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Gene Review

PAK1  -  p21 protein (Cdc42/Rac)-activated kinase 1

Homo sapiens

Synonyms: Alpha-PAK, PAK-1, Serine/threonine-protein kinase PAK 1, p21-activated kinase 1, p65-PAK
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Disease relevance of PAK1

  • The inhibition of E. coli invasion by these PAK1 mutants is due to the absence of phospho-MLC at the actin condensation points [1].
  • A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor [2].
  • PAK1 has previously been shown to play a central role in regulating cell motility and invasiveness in other cell types, and increased expression has been observed in breast and colorectal carcinomas [3].
  • Using small interfering RNA-mediated PAK1 knockdown, we showed up to a five-fold decrease in invasion through matrigel, indicating that elevated levels of PAK1 are associated with invasive potential in uveal melanoma [3].
  • Furthermore, we and others have demonstrated that the growth of mouse RAS-induced sarcomas allografts in mice is almost completely suppressed by either FK228 or a combination of two complimentary Tyr-kinase inhibitors, PP1 and AG 879, all of which block the RAS-induced activation of PAK1 [4].

Psychiatry related information on PAK1


High impact information on PAK1

  • We propose here a key role for PAK action in coordinating the dynamics of the actin and microtubule cytoskeletons during directional motility of cells, as well as in other functions requiring cytoskeletal polarization [6].
  • We summarize relevant effects of p21-activated kinase, LIM-kinase, and focal adhesion kinase [7].
  • When activated by extracellular signals via membrane signaling receptors, Rac executes its functions through engaging downstream effectors such as p21-activated kinase (PAK), a serine/threonine protein kinase [8].
  • In this issue, report direct communication between guanylyl cyclases and the Rac-p21-activated kinase (PAK) signaling pathway-which is essential for cell migration-to promote cell motility, through allosteric activation of guanylyl cyclases by autophosphorylated PAK [9].
  • This Rac/PAK/GC/cGMP pathway is involved in platelet-derived growth factor-induced fibroblast cell migration and lamellipodium formation [8].

Chemical compound and disease context of PAK1


Biological context of PAK1

  • MLCK activity and MLC phosphorylation were decreased, and cell spreading was inhibited in baby hamster kidney-21 and HeLa cells expressing constitutively active PAK1 [12].
  • During the elongation, not only PAK1 but also PAK3 play an essential role through the phosphorylation of their conservative autophosphorylation sites and catalytic domain [13].
  • PAK1 regulates myosin II-B phosphorylation, filament assembly, localization and cell chemotaxis [14].
  • To further investigate its functions, we used the yeast two-hybrid system to screen a human fetal brain cDNA library and identified dynein light chain 2 (DLC2)/myosin light chain (MLC) as an interacting partner of PAK1 [15].
  • We have now determined structures at 1.8 A resolution for the free PAK1 kinase domain, with a mutation in the active site that blocks enzymatic activity, and for the same domain with a "phosphomimetic" mutation in the activation loop [16].

Anatomical context of PAK1


Associations of PAK1 with chemical compounds

  • These phenotypic effects of PAK1 in model systems are mechanistically linked with the ability of PAK1 to phosphorylate ER-alpha on serine 305 and subsequent secondary activation of serine 118 [11].
  • These findings prompt further investigation of how nuclear signaling by PAK1 may affect estrogen's action and whether tamoxifen resistance might be prevented or reversed by PAK1 inhibition [11].
  • However, the Cdc42-binding domain from mPAK-3, a member of the PAK (p21 activated kinase) family of serine/threonine kinases, competed with both proteins [20].
  • Expression of mutant S56A vimentin depressed PAK phosphorylation at Thr-423 induced by 5-HT [19].
  • The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced cell survival; this study explored the effect of ZD1839 on the stimulation of c-Src and p21-activated kinase 1 (Pak1), which are vital for transformation, directional motility, and cell survival of cancer cells [21].
  • We show that high pak1 protein levels may predict tamoxifen insensitivity [22].
  • Mammary tissues can resist apoptotic stimuli by activating NF-kappaB through alpha6beta4 integrin-dependent Rac-Pak1 signaling [23].
  • Taken together, the data indicate that p70 S6 kinase activates PAK1 and contributes to phosphatidylinositol 3-kinase- and ERK-mediated regulation of HCV RNA replication [24].

