PAK2

The human PAK2 was identified as a downstream effector of Rac or Cdc42. == 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. == 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. 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. == Upstream activators ==

PAK2 kinase activity is stimulated by transforming growth factor β in fibroblasts, by proteinase inhibitor alpha2-macroglobulin binding to GRP78 in prostate cancer cells, by its phosphorylation by AMP-activated protein kinase in stem and cancer cells and eryptosis. PAK2 is cleaved through activated caspase-3 in fibroblast and cancer cells exposed to ultraviolet, hyperosmotic shock, and ionizing radiation. == 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; FRAX597 suppresses PAK2 activity in neurofibromatosis type 2 (NF2)-associated tumorigenesis; and miR-23b and miR-137 inhibits PAK2 expression in tumor cells. Insulin stimulation of neuronal cells also antagonizes PAK2 kinase activity, leading to an increased glucose uptake. == Downstream targets ==

PAK2-mediated phosphorylation of merlin at S518 modulates its tumor suppressor activity, c-Jun phosphorylation at T2, T8, T89, T93 and T286 contributes to the growth of growth factor-stimulated melanoma cells, Caspase-7 phosphorylation at S30, T173 and S239 inhibits apoptotic activity in breast cancer cells, and STAT5 phosphorylation at S779 modulates BCL-ABL-mediated leukemogenesis. PAK2 activity negatively regulates the function and expression of c-Myc: PAK2 phosphorylation of c-Myc at T358-S373-T400 inhibits its transactivation function and PAK2 depletion stimulates c-Myc expression during granulocyte-monocyte lineage. ==Notes==