PAK2
Template:Cs1 config Template:Short description Template:Infobox gene Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.[1][2]
PAK2 is one of three members of Group I PAK family of serine/threonine kinases.[3][4] The PAKs are evolutionary conserved.[5] PAK2 and its cleaved fragment localize in both the cytoplasmic or nuclear compartments. PAK2 signaling modulates apoptosis,[6] endothelial lumen formation,[7] viral pathogenesis,[8] and cancer including, breast,[9] hepatocarcinoma,[10] gastric [11] and cancer, at-large,[12] and, based on its kinase activity alone, peripheral nerve myelination during embryonic development. [13]
Discovery
The human PAK2 was identified as a downstream effector of Rac or Cdc42.[3][4]
Gene and spliced variants
The PAK2 gene is about 92.7-kb long. The gene contains 15 exons and generates three alternatively spliced transcripts - two of which code proteins of 524 amino acids and 221 amino acids, while the third one is a 371-bp non-coding RNA transcript(Gene from review) There are two transcripts generated from the murine PAK2 gene, a 5.7-kb transcript coding a 524 amino acids long polypeptide and a 1.2-kb long non-coding RNA transcript.
Protein domains
Similar to PAK1, PAK2 contains a p21-binding domain (PBD) and an auto-inhibitory domain (AID) and exists in an inactive conformation.[12]
The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.[14]
Function
The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.[15] Finally, while both PAK 1 and PAK 2 proteins have been shown to be elevated during the embryonic phase, PAK 2 kinase activity specifically has been demonstrated to be a requirement during the myelenation of developing nerves. [13]
Upstream activators
PAK2 kinase activity is stimulated by transforming growth factor β in fibroblasts,[16] by proteinase inhibitor alpha2-macroglobulin binding to GRP78 in prostate cancer cells,[17] by its phosphorylation by AMP-activated protein kinase in stem and cancer cells [18] and eryptosis.[19] PAK2 is cleaved through activated caspase-3 in fibroblast and cancer cells exposed to ultraviolet,[20] hyperosmotic shock,[21] and ionizing radiation.[22]
Inhibitors
The levels of PAK2 activation in experimental systems are inhibited by synthetic PAK-inhibitors and miRs. For example, FRAX1036 differentially inhibits PAK2 and PAK1 activities;[23] FRAX597 suppresses PAK2 activity in neurofibromatosis type 2 (NF2)-associated tumorigenesis;[24] and miR-23b and miR-137 inhibits PAK2 expression in tumor cells.[25][26] Insulin stimulation of neuronal cells also antagonizes PAK2 kinase activity, leading to an increased glucose uptake.[27]
Downstream targets
PAK2-mediated phosphorylation of merlin at S518 modulates its tumor suppressor activity,[28] c-Jun phosphorylation at T2, T8, T89, T93 and T286 contributes to the growth of growth factor-stimulated melanoma cells,[29] Caspase-7 phosphorylation at S30, T173 and S239 inhibits apoptotic activity in breast cancer cells,[9] Paxillin phosphorylation at S272 and S274 activates ADAM10 protease,[30] and STAT5 phosphorylation at S779 modulates BCL-ABL-mediated leukemogenesis.[31] PAK2 activity negatively regulates the function and expression of c-Myc: PAK2 phosphorylation of c-Myc at T358-S373-T400 inhibits its transactivation function [32] and PAK2 depletion stimulates c-Myc expression during granulocyte-monocyte lineage.[33]
Notes
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References
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External links
- PAK2 Info with links in the Cell Migration Gateway Template:Webarchive
- Template:PDBe-KB2