MAPKAPK5

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]

Mitogen-Activated Protein Kinase-Activated Protein Kinase 5

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.

Cellular senescenceTAS:Reactome
Intracellular signal transductionManual Assertion Based On ExperimentIBA:GO_Central
Negative regulation of TOR signalingISS:UniProtKB
Peptidyl-serine phosphorylationManual Assertion Based On ExperimentIBA:GO_Central
Positive regulation of telomerase activityManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of telomere cappingManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of telomere maintenance via telomeraseManual Assertion Based On ExperimentIMP:BHF-UCL
Protein autophosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Ras protein signal transductionManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of signal transduction by p53 class mediatorTAS:Reactome
Regulation of translationManual Assertion Based On ExperimentIDA:UniProtKB
Signal transductionManual Assertion Based On ExperimentTAS:ProtInc
Stress-induced premature senescenceManual Assertion Based On ExperimentIDA:UniProtKB

Cytoplasm
Nucleus
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.

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).