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2009 | 56 | 2 | 225-234

Article title

Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements


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The p21-activated kinases (PAKs) are serine/threonine protein kinases interacting with small GTPases - Rac and Cdc42. PAKs are found in most eukaryotes and play an evolutionarily conserved role in many cellular processes. Six human PAKs have been identified, and based on homology, they can be classified into two groups. This review focuses specifically on the role of Rac/Cdc42 regulated PAKs in maintaining and remodeling cytoskeletal structure in various organisms. A list of PAKs substrates and binding partners implicated directly and indirectly in cytoskeletal reorganization is presented. Also perturbations of the Rac/Cdc42/PAK pathway leading to tumorigenesis and neurodegenerative diseases are reviewed.








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  • Laboratory of Bioenergetics and Biomembranes, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland


  • Acconcia F, Barnes CJ, Singh RR, Talukder AH, Kumar R (2007) Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase. Proc Natl Acad Sci USA 104: 6782-6787.
  • Alberts AS, Qin H, Carr HS, Frost JA (2005) PAK1 negatively regulates the activity of the Rho exchange factor NET1. J Biol Chem 280: 12152-12161.
  • Aoki H, Yokoyama T, Fujiwara K, Tari AM, Sawaya R, Suki D, Hess KR, Aldape KD, Kondo S, Kumar R, Kondo Y (2007) Phosphorylated Pak1 level in the cytoplasm correlates with shorter survival time in patients with glioblastoma. Clin Cancer Res 13: 6603-6609.
  • Arber S, Barbayannis FA, Hanser H, Schneider C, Stanyon CA, Bernard O, Caroni P (1998) Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393: 805-809.
  • Arias-Romero LE, Chernoff J (2008) A tale of two Paks. Biol Cell 100: 97-108.
  • Ayala I, Baldassarre M, Giacchetti G, Caldieri G, Tetè S, Luini A, Buccione R (2008) Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation. J Cell Sci 121: 369-378.
  • Ballif BA, Villén J, Beausoleil SA, Schwartz D, Gygi SP (2004) Phosphoproteomic analysis of the developing mouse brain. Mol Cell Proteomics 3: 1093-1101.
  • Banerjee M, Worth D, Prowse DM, Nikolic M (2002) Pak1 phosphorylation on T212 affects microtubules in cells undergoing mitosis. Curr Biol 12: 1233-1239.
  • Barac A, Basile J, Vázquez-Prado J, Gao Y, Zheng Y, Gutkind JS (2004) Direct interaction of p21-activated kinase 4 with PDZ-RhoGEF, a G protein-linked Rho guanine exchange factor. J Biol Chem 279: 6182-6189.
  • Bernard O (2007) Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol 39: 1071-1076.
  • Bisson N, Islam N, Poitras L, Jean S, Bresnick A, Moss T (2003) The catalytic domain of xPAK1 is sufficient to induce myosin II dependent in vivo cell fragmentation independently of other apoptotic events. Dev Biol 263: 264-281.
  • Bokoch GM (2003) Biology of the p21-activated kinases. Annu Rev Biochem 72: 743-781.
  • Brzeska H, Korn ED (1996) Regulation of class I and class II myosins by heavy chain phosphorylation. J Biol Chem 271: 16983-16986.
  • Brzeska H, Lynch TJ, Martin B, Korn ED (1989) The localization and sequence of the phosphorylation sites of Acanthamoeba myosin I. An improved method for locating the phosphorylated amino acid. J Biol Chem 264: 19340-19348.
  • Brzeska H, Szczepanowska J, Hoey J, Korn ED (1996) The catalytic domain of acanthamoeba myosin 1 heavy chain kinase II. Expression of active catalytic domain and sequence homology to p21-activated kinase (PAK). J Biol Chem 271: 27056-27062.
  • Brzeska H, Knaus UG, Wang ZY, Bokoch GM, Korn ED (1997) p21-activated kinase has substrate specificity similar to Acanthamoeba myosin I heavy chain kinase and activates Acanthamoeba myosin I. Proc Natl Acad Sci USA 94: 1092-1095.
