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Gene Review

PAK3  -  p21 protein (Cdc42/Rac)-activated kinase 3

Homo sapiens

Synonyms: Beta-PAK, CDKN1A, MRX30, MRX47, OPHN3, ...
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Disease relevance of PAK3

  • Prompted by the Pak3 screen hit, we further investigated the involvement of group I PAK kinases in HIV using siRNA [1].
  • Recent human genetic approaches showed that mutations in three genes encoding OPHN1, PAK3, and alphaPIX cause nonspecific X-linked mental retardation [2].
  • PAK3 activation is sensitive to pertussis toxin, but insensitive to LY 294002, an inhibitor of phosphatidylinositol 3'-kinase [3].

Psychiatry related information on PAK3

  • Recently, a study using the candidate gene approach demonstrated the presence of mutations in PAK3 (p21-activating kinase) associated with nonspecific mental retardation [4].

High impact information on PAK3

  • The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338 [5].
  • Here we show that the p21-activated protein kinase Pak3 phosphorylates Raf-1 on serine 338 in vitro and in vivo [5].
  • Taken together, our data show that growth factor-stimulated Raf-1 activity is independent of Pl3-K activity and argue against Pak3 being a physiological mediator of S338 phosphorylation in growth factor-stimulated cells [6].
  • The inability of Pak3 to activate Raf-1 was not due to an inability to stimulate phosphorylation of the tyrosine at position 341 but may be due to its inability to recruit Raf-1 to the plasma membrane [6].
  • We examined several representative focal adhesion proteins, and found that paxillin is the sole protein that associates with PAK3 [7].

Biological context of PAK3


Anatomical context of PAK3

  • PAK3 is induced by the activation of T cells, whereas PAK1 is constitutively expressed in both naive and activated T cells [8].
  • Together, these results indicate that ARHGEF6 is localized in dendritic spines where it contributes to regulate spine morphogenesis probably by acting through a downstream activation of PAK3 [9].
  • Independent activation of endogenous p21-activated protein kinase-3 (PAK3) and JNK by thrombin in CCL39 fibroblasts [3].
  • Ultrastructural analysis of the changes induced by expression of PAK3 carrying the MRX30 mutation reveals that many elongated spines fail to express postsynaptic densities or contact presynaptic terminals [11].
  • The cyclin kinase inhibitor 1A (CDKN1A) is overexpressed in MM compared to normal plasma cells [12].

Associations of PAK3 with chemical compounds

  • Moreover, paxillin alpha can be phosphorylated by PAK3 at serine [7].
  • In addition, many novel factors whose knockdown inhibited infection were identified, including Pak3, a member of the serine/threonine group I PAK kinases [1].
  • The recent suggestion that Pak3 could stimulate Raf-1 activity by directly phosphorylating S338 through a Ras/phosphatidylinositol 3-kinase (Pl3-K)/-Cdc42-dependent pathway has attracted much attention [6].

Regulatory relationships of PAK3


Other interactions of PAK3


Analytical, diagnostic and therapeutic context of PAK3


  1. "UnPAKing" human immunodeficiency virus (HIV) replication: using small interfering RNA screening to identify novel cofactors and elucidate the role of group I PAKs in HIV infection. Nguyen, D.G., Wolff, K.C., Yin, H., Caldwell, J.S., Kuhen, K.L. J. Virol. (2006) [Pubmed]
  2. The RhoGAP activity of OPHN1, a new F-actin-binding protein, is negatively controlled by its amino-terminal domain. Fauchereau, F., Herbrand, U., Chafey, P., Eberth, A., Koulakoff, A., Vinet, M.C., Ahmadian, M.R., Chelly, J., Billuart, P. Mol. Cell. Neurosci. (2003) [Pubmed]
  3. Independent activation of endogenous p21-activated protein kinase-3 (PAK3) and JNK by thrombin in CCL39 fibroblasts. Malcolm, K.C., Chambard, J.C., Grall, D., Pouysségur, J., van Obberghen-Schilling, E. J. Cell. Physiol. (2000) [Pubmed]
  4. Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation. Bienvenu, T., des Portes, V., McDonell, N., Carrié, A., Zemni, R., Couvert, P., Ropers, H.H., Moraine, C., van Bokhoven, H., Fryns, J.P., Allen, K., Walsh, C.A., Boué, J., Kahn, A., Chelly, J., Beldjord, C. Am. J. Med. Genet. (2000) [Pubmed]
  5. The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. King, A.J., Sun, H., Diaz, B., Barnard, D., Miao, W., Bagrodia, S., Marshall, M.S. Nature (1998) [Pubmed]
  6. S338 phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3. Chiloeches, A., Mason, C.S., Marais, R. Mol. Cell. Biol. (2001) [Pubmed]
  7. Interaction of paxillin with p21-activated Kinase (PAK). Association of paxillin alpha with the kinase-inactive and the Cdc42-activated forms of PAK3. Hashimoto, S., Tsubouchi, A., Mazaki, Y., Sabe, H. J. Biol. Chem. (2001) [Pubmed]
  8. AILIM/ICOS-mediated elongation of activated T cells is regulated by both the PI3-kinase/Akt and Rho family cascade. Nukada, Y., Okamoto, N., Konakahara, S., Tezuka, K., Ohashi, K., Mizuno, K., Tsuji, T. Int. Immunol. (2006) [Pubmed]
  9. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Nod??-Langlois, R., Muller, D., Boda, B. J. Cell. Sci. (2006) [Pubmed]
  10. A novel regulator of p21-activated kinases. Bagrodia, S., Taylor, S.J., Jordon, K.A., Van Aelst, L., Cerione, R.A. J. Biol. Chem. (1998) [Pubmed]
  11. The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. Boda, B., Alberi, S., Nikonenko, I., Node-Langlois, R., Jourdain, P., Moosmayer, M., Parisi-Jourdain, L., Muller, D. J. Neurosci. (2004) [Pubmed]
  12. Identification and characterization of HLA-class-I-restricted T-cell epitopes in the putative tumor-associated antigens P21-activated serin kinase 2 (PAK2) and cyclin-dependent kinase inhibitor 1A (CDKN1A). Li, G., Hundemer, M., Wolfrum, S., Ho, A.D., Goldschmidt, H., Witzens-Harig, M. Ann. Hematol. (2006) [Pubmed]
  13. Regulation of the protein kinase Raf-1 by oncogenic Ras through phosphatidylinositol 3-kinase, Cdc42/Rac and Pak. Sun, H., King, A.J., Diaz, H.B., Marshall, M.S. Curr. Biol. (2000) [Pubmed]
  14. Up-regulation of p21- and RhoA-activated protein kinases in human pregnant myometrium. Moore, F., Da Silva, C., Wilde, J.I., Smarason, A., Watson, S.P., López Bernal, A. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  15. X-linked mild non-syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3. Gedeon, A.K., Nelson, J., Gécz, J., Mulley, J.C. Am. J. Med. Genet. A (2003) [Pubmed]
  16. Regional localisation of two non-specific X-linked mental retardation genes (MRX30 and MRX31). Donnelly, A.J., Partington, M.W., Ryan, A.K., Mulley, J.C. Am. J. Med. Genet. (1996) [Pubmed]
  17. A YAC contig in Xq22.3-q23, from DXS287 to DXS8088, spanning the brain-specific genes doublecortin (DCX) and PAK3. Allen, K.M., Gleeson, J.G., Shoup, S.M., Walsh, C.A. Genomics (1998) [Pubmed]
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