK6-, ERK4/MAPK4-induced activation. Ref.1 Ref.6 Ref.10 Ref.19
Mutagenesis511K → R or M: Kinase defective mutant, abolishes activity. Ref.1 Ref.6 Ref.10 Ref.19
Mutagenesis1151S → A: Impairs shuttling to the cytoplasm. Ref.17
Mutagenesis1151S → D: Mimicks phosphorylation state, lesding to localization to the cytoplasm. Ref.17
Mutagenesis1821T → A: Impairs protein kinase activity and shuttling to the cytoplasm. Ref.6 Ref.7 Ref.10 Ref.16
Mutagenesis3371L → 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. Ref.9

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (MK-5 type 1) [UniParc].

Last modified June 1, 1998. Version 1.
Checksum: 45441A735075B247

FASTA47354,152
        10         20         30         40         50         60 
MSEDSDMEKA IKETSILEEY SINWTQKLGA GISGPVRVCV KKSTQERFAL KILLDRPKAR 

        70         80         90        100        110        120 
NEVRLHMMCA THPNIVQIIE VFANSVQFPH ESSPRARLLI VMEMMEGGEL FHRISQHRHF 

       130        140        150        160        170        180 
TEKQASQVTK QIALALQHCH LLNIAHRDLK PENLLFKDNS LDAPVKLCDF GFAKVDQGDL 

       190        200        210        220        230        240 
MTPQFTPYYV APQVLEAQRR HQKEKSGIIP TSPTPYTYNK SCDLWSLGVI IYVMLCGYPP 

       250        260        270        280        290        300 
FYSKHHSRTI PKDMRKKIMT GSFEFPEEEW SQISEMAKDV VRKLLKVKPE ERLTIEGVLD 

       310        320        330        340        350        360 
HPWLNSTEAL DNVLPSAQLM MDKAVVAGIQ QAHAEQLANM RIQDLKVSLK PLHSVNNPIL 

       370        380        390        400        410        420 
RKRKLLGTKP KDGIYIHDHE NGTEDSNVAL EKLRDVIAQC ILPQAGKGEN EDEKLNEVMQ 

       430        440        450        460        470 
EAWKYNRECK LLRDALQSFS WNGRGFTDKV DRLKLAEVVK QVIEEQTLPH EPQ 

« Hide

Isoform 2 (MK-5 type 3) [UniParc].

Checksum: 7EEAF061669A3F61
Show »

FASTA40947,103
Isoform 3 (MK-5 type 4) [UniParc].

Checksum: 25BF2CB86528174D
Show »

FASTA32437,042
Isoform 4 (MK-5 type 5) [UniParc].

Checksum: BADC2B6FEB4AEA4A
Show »

FASTA32236,856
Isoform 5 (MK-5 type 2) [UniParc].

Checksum: AC171E324E40A3D4
Show »