Physical interactions of PAK1


Enzymatic interactions of PAK1


Co-localisations of PAK1


Regulatory relationships of PAK1


Other interactions of PAK1


Analytical, diagnostic and therapeutic context of PAK1


  1. Modulation of myosin light-chain phosphorylation by p21-activated kinase 1 in Escherichia coli invasion of human brain microvascular endothelial cells. Rudrabhatla, R.S., Sukumaran, S.K., Bokoch, G.M., Prasadarao, N.V. Infect. Immun. (2003) [Pubmed]
  2. A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Hirokawa, Y., Tikoo, A., Huynh, J., Utermark, T., Hanemann, C.O., Giovannini, M., Xiao, G.H., Testa, J.R., Wood, J., Maruta, H. Cancer journal (Sudbury, Mass.) (2004) [Pubmed]
  3. Increased p21-activated kinase-1 expression is associated with invasive potential in uveal melanoma. Pavey, S., Zuidervaart, W., van Nieuwpoort, F., Packer, L., Jager, M., Gruis, N., Hayward, N. Melanoma Res. (2006) [Pubmed]
  4. Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Hirokawa, Y., Levitzki, A., Lessene, G., Baell, J., Xiao, Y., Zhu, H., Maruta, H. Cancer Lett. (2007) [Pubmed]
  5. Central Nervous System Functions of PAK Protein Family: From Spine Morphogenesis to Mental Retardation. Boda, B., Nikonenko, I., Alberi, S., Muller, D. Mol. Neurobiol. (2006) [Pubmed]
  6. Biology of the p21-activated kinases. Bokoch, G.M. Annu. Rev. Biochem. (2003) [Pubmed]
  7. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Somlyo, A.P., Somlyo, A.V. Physiol. Rev. (2003) [Pubmed]
  8. A Rac-cGMP Signaling Pathway. Guo, D., Tan, Y.C., Wang, D., Madhusoodanan, K.S., Zheng, Y., Maack, T., Zhang, J.J., Huang, X.Y. Cell (2007) [Pubmed]
  9. PAK-in' Up cGMP for the Move. Settleman, J. Cell (2007) [Pubmed]
  10. Activation of p21-activated kinase 1 is required for lysophosphatidic acid-induced focal adhesion kinase phosphorylation and cell motility in human melanoma A2058 cells. Jung, I.D., Lee, J., Lee, K.B., Park, C.G., Kim, Y.K., Seo, D.W., Park, D., Lee, H.W., Han, J.W., Lee, H.Y. Eur. J. Biochem. (2004) [Pubmed]
  11. Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity. Rayala, S.K., Molli, P.R., Kumar, R. Cancer Res. (2006) [Pubmed]
  12. Inhibition of myosin light chain kinase by p21-activated kinase. Sanders, L.C., Matsumura, F., Bokoch, G.M., de Lanerolle, P. Science (1999) [Pubmed]
  13. 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]
  14. PAK1 regulates myosin II-B phosphorylation, filament assembly, localization and cell chemotaxis. Even-Faitelson, L., Rosenberg, M., Ravid, S. Cell. Signal. (2005) [Pubmed]
  15. Identification of dynein light chain 2 as an interaction partner of p21-activated kinase 1. Lu, J., Sun, Q., Chen, X., Wang, H., Hu, Y., Gu, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  16. The active conformation of the PAK1 kinase domain. Lei, M., Robinson, M.A., Harrison, S.C. Structure (Camb.) (2005) [Pubmed]
  17. PAK1 hyperactivation is sufficient for mammary gland tumor formation. Wang, R.A., Zhang, H., Balasenthil, S., Medina, D., Kumar, R. Oncogene (2006) [Pubmed]
  18. Paxillin-dependent paxillin kinase linker and p21-activated kinase localization to focal adhesions involves a multistep activation pathway. Brown, M.C., West, K.A., Turner, C.E. Mol. Biol. Cell (2002) [Pubmed]
  19. Critical Role of Vimentin Phosphorylation at Ser-56 by p21-activated Kinase in Vimentin Cytoskeleton Signaling. Li, Q.F., Spinelli, A.M., Wang, R., Anfinogenova, Y., Singer, H.A., Tang, D.D. J. Biol. Chem. (2006) [Pubmed]
  20. Identification of a putative effector for Cdc42Hs with high sequence similarity to the RasGAP-related protein IQGAP1 and a Cdc42Hs binding partner with similarity to IQGAP2. McCallum, S.J., Wu, W.J., Cerione, R.A. J. Biol. Chem. (1996) [Pubmed]
  21. The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells. Yang, Z., Bagheri-Yarmand, R., Wang, R.A., Adam, L., Papadimitrakopoulou, V.V., Clayman, G.L., El-Naggar, A., Lotan, R., Barnes, C.J., Hong, W.K., Kumar, R. Clin. Cancer Res. (2004) [Pubmed]
  22. Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer. Bostner, J., Ahnström Waltersson, M., Fornander, T., Skoog, L., Nordenskjöld, B., Stål, O. Oncogene (2007) [Pubmed]
  23. alpha6beta4 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-kappaB-dependent resistance to apoptosis in 3D mammary acini. Friedland, J.C., Lakins, J.N., Kazanietz, M.G., Chernoff, J., Boettiger, D., Weaver, V.M. J. Cell. Sci. (2007) [Pubmed]
