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p21-activated kinase 2 (PAK2), S6/H4 kinase, PAK65 or gamma-PAK

Function: - serine/threonine protein kinase - role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation - acts as downstream effector of the small GTPases CDC42 & RAC1 - activation by the binding of active CDC42 & RAC1 results in a conformational change & a subsequent autophosphorylation on several Ser &/or Thr - full length PAK 2 stimulates cell survival & cell growth; at least in part, mediated by phosphorylation & inhibition of pro-apoptotic BAD - phosphorylates MAPK4 & MAPK6 & activates the downstream target MAPKAPK5, a regulator of F-actin polymerization & cell migration - phosphorylates JUN & plays a role in EGF-induced cell proliferation. - phosphorylates many other substrates including histone H4 to promote assembly of H3.3 & H4 into nucleosomes, BAD, ribosomal protein S6, or myelin basic protein (MBP) - associates with ARHGEF7 & GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis - interacts tightly with GTP-bound but not GDP-bound CDC42/p21 & RAC1 - interacts with SH3MD4 - interacts with & activated by HIV-1 Nef - activated by binding small G proteins - binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-402 & allows the kinase domain to adopt an active structure (putative) - full length PAK 2 is autophosphorylated when activated by CDC42/p21 - ubiquitinated, leading to its proteosomal degradation - apoptotic stimuli such as DNA damage lead to caspase-mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment that translocates to the nucleus & promotes apoptosis involving the JNK signaling pathway - the other fragment is PAK-2p27 - both fragments are autophosphorylated, PAK-2p27 on Ser & PAK-2p34 on Thr - caspase-activated PAK2 phosphorylates MKNK1 & reduces cellular translation. - PAK-2p34 interacts with ARHGAP10 Structure: - PAK-2p34 may be myristoylated - belongs to the protein kinase superfamily, STE Ser/Thr protein kinase family, STE20 subfamily - contains 1 CRIB domain - contains 1 protein kinase domain Compartment: - serine/threonine protein kinase PAK 2: cytoplasm - PAK-2p34: a) nucleus, cytoplasm, perinuclear region, lipid-anchor b) interaction with ARHGAP10 probably changes PAK-2p34 location to cytoplasmic perinuclear region c) myristoylation changes PAK-2p34 location to the membrane Expression: - ubiquitously expressed - higher levels in skeletal muscle, ovary, thymus & spleen Genetics: - segmental duplication of chromosome 3 involving PAK2 is one of the few features distinguishing the human genome from the chimpanzee genome. [1]

Related

PAK2 (p21-associated kinase 2) gene

General

evolutionary divergent human protein p21 (CDKN1A)-activated kinase (PAK)

Properties

SIZE: entity length = 524 aa MW = 58 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: acetylation site SITE: N-TERMINUS EFFECTOR-BOUND: acetyl Ser phosphorylation site {S2} Thr phosphorylation site {T60} Autoregulatory {69-137} MOTIF: binding site SITE: 69-112 FOR-BINDING-OF: guanosine triphosphatase (GTPase) CRIB domain {74-87} Ser phosphorylation site {S141} Thr phosphorylation site {T169} Ser phosphorylation site {S197} peptide motif {212-213} MOTIF: myristoylation site SITE: G213 EFFECTOR-BOUND: myristate nuclear translocation signal {245-251} kinase domain SITE: 249-499 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 255-263 ATP-binding site NAME: ATP-binding site SITE: 278-278 arginine residue {R367} Thr phosphorylation site {T402} STATE: active state

Database Correlations

OMIM 605022 UniProt Q13177 PFAM correlations Entrez Gene 5062 Kegg hsa:5062 ENZYME 2.7.11.1

References

  1. Fortna A, Kim Y, MacLaren E, Marshall K, Hahn G, Meltesen L, Brenton M, Hink R, Burgers S, Hernandez-Boussard T, Karimpour- Fard A, Glueck D, McGavran L, Berry R, Pollack J, Sikela JM. Lineage-specific gene duplication and loss in human and great ape evolution. PLoS Biol. 2004 Jul;2(7):E207. Epub 2004 Jul 13. PMID: 15252450
  2. UniProt :accession Q13177
  3. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/PAK2ID41634ch3q29.html