PAK2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3PCS
Identifiers
Aliases	PAK2, PAK65, PAKgamma, p21 (RAC1) activated kinase 2
External IDs	OMIM: 605022 MGI: 1339984 HomoloGene: 99711 GeneCards: PAK2
Gene location ( Human) Chr. Chromosome 3 (human) [1] Band 3q29 Start 196,739,857 bp [1] End 196,832,647 bp [1]
Gene location ( Mouse) Chr. Chromosome 16 (mouse) [2] Band 16 B2|16 22.4 cM Start 31,835,108 bp [2] End 31,898,160 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence corpus callosum monocyte superficial temporal artery stromal cell of endometrium Achilles tendon pericardium internal globus pallidus synovial joint saphenous vein Top expressed in Paneth cell retinal pigment epithelium aortic valve ciliary body renal corpuscle utricle ascending aorta primitive streak medullary collecting duct corneal stroma More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding protein tyrosine kinase activator activity kinase activity protein serine/threonine kinase activity protein binding catalytic activity identical protein binding ATP binding protein kinase binding cadherin binding small GTPase binding Cellular component membrane plasma membrane perinuclear region of cytoplasm nucleus cytoplasm cytosol postsynaptic density glutamatergic synapse Biological process negative regulation of protein kinase activity phosphorylation T cell costimulation cellular response to organic cyclic compound stimulatory C-type lectin receptor signaling pathway mitigation of host defenses by virus Fc-epsilon receptor signaling pathway protein phosphorylation dendritic spine development negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis vascular endothelial growth factor receptor signaling pathway peptidyl-serine phosphorylation positive regulation of peptidyl-tyrosine phosphorylation positive regulation of extrinsic apoptotic signaling pathway protein autophosphorylation regulation of growth metabolism T cell receptor signaling pathway signal transduction positive regulation of protein tyrosine kinase activity apoptotic process negative regulation of apoptotic process viral process Rho protein signal transduction regulation of mitotic cell cycle cell migration actin cytoskeleton organization stress-activated protein kinase signaling cascade regulation of apoptotic process regulation of MAPK cascade interleukin-12-mediated signaling pathway activation of protein kinase activity Sources: Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5062 224105 Ensembl ENSG00000180370 ENSMUSG00000022781 UniProt Q13177 Q8CIN4 RefSeq (mRNA) NM_002577 NM_177326 RefSeq (protein) NP_002568 NP_796300 Location (UCSC) Chr 3: 196.74 – 196.83 Mb Chr 16: 31.84 – 31.9 Mb PubMed search [3] [4]
Wikidata
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Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene. ^{[5] [6]}

PAK2 is one of three members of Group I PAK family of serine/threonine kinases. ^{[7] [8]} The PAKs are evolutionary conserved. ^[9] PAK2 and its cleaved fragment localize in both the cytoplasmic or nuclear compartments. PAK2 signaling modulates apoptosis, ^[10] endothelial lumen formation, ^[11] viral pathogenesis, ^[12] and cancer including, breast, ^[13] hepatocarcinoma, ^[14] and gastric ^[15] and cancer, at-large. ^[16]

Discovery

The human PAK2 was identified as a downstream effector of Rac or Cdc42. ^{[7] [8]}

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. ^[16]

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. ^[17]

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. ^[18]

Upstream activators

PAK2 kinase activity is stimulated by transforming growth factor β in fibroblasts, ^[19] by proteinase inhibitor alpha2-macroglobulin binding to GRP78 in prostate cancer cells, ^[20] by its phosphorylation by AMP-activated protein kinase in stem and cancer cells ^[21] and eryptosis. ^[22] PAK2 is cleaved through activated caspase-3 in fibroblast and cancer cells exposed to ultraviolet, ^[23] hyperosmotic shock, ^[24] and ionizing radiation. ^[25]

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; ^[26] FRAX597 suppresses PAK2 activity in neurofibromatosis type 2 (NF2)-associated tumorigenesis; ^[27] and miR-23b and miR-137 inhibits PAK2 expression in tumor cells. ^{[28] [29]} Insulin stimulation of neuronal cells also antagonizes PAK2 kinase activity, leading to an increased glucose uptake. ^[30]

Downstream targets

PAK2-mediated phosphorylation of merlin at S518 modulates its tumor suppressor activity, ^[31] c-Jun phosphorylation at T2, T8, T89, T93 and T286 contributes to the growth of growth factor-stimulated melanoma cells, ^[32] Caspase-7 phosphorylation at S30, T173 and S239 inhibits apoptotic activity in breast cancer cells, ^[13] Paxillin phosphorylation at S272 and S274 activates ADAM10 protease, ^[33] and STAT5 phosphorylation at S779 modulates BCL-ABL-mediated leukemogenesis. ^[34] PAK2 activity negatively regulates the function and expression of c-Myc: PAK2 phosphorylation of c-Myc at T358-S373-T400 inhibits its transactivation function ^[35] and PAK2 depletion stimulates c-Myc expression during granulocyte-monocyte lineage. ^[36]

Notes

The 2016 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: Rakesh Kumar, Rahul Sanawar, Xiaodong Li, Feng Li (19 December 2016). "Structure, biochemistry, and biology of PAK kinases". Gene. 605: 20–31. doi: 10.1016/J.GENE.2016.12.014. PMC  5250584. PMID  28007610.

References

External links

• PAK2 Info with links in the Cell Migration Gateway Archived 2014-12-11 at the Wayback Machine
• Overview of all the structural information available in the PDB for UniProt: Q13177 (Serine/threonine-protein kinase PAK 2) at the PDBe-KB.