  24. p21-activated kinase 1 is activated through the mammalian target of rapamycin/p70 S6 kinase pathway and regulates the replication of hepatitis C virus in human hepatoma cells. Ishida, H., Li, K., Yi, M., Lemon, S.M. J. Biol. Chem. (2007) [Pubmed]
  25. Involvement of alpha-PAK-interacting exchange factor in the PAK1-c-Jun NH(2)-terminal kinase 1 activation and apoptosis induced by benzo[a]pyrene. Yoshii, S., Tanaka, M., Otsuki, Y., Fujiyama, T., Kataoka, H., Arai, H., Hanai, H., Sugimura, H. Mol. Cell. Biol. (2001) [Pubmed]
  26. Androgen receptor specifically interacts with a novel p21-activated kinase, PAK6. Yang, F., Li, X., Sharma, M., Zarnegar, M., Lim, B., Sun, Z. J. Biol. Chem. (2001) [Pubmed]
  27. Regulation of actin polymerization in cell-free systems by GTPgammaS and Cdc42. Zigmond, S.H., Joyce, M., Borleis, J., Bokoch, G.M., Devreotes, P.N. J. Cell Biol. (1997) [Pubmed]
  28. Phosphorylation of RhoGDI by p21-activated kinase 1. DerMardirossian, C.M., Bokoch, G.M. Meth. Enzymol. (2006) [Pubmed]
  29. Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling. Turner, C.E., Brown, M.C., Perrotta, J.A., Riedy, M.C., Nikolopoulos, S.N., McDonald, A.R., Bagrodia, S., Thomas, S., Leventhal, P.S. J. Cell Biol. (1999) [Pubmed]
  30. p21-activated kinase 1 interacts with and phosphorylates histone H3 in breast cancer cells. Li, F., Adam, L., Vadlamudi, R.K., Zhou, H., Sen, S., Chernoff, J., Mandal, M., Kumar, R. EMBO Rep. (2002) [Pubmed]
  31. Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding. Thaxton, C., Lopera, J., Bott, M., Baldwin, M.E., Kalidas, P., Fernandez-Valle, C. Mol. Cell. Neurosci. (2007) [Pubmed]
  32. Phosphorylation of serine 709 in GIT1 regulates protrusive activity in cells. Webb, D.J., Kovalenko, M., Whitmore, L., Horwitz, A.F. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  33. p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils. Martyn, K.D., Kim, M.J., Quinn, M.T., Dinauer, M.C., Knaus, U.G. Blood (2005) [Pubmed]
  34. Signaling through Raf-1 in the neovasculature and target validation by nanoparticles. Wary, K.K. Mol. Cancer (2003) [Pubmed]
  35. Cell surface heparan sulfate participates in CXCL1-induced signaling. Wang, D., Sai, J., Richmond, A. Biochemistry (2003) [Pubmed]
  36. The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family. Koh, C.G., Tan, E.J., Manser, E., Lim, L. Curr. Biol. (2002) [Pubmed]
  37. Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition. Tran, N.H., Frost, J.A. J. Biol. Chem. (2003) [Pubmed]
  38. A p21-activated kinase-controlled metabolic switch up-regulates phagocyte NADPH oxidase. Shalom-Barak, T., Knaus, U.G. J. Biol. Chem. (2002) [Pubmed]
  39. Structural requirements for PAK activation by Rac GTPases. Knaus, U.G., Wang, Y., Reilly, A.M., Warnock, D., Jackson, J.H. J. Biol. Chem. (1998) [Pubmed]
  40. Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. Bagheri-Yarmand, R., Vadlamudi, R.K., Wang, R.A., Mendelsohn, J., Kumar, R. J. Biol. Chem. (2000) [Pubmed]
  41. PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. Coles, L.C., Shaw, P.E. Oncogene (2002) [Pubmed]
  42. Lim kinase regulates the development of olfactory and neuromuscular synapses. Ang, L.H., Chen, W., Yao, Y., Ozawa, R., Tao, E., Yonekura, J., Uemura, T., Keshishian, H., Hing, H. Dev. Biol. (2006) [Pubmed]
  43. Filopodia are conduits for melanosome transfer to keratinocytes. Scott, G., Leopardi, S., Printup, S., Madden, B.C. J. Cell. Sci. (2002) [Pubmed]
  44. Pak-1 expression increases with progression of colorectal carcinomas to metastasis. Carter, J.H., Douglass, L.E., Deddens, J.A., Colligan, B.M., Bhatt, T.R., Pemberton, J.O., Konicek, S., Hom, J., Marshall, M., Graff, J.R. Clin. Cancer Res. (2004) [Pubmed]
  45. A method to measure the interaction of Rac/Cdc42 with their binding partners using fluorescence resonance energy transfer between mutants of green fluorescent protein. Graham, D.L., Lowe, P.N., Chalk, P.A. Anal. Biochem. (2001) [Pubmed]
  46. Basic fibroblast growth factor-induced translocation of p21-activated kinase to the membrane is independent of phospholipase C-gamma1 in the differentiation of PC12 cells. Shin, K.S., Shin, E.Y., Lee, C.S., Quan, S.H., Woo, K.N., Soung, N.K., Kwak, S.J., Kim, S.R., Kim, E.G. Exp. Mol. Med. (2002) [Pubmed]
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