  • Brzeska H, Szczepanowska J, Matsumura F, Korn ED (2004) Rac-induced increase of phosphorylation of myosin regulatory light chain in HeLa cells. Cell Motil Cytoskeleton 58: 186-199.
  • Buss F, Kendric-Jones J, Lionne C, Knight AE, Cote GP, Luzio JP (1998) The localization of myosin VI at the Golgi complex and leading edge of fibroblasts and its phosphorylation and recruitment into membrane ruffles at A431 cells after growth factor stimulation. J Cell Biol 143: 1535-1545.
  • Callow MG, Clairvoyant F, Zhu S, Schryver B, Whyte DB, Bischoff JR, Jallal B, Smeal T (2002) Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. J Biol Chem 277: 550-558.
  • Callow MG, Zozulya S, Gishizky ML, Jallal B, Smeal T (2005) PAK4 mediates morphological changes through the regulation of GEF-H1. J Cell Sci 118: 1861-1872.
  • Chew TL, Masaracchia RA, Goeckeler ZM, Wysolmersky RB (1998) Phosphorylation of non-muscle myosin II regulatory light chain by p21-activated kinase (gamma-PAK). J Muscle Res Cell Motil 19: 839-854.
  • Coniglio SJ, Zavarella S, Symons MH (2008) Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms. Mol Cell Biol 28: 4162-4172.
  • Crawford JM, Su Z, Varlamova O, Bresnic AR, Kiehart DP (2001) Role of myosin-II phosphorylation in V12Cdc42-mediated disruption of Drosophila cellularization. Eur J Cell Biol 80: 240-244.
  • Dan C, Kelly A, Bernard O, Minden A (2001) Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin. J Biol Chem 276: 32115-32121.
  • Daniels RH, Bokoch GM (1999) p21-activated protein kinase: a crucial component of molecular signaling? Trends Biochem Sci 24: 350-355.
  • DerMardirossian C, Schnelzer A, Bokoch GM (2004) Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Mol Cell 15: 117-127.
  • Edwards DC, Sanders LC, Bokoch GM, Gordon NG (1999) Activation of LIM-kinase by PAK1 couples Rac/Cdc42 GTPase signaling to actin cytoskeletal dynamics. Nat Cell Biol 1: 253-259.
  • Eppinga RD, Li Y, Lin JL, Mak AS, Lin JJ (2006) Requirement of reversible caldesmon phosphorylation at P21-activated kinase-responsive sites for lamellipodia extensions during cell migration. Cell Motil Cytoskeleton 63: 543-562.
  • Eswaran J, Soundararajan M, Kumar R, Knapp S (2008) UnPAKing the class differences among p21-activated kinases. Trends Biochem Sci 33: 394-403.
  • Foster DB, Shen LH, Kelly J, Thibault P, Van Eyk JE, Mak AS (2000) Phosphorylation of caldesmon by p21-activated kinase. Implications for the Ca2+ sensitivity of smooth muscle contraction. J Biol Chem 275: 1959-1965.
  • Fryer BH, Field J (2005) Rho, Rac, Pak and angiogenesis: old roles and newly identified responsibilities in endothelial cells. Cancer Lett 229: 13-23.
  • Goeckeler ZM, Masaracchia RA, Zeng Q, Chew TL, Gallagher P, Wysomerki RB (2000) Phosphorylation of myosin light chain kinase by p21-activated kinase PAK2. J Biol Chem 275: 18366-18374.
  • Goto H, Tanabe K, Manser E, Lim L, Yasui Y, Inagaki M (2002) Phosphorylation and reorganization of vimentin by p21-activated kinase (PAK). Genes Cells 7: 91-97.
  • Guo D, Tan YC, Wang D, Madhusoodanan KS, Zheng Y, Maack T, Zhang JJ, Huang XY (2007) A Rac-cGMP signaling pathway. Cell 128: 341-355.
  • Hashimoto S, Tsubouchi A, Mazaki Y, Sabe H (2001) Interaction of paxillin with p21-activated kinase (PAK). Association of paxillin alpha with the kinase-inactive and the Cdc42-activated forms of PAK3. J Biol Chem 276: 6037-6045.
  • Hofmann C, Shepelev M, Chernoff J (2004) The genetics of PAK. J Cell Sci 117: 4343-4354.
  • Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21: 247-269.
  • Jaffer ZM, Chernoff J (2002) p21-activated kinases: three more join the PAK. Int J Biochem Cell Biol 34: 713-717.
  • King AJ, Sun H, Diaz B, Barnard D, Miao W, Bagrodia S, Marshall MS (1998) The protein kinase PAK3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature 396: 180-183.
  • Knaus UG, Bokoch G (1998) The p21Rac/Cdc42-activated kinase (PAKs). Int J Biochem Cell Biol 30: 857-862.
  • Kreis P, Barnier JV (2009) PAK signalling in neuronal physiology. Cell Signal 21: 384-393.
  • Kreis P, Thévenot E, Rousseau V, Boda B, Muller D, Barnier JV (2007) The p21-activated kinase 3 implicated in mental retardation regulates spine morphogenesis through a Cdc42-dependent pathway. J Biol Chem 282: 21497-21506.
  • Kumar R, Vadlamudi RK (2002) Emerging functions of p21-activated kinases in human cancer cells. J Cell Physiol 193: 133-144.
  • Kumar R, Gururaj AE, Barnes CJ (2006) p21-activated kinases in cancer. Nat Rev Cancer 6: 459-471.
  • Leberer E, Dignard D, Harcus D, Thomas DY, Whiteway M (1992) The protein kinase homologue Ate20p is required to link the yeast pheromone response G-protein beta gamma subunits to downstream signaling components. EMBO J 11: 4815-4824.
  • Lechler T, Shevchenko A, Li R (2000) Direct involvement of yeast type I myosins in Cdc42-dependent actin polymerization. J Cell Biol 148: 363-373.
  • Lee SF, Côté GP (1995) Purification and characterization of a Dictyostelium protein kinase required for actin activation of the Mg2+ATPase activity of Dictyostelium myosin ID. J Biol Chem 270: 11776-11782.
  • Lee SF, Egelhoff TT, Mahasneh A, Côté GP (1996) Cloning and characterization of a Dictyostelium myosin I heavy chain kinase activated by Cdc42 and Rac. J Biol Chem 271: 27044-27048.
  • Li Z, Hannigan M, Mo Z, Liu B, Lu W, Wu Y, Smrcka AV, Wu G, Li L, Liu M, Huang CK, Wu D (2003) Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42. Cell 114: 215-227.
  • Loo T-H, Balasubramanian M (2008) Schizosaccharomyces pombe Pak-related protein, Pak1p/Orb2p, phosphorylates mosin regulatory light chain to inhibit cytokinesis. J Cell Biol 183: 785-793.
  • Luo T, Xu Y, Hoffman TL, Zhang T, Schilling T, Sargent D (2007) Inca: a novel p21-activated kinase-associated protein required for cranial neural crest development. Development 134: 1279-1289.
  • Luo S, Mizuta H, Rubinsztein DC (2008) p21-activated kinase 1 promotes soluble mutant huntingtin self-interaction and enhances toxicity. Hum Mol Genet 17: 895-905.
  • Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L (1994) A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367: 40-46.
  • Manser E, Loo TH, Koh CG, Zhao ZS, Chen XQ, Tan L, Tan I, Leung T, Lim L (1998) PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol Cell 1: 183-192.
  • Matenia D, Griesshaber B, Li X, Thiesses A, Johne C, Jiao J, Mandelkow E, Mandelkow E-M (2005) PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin. Mol Biol Cell 16: 4410-4422.
  • Matsumura F, Ono S, Yamakita Y, Totsukawa G, Yamashiro S (1998) Specific localization of serine 19 phosphorylation myosin II during cell locomotion and mitosis in cultured cells. J Cell Biol 140: 119-129.
  • Mentzel B, Raabe T (2005) Phylogenetic and structural analysis of the Drosophila melanogaster p21-activated kinase DmPAK3. Gene 349: 25-33.
  • Menzel N, Melzer J, Waschke J, Lenz C, Wecklein H, Lochnit G, Dreckhahn D, Raabe T (2008) The Drosophila p21-activated kinase Mbt modulates DE-cadherin-mediated cell adhesion by phosphorylation of Armadillo. Biochem J 416: 231-241.