FASTA47153,967

References

« Hide 'large scale' references
[1]"MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase."
Ni H., Wang X.S., Diener K., Yao Z.
Biochem. Biophys. Res. Commun. 243:492-496(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, MUTAGENESIS OF LYS-51, ENZYME REGULATION, PHOSPHORYLATION BY ERK2/MAPK1 AND MAPK14.
Tissue: Spleen.
[2]"Novel splice variants of MK5 from mouse heart."
Benoit M.-J., Moise N., Mamarbachi A.M., Allen B.G.
Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4 AND 5).
[3]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Strain: FVB/N-3.
Tissue: Mammary tumor.
[5]"Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination."
Shi Y., Kotlyarov A., Laabeta K., Gruber A.D., Butt E., Marcus K., Meyer H.E., Friedrich A., Volk H.D., Gaestel M.
Mol. Cell. Biol. 23:7732-7741(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[6]"Scaffolding by ERK3 regulates MK5 in development."
Schumacher S., Laass K., Kant S., Shi Y., Visel A., Gruber A.D., Kotlyarov A., Gaestel M.
EMBO J. 23:4770-4779(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF MAPK6, SUBCELLULAR LOCATION, INTERACTION WITH MAPK6, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT THR-182, MUTAGENESIS OF LYS-51 AND THR-182, DISRUPTION PHENOTYPE.
[7]"Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway."
Seternes O.M., Mikalsen T., Johansen B., Michaelsen E., Armstrong C.G., Morrice N.A., Turgeon B., Meloche S., Moens U., Keyse S.M.
EMBO J. 23:4780-4791(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF MAPK6, SUBCELLULAR LOCATION, INTERACTION WITH MAPK6, PHOSPHORYLATION AT THR-182, MUTAGENESIS OF THR-182.
[8]"Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5."
Kant S., Schumacher S., Singh M.K., Kispert A., Kotlyarov A., Gaestel M.
J. Biol. Chem. 281:35511-35519(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF MAPK4, SUBCELLULAR LOCATION, INTERACTION WITH MAPK4.
[9]"Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity."
Gerits N., Van Belle W., Moens U.
Behav. Brain Funct. 3:58-58(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF LEU-337.
[10]"PRAK is essential for ras-induced senescence and tumor suppression."
Sun P., Yoshizuka N., New L., Moser B.A., Li Y., Liao R., Xie C., Chen J., Deng Q., Yamout M., Dong M.Q., Frangou C.G., Yates J.R. III, Wright P.E., Han J.
Cell 128:295-308(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF TP53, DISRUPTION PHENOTYPE, MUTAGENESIS OF LYS-51 AND THR-182.
[11]"Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5."
Gerits N., Mikalsen T., Kostenko S., Shiryaev A., Johannessen M., Moens U.
J. Biol. Chem. 282:37232-37243(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[12]"The Ser(186) phospho-acceptor site within ERK4 is essential for its ability to interact with and activate PRAK/MK5."
Perander M., Aberg E., Johansen B., Dreyer B., Guldvik I.J., Outzen H., Keyse S.M., Seternes O.M.
Biochem. J. 411:613-622(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MAPK4.
[13]"Determinants that control the distinct subcellular localization of p38alpha-PRAK and p38beta-PRAK complexes."
Li Q., Zhang N., Zhang D., Wang Y., Lin T., Wang Y., Zhou H., Ye Z., Zhang F., Lin S.C., Han J.
J. Biol. Chem. 283:11014-11023(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[14]"Activation loop phosphorylation of the atypical MAP kinases ERK3 and ERK4 is required for binding, activation and cytoplasmic relocalization of MK5."
Deleris P., Rousseau J., Coulombe P., Rodier G., Tanguay P.L., Meloche S.
J. Cell. Physiol. 217:778-788(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MAPK4 AND MAPK6.
[15]"Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif."
Aberg E., Torgersen K.M., Johansen B., Keyse S.M., Perander M., Seternes O.M.
J. Biol. Chem. 284:19392-19401(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MAPK4 AND MAPK6.
[16]"The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor."
Kostenko S., Khan M.T., Sylte I., Moens U.
Cell. Mol. Life Sci. 68:289-301(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ENZYME REGULATION, MUTAGENESIS OF THR-182.
[17]"Serine residue 115 of MAPK-activated protein kinase MK5 is crucial for its PKA-regulated nuclear export and biological function."
Kostenko S., Shiryaev A., Gerits N., Dumitriu G., Klenow H., Johannessen M., Moens U.
Cell. Mol. Life Sci. 68:847-862(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-115, SUBCELLULAR LOCATION, MUTAGENESIS OF SER-115.
[18]"Distinct roles of MK2 and MK5 in cAMP/PKA- and stress/p38MAPK-induced heat shock protein 27 phosphorylation."
Shiryaev A., Dumitriu G., Moens U.
J. Mol. Signal. 6:4-4(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF HSPB1.
[19]"Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1."
Zheng M., Wang Y.H., Wu X.N., Wu S.Q., Lu B.J., Dong M.Q., Zhang H., Sun P., Lin S.C., Guan K.L., Han J.
Nat. Cell Biol. 13:263-272(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF RHEB, MUTAGENESIS OF LYS-51.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
PIRJC5952.
RefSeqNP_034895.1. NM_010765.2.
UniGeneMm.272206.

3D structure databases

ProteinModelPortalO54992.
SMRO54992. Positions 11-458.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid201309. 2 interactions.
IntActO54992. 2 interactions.

PTM databases

PhosphoSiteO54992.

Proteomic databases

PRIDEO54992.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000031410; ENSMUSP00000031410; ENSMUSG00000029454. [O54992-1]
ENSMUST00000111782; ENSMUSP00000107412; ENSMUSG00000029454. [O54992-4]
ENSMUST00000111783; ENSMUSP00000107413; ENSMUSG00000029454. [O54992-5]
ENSMUST00000111786; ENSMUSP00000107416; ENSMUSG00000029454. [O54992-3]
ENSMUST00000153763; ENSMUSP00000119182; ENSMUSG00000029454.
GeneID17165.
KEGGmmu:17165.
UCSCuc008zjq.1. mouse. [O54992-1]
uc008zjr.1. mouse. [O54992-3]
uc008zjs.1. mouse. [O54992-4]

Organism-specific databases

CTD8550.
MGIMGI:1333110. Mapkapk5.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00730000110339.
HOGENOMHOG000233031.
HOVERGENHBG106948.
InParanoidO54992.
KOK04442.
OMAQVTKQIA.
OrthoDBEOG786H3M.
PhylomeDBO54992.
TreeFamTF312891.

Gene expression databases

ArrayExpressO54992.
BgeeO54992.
CleanExMM_MAPKAPK5.
GenevestigatorO54992.

Family and domain databases

Gene3D4.10.1170.10. 1 hit.
InterProIPR011009. Kinase-like_dom.
IPR027442. MAPKAPK_C.
IPR000719. Prot_kinase_dom.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSMAPKAPK5. mouse.
NextBio291446.
PROO54992.
SOURCESearch...

Entry information

Entry nameMAPK5_MOUSE
AccessionPrimary (citable) accession number: O54992
Secondary accession number(s): E9QQ45 expand/collapse secondary AC list , Q6QME4, Q6QME5, Q6QME6, Q6QME7
Entry history
Integrated into UniProtKB/Swiss-Prot: September 13, 2004
Last sequence update: June 1, 1998
Last modified: April 16, 2014
This is version 117 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot