p21-activated kinase 2 (PAK2), S6/H4 kinase, PAK65 or gamma-PAK
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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:
- nucleus, cytoplasm, perinuclear region, lipid-anchor
- interaction with ARHGAP10 probably changes PAK-2p34 location to cytoplasmic perinuclear region
- 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]
More general terms
References
- ↑ Jump up to: 1.0 1.1 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: https://www.ncbi.nlm.nih.gov/pubmed/15252450
- ↑ UniProt http://www.uniprot.org/uniprot/Q13177.html
- ↑ Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/PAK2ID41634ch3q29.html
Database
- UniProt: http://www.uniprot.org/uniprot/Q13177.html
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5062
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5062
- OMIM: https://mirror.omim.org/entry/605022
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5062