  • Morita T, Mayanagi T, Yoshio T, Sobue K (2007) Changes in the balance between caldesmon regulated by p21-activated kinases and the Arp2/3 complex govern podosome formation. J Biol Chem 282: 8454-8463.
  • Nguyen TV, Galvan V, Huang W, Banwait S, Tang H, Zhang J, Bredesen DE (2008) Signal transduction in Alzheimer disease: p21-activated kinase signaling requires C-terminal cleavage of APP at Asp664. J Neurochem 104: 1065-1080.
  • Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai LH (1998) The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 395: 194-198.
  • Nodé-Langlois R, Muller D, Boda B (2006) Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. J Cell Sci 119: 4986-4993.
  • Ohtakara K, Inada H, Goto H, Taki W, Manser E, Lim L, Izawa I, Inagaki M (2000) p21-activated kinase PAK phosphorylates desmin at sites different from those for Rho-associated kinase. Biochem Biophys Res Commun 272: 712-716.
  • Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (2006) Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127: 635-648.
  • Pollard TD, Korn ED (1973) Acanthamoeba myosin. I. Isolation from Acanthamoeba castellanii of an enzyme similar to muscle myosin. J Biol Chem 248: 4691-4697.
  • Ramos E, Wysolmerski RB, Masaracchia RA (1997) Myosin phosphorylation by human cdc42-dependent S6/H4 kinase/gammaPAK from placenta and lymphoid cells. Recept Signal Transduct 7: 99-110.
  • Redowicz MJ (2007) Unconventional myosins in muscle. Eur J Cell Biol 86: 549-558.
  • Rennefahrt UE, Deacon SW, Parker SA, Devarajan K, Beeser A, Chernoff J, Knapp S, Turk BE, Peterson JR (2007) Specificity profiling of Pak kinases allows identification of novel phosphorylation sites. J Biol Chem 282: 15667-15678.
  • Salminen A, Suuronen T, Kaarniranta K (2008) ROCK, PAK, and Toll of synapses in Alzheimer's disease. Biochem Biophys Res Commun 371: 587-590.
  • Sanders LC, Matsumura F, Bokoch GM, de Lanerolle P (1999) Inhibition of myosin light chain kinase by p21-activated kinase. Science 283: 2083-2085.
  • Scoles DR (2008) The merlin interacting proteins reveal multiple targets for NF2 therapy. Biochim Biophys Acta 1785: 32-54.
  • Schürmann A, Mooney AF, Sanders LC, Sells MA, Wang HG, Reed JC, Bokoch GM (2000) p21-activated kinase 1 phosphorylates the death agonist Bad and protects cells from apoptosis. Mol Cell Biol 20: 453-461.
  • Sellers JR (2000) Myosins: a diverse superfamily. Biochim Biophys Acta 1496: 3-22.
  • Shin EY, Shin KS, Lee CS, Woo KN, Quan SH, Soung NK, Kim YG, Cha CI, Kim SR, Park D, Bokoch GM, Kim EG (2002) Phosphorylation of p85 beta PIX, a Rac/Cdc42-specific guanine nucleotide exchange factor, via the Ras/ERK/PAK2 pathway is required for basic fibroblast growth factor-induced neurite outgrowth. J Biol Chem 277: 44417-44430.
  • Shin EY, Shim ES, Lee CS, Kim HK, Kim EG (2009) Phosphorylation of RhoGDI1 by p21-activated kinase 2 mediates basic fibroblast growth factor-stimulated neurite outgrowth in PC12 cells. Biochem Biophys Res Commun 379: 384-389.
  • Small DH (2008) Neural network dysfunction in Alzheimer's disease: a drug development perspective. Trends Mol Med 14: 103-108.
  • Szczepanowska J, Korn ED, Brzeska H (2006) Activation of myosin in HeLa cells causes redistribution of focal adhesions and F-actin from cell center to cell periphery. Cell Motil Cytoskeleton 63: 356-374.
  • Thaxton C, Lopera J, Bott M, Baldwin ME, Kalidas P, Fernandez-Valle C (2007) Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding. Mol Cell Neurosci 34: 231-242.
