9d51

Structural highlights

Function

PAK2_HUMAN Serine/threonine protein kinase that plays a 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 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Full-length PAK2 stimulates cell survival and cell growth. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Phosphorylates JUN and plays an important role in EGF-induced cell proliferation. Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP. Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis. On the other hand, 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 and promotes cellular apoptosis involving the JNK signaling pathway. Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation.^{[1] [2] [3] [4] [5] [6] [7] [8]}

References

1. ↑ Jakobi R, McCarthy CC, Koeppel MA, Stringer DK. Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation. J Biol Chem. 2003 Oct 3;278(40):38675-85. Epub 2003 Jul 9. PMID:12853446 doi:http://dx.doi.org/10.1074/jbc.M306494200
2. ↑ Orton KC, Ling J, Waskiewicz AJ, Cooper JA, Merrick WC, Korneeva NL, Rhoads RE, Sonenberg N, Traugh JA. Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk. J Biol Chem. 2004 Sep 10;279(37):38649-57. Epub 2004 Jul 2. PMID:15234964 doi:http://dx.doi.org/10.1074/jbc.M407337200
3. ↑ Vilas GL, Corvi MM, Plummer GJ, Seime AM, Lambkin GR, Berthiaume LG. Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events. Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6542-7. Epub 2006 Apr 14. PMID:16617111 doi:http://dx.doi.org/0600824103
4. ↑ Hsu RM, Tsai MH, Hsieh YJ, Lyu PC, Yu JS. Identification of MYO18A as a novel interacting partner of the PAK2/betaPIX/GIT1 complex and its potential function in modulating epithelial cell migration. Mol Biol Cell. 2010 Jan 15;21(2):287-301. doi: 10.1091/mbc.E09-03-0232. Epub 2009, Nov 18. PMID:19923322 doi:http://dx.doi.org/10.1091/mbc.E09-03-0232
5. ↑ Li T, Zhang J, Zhu F, Wen W, Zykova T, Li X, Liu K, Peng C, Ma W, Shi G, Dong Z, Bode AM, Dong Z. P21-activated protein kinase (PAK2)-mediated c-Jun phosphorylation at 5 threonine sites promotes cell transformation. Carcinogenesis. 2011 May;32(5):659-66. doi: 10.1093/carcin/bgq271. Epub 2010 Dec , 22. PMID:21177766 doi:http://dx.doi.org/10.1093/carcin/bgq271
6. ↑ De la Mota-Peynado A, Chernoff J, Beeser A. Identification of the atypical MAPK Erk3 as a novel substrate for p21-activated kinase (Pak) activity. J Biol Chem. 2011 Apr 15;286(15):13603-11. doi: 10.1074/jbc.M110.181743. Epub, 2011 Feb 11. PMID:21317288 doi:http://dx.doi.org/10.1074/jbc.M110.181743
7. ↑ Kang B, Pu M, Hu G, Wen W, Dong Z, Zhao K, Stillman B, Zhang Z. Phosphorylation of H4 Ser 47 promotes HIRA-mediated nucleosome assembly. Genes Dev. 2011 Jul 1;25(13):1359-64. doi: 10.1101/gad.2055511. PMID:21724829 doi:http://dx.doi.org/10.1101/gad.2055511
8. ↑ Rudel T, Bokoch GM. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science. 1997 Jun 6;276(5318):1571-4. PMID:9171063