Description: Homo sapiens mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5), transcript variant 2, mRNA. RefSeq Summary (NM_139078): The protein encoded by this gene is a tumor suppressor and member of the serine/threonine kinase family. In response to cellular stress and proinflammatory cytokines, this kinase is activated through its phosphorylation by MAP kinases including MAPK1/ERK, MAPK14/p38-alpha, and MAPK11/p38-beta. The encoded protein is found in the nucleus but translocates to the cytoplasm upon phosphorylation and activation. This kinase phosphorylates heat shock protein HSP27 at its physiologically relevant sites. Two alternately spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2012]. Sequence Note: The RefSeq transcript and protein were derived from genomic sequence to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on alignments. Transcript (Including UTRs) Position: hg19 chr12:112,280,032-112,331,228 Size: 51,197 Total Exon Count: 14 Strand: + Coding Region Position: hg19 chr12:112,280,538-112,330,865 Size: 50,328 Coding Exon Count: 14
ID:MAPK5_HUMAN DESCRIPTION: RecName: Full=MAP kinase-activated protein kinase 5; Short=MAPK-activated protein kinase 5; Short=MAPKAP kinase 5; Short=MAPKAP-K5; Short=MAPKAPK-5; Short=MK-5; Short=MK5; EC=2.7.11.1; AltName: Full=p38-regulated/activated protein kinase; Short=PRAK; 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. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. 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 H(2)O(2), 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. SUBUNIT: 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. INTERACTION: P04792:HSPB1; NbExp=2; IntAct=EBI-1201460, EBI-352682; P04637:TP53; NbExp=2; IntAct=EBI-1201460, EBI-366083; 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. TISSUE SPECIFICITY: Expressed ubiquitously. INDUCTION: Directly regulated by MYC: expression is activated by MYC, suggesting the existence of a feedback regulatory loop. PTM: 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). SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SIMILARITY: 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 (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.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF06293 - Lipopolysaccharide kinase (Kdo/WaaP) family PF07714 - Protein tyrosine kinase
SCOP Domains: 47473 - EF-hand 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on Q8IW41
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000165 MAPK cascade GO:0000187 activation of MAPK activity GO:0006417 regulation of translation GO:0006468 protein phosphorylation GO:0007165 signal transduction GO:0007166 cell surface receptor signaling pathway GO:0007265 Ras protein signal transduction GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0032007 negative regulation of TOR signaling GO:0032212 positive regulation of telomere maintenance via telomerase GO:0046777 protein autophosphorylation GO:0051973 positive regulation of telomerase activity GO:0090400 stress-induced premature senescence GO:1901796 regulation of signal transduction by p53 class mediator GO:1904355 positive regulation of telomere capping
US Server