  • Thaxton C, Lopera J, Bott M, Fernandez-Valle C (2008) Neuregulin and laminin stimulate phosphorylation of the NF2 tumor suppressor in Schwann cells by distinct protein kinase A and p21-activated kinase-dependent pathways. Oncogene 27: 2705-2715.
  • Timm T, Matenia D, Griesshaber B, Mandelkow EM (2006) Signaling from MARK to tau: regulation, cytoskeletal crosstalk, and pathological phosphorylation. Neurodegener Dis 3: 207-217.
  • Vadlamudi RK, Kumar R (2003) P21-activated kinases in human cancer. Cancer Metastasis Rev 22: 385-393.
  • Vadlamudi RK, Li F, Adam L, Nguyen D, Ohta Y, Stossel TP, Kumar R (2002) Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1. Nat Cell Biol 4: 681-690.
  • Vadlamudi RK, Bagheri-Yarmand R, Yang Z, Balasenthil S, Nguyen D, Sahin AA, den Hollander P, Kumar R (2004a) Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes. Cancer Cell 5: 575-585.
  • Vadlamudi RK, Li F, Barnes CJ, Bagheri-Yarmand R, Kumar R (2004b) p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate. EMBO Rep 5: 154-160.
  • Vadlamudi RK, Barnes CJ, Rayala S, Li F, Balasenthil S, Marcus S, Goodson HV, Sahin AA, Kumar R (2005) p21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor B. Mol Cell Biol 25: 3726-3736.
  • Van Eyk JE, Arrel DK, Foster DB, Strauss JD, Heinonen TY, Furmaniak-Kazmierczak E, Cote GP, Mak AS (1998) Different molecular mechanisms for Rho family GTPase-dependent, Ca2+-independent contraction of smooth muscle. J Biol Chem 273: 23433-23439.
  • Webb BA, Zhou S, Eves R, Shen L, Jia L, Mak AS (2006a) Phosphorylation of cortactin by p21-activated kinase. Arch Biochem Biophys 456: 183-193.
  • Webb DJ, Mayhew MW, Kovalenko M, Schroeder MJ, Jeffery ED, Whitmore L, Shabanowitz J, Hunt DF, Horwitz AF (2006b) Identification of phosphorylation sites in GIT1. J Cell Sci 119: 2847-2850.
  • Wittmann T, Bokoch GM, Waterman-Storer CM (2004) Regulation of microtubule destabilizing activity of Op18/stathmin downstream of Rac1. J Biol Chem 279: 6196-6203.
  • Wu C, Lytvyn V, Thomas DY, Leberer E (1997) The phosphorylation site for Ste20p-like protein kinases is essential for the function of myosin-1 in yeast. J Biol Chem 272: 30623-30626.
  • Yang N, Higuchi O, Ohashi K, Nagata K, Wada A, Kangawa K, Nishida E, Mizuno K (1998) Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature 393: 809-812.
  • Yang Z, Vadlamudi RK, Kumar R (2005) Dynein light chain 1 phosphorylation controls macropinocytosis. J Biol Chem 280: 654-659.
  • Zegers MM, Forget MA, Chernoff J, Mostov KE, ter Beest MB, Hansen SH (2003) Pak1 and PIX regulate contact inhibition during epithelial wound healing. EMBO J 22: 4155-4165.
  • Zenke FT, Krendel M, DerMardirossian C, King CC, Bohl BP, Bokoch GM (2004) p21-activated kinase 1 phosphorylates and regulates 14-3-3 binding to GEF-H1, a microtubule-localized Rho exchange factor. J Biol Chem 279: 18392-18400.
  • Zhang H, Li Z, Viklund EK, Strömblad S (2002) p21-Activated kinase 4 interacts with integrin αvβ5 and regulates αvβ5-mediated cell migration. J Cell Biol 158: 1287-1297.
  • Zhang H, Webb DJ, Assmunsen H, Niu S, Horwitz AF (2005) A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci 25: 3379-3388.
  • Zhao ZS, Lim JP, Ng YW, Lim L, Manser E (2005) The GIT-associated kinase PAK targets to the centrosome and regulates Aurora-A. Mol Cell 20: 237-249.
  • Zhao ZS, Manser E (2005) PAK and other Rho-associated kinases-effectors with surprisingly diverse mechanisms of regulation. Biochem J 386: 201-214.

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