PAK1 as a therapeutic target

Expert Opinion on Therapeutic Targets

Volumn 14, Issue 7, 2010, Pages 703-725

  Kichina, Julia V ^a   Goc, Anna ^b   Al Husein, Belal ^b   Somanath, Payaningal R ^b   Kandel, Eugene S ^a  

^a ROSWELL PARK CANCER INSTITUTE   (United States)

^b MEDICAL COLLEGE OF GEORGIA   (United States)

Author keywords

Allergy; Angiogenesis; Cancer; P21 activated kinases; Rho GTPases; Signal transduction

Indexed keywords

2 AMINO N [4 [5 (2 PHENANTHRENYL) 3 TRIFLUOROMETHYL 1H PYRAZOL 1 YL]PHENYL]ACETAMIDE; CEP 1347; GUANINE NUCLEOTIDE EXCHANGE FACTOR; GUANOSINE TRIPHOSPHATASE; KT D606; MESSENGER RNA; P21 ACTIVATED KINASE 1; P21 ACTIVATED KINASE 2; PROTEIN SERINE THREONINE KINASE INHIBITOR; STAUROSPORINE; UNCLASSIFIED DRUG; ISOENZYME; P21 ACTIVATED KINASE; PAK1 PROTEIN, HUMAN;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANGIOGENESIS; CELL CYCLE; CELL MIGRATION; CELL MOTILITY; CELL PROLIFERATION; CELL SURVIVAL; CELLULAR IMMUNITY; DRUG BINDING; DRUG INHIBITION; DRUG MECHANISM; EXTRACELLULAR MATRIX; GENE EXPRESSION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; MENTAL DISEASE; NEOPLASM; NEUROLOGIC DISEASE; NONHUMAN; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; TISSUE DISTRIBUTION; ANIMAL; ANTAGONISTS AND INHIBITORS; ANTIBODY SPECIFICITY; CHEMISTRY; DRUG EFFECTS; ENZYME ACTIVATION; ENZYME SPECIFICITY; GENE EXPRESSION REGULATION; GENETICS; HYPERSENSITIVITY; IMMUNITY; INTELLECTUAL IMPAIRMENT; NEOPLASMS; PATHOPHYSIOLOGY; PHYSIOLOGY; PROTEIN TERTIARY STRUCTURE;

ANIMALS; ENZYME ACTIVATION; GENE EXPRESSION REGULATION, ENZYMOLOGIC; HUMANS; HYPERSENSITIVITY; IMMUNITY; ISOENZYMES; MENTAL RETARDATION; NEOPLASMS; ORGAN SPECIFICITY; P21-ACTIVATED KINASES; PROTEIN STRUCTURE, TERTIARY; SIGNAL TRANSDUCTION; SUBSTRATE SPECIFICITY; INTELLECTUAL DISABILITY;

EID: 77953590185     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.2010.492779     Document Type: Review

References (235)

1. Manser E, Leung T, Salihuddin H, et al. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 1994;367(6458):40-46
2. Martin GA, Bollag G, McCormick F, Abo A. A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20. EMBO J 1995;14(9):1970-1978
3. Knaus UG, Morris S, Dong HJ, et al. Regulation of human leukocyte p21-activated kinases through G protein-coupled receptors. Science 1995;269(5221):221-223
4. Bagrodia S, Taylor SJ, Creasy CL, et al. Identification of a mouse p21Cdc42/Rac activated kinase. J Biol Chem 1995;270(39):22731-22737
5. Kumar A, Molli PR, Pakala SB, et al. PAK thread from amoeba to mammals. J Cell Biochem 2009;107(4):579-585
6. Somanath PR, Vijai J, Kichina JV, et al. The role of PAK-1 in activation of MAP kinase cascade and oncogenic transformation by Akt. Oncogene 2009;28(25):2365-2369
7. Marlin JW, Eaton A, Montano GT, et al. Elevated p21-activated kinase 2 activity results in anchorage-independent growth and resistance to anticancer drug-induced cell death. Neoplasia 2009;11(3):286-297
8. Maroto B, Ye MB, von Lohneysen K, et al. P21-Activated kinase is required for mitotic progression and regulates Plk1. Oncogene 2008;27(36):4900-4908
9. Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem 2003;72:743-781
10. Beeser A, Jaffer ZM, Hofmann C, Chernoff J. Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors. J Biol Chem 2005;280:36609-36615
11. Somanath PR, Byzova TV. 14-3-3beta- Rac1-p21 activated kinase signaling regulates Akt1-mediated cytoskeletal organization, lamellipodia formation and fibronectin matrix assembly. J Cell Physiol 2009;218:394-404
12. Kumar R, Gururaj AE, Barnes CJ. p21-activated kinases in cancer. Nat Rev 2006;6:459-471
13. Jaffer ZM, Chernoff J. p21-activated kinases: three more join the Pak. Int J Biochem Cell Biol 2002;34:713-717
14. Eswaran J, Lee WH, Debreczeni JE, et al. Crystal structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs. Structure 2007;15:201-213
15. Arias-Romero LE, Chernoff J. A tale of two Paks. Biol Cell 2008;100:97-108
16. Eswaran J, Soundararajan M, Knapp S. Targeting group II PAKs in cancer and metastasis. Cancer Metastasis Rev 2009;28:209-217
17. Rennefahrt UE, Deacon SW, Parker SA, et al. Specificity profiling of Pak kinases allows identification of novel phosphorylation sites. J Biol Chem 2007;282:15667-15678
18. Bright MD, Garner AP, Ridley AJ. PAK1 and PAK2 have different roles in HGF-induced morphological responses. Cell Signal 2009;21:1738-1747
19. Coniglio SJ, Zavarella S, Symons MH. Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms. Mol Cell Biol 2008;28:4162-4172
20. Dummler B, Ohshiro K, Kumar R, Field J. Pak protein kinases and their role in cancer. Cancer Metastasis Rev 2009;28:51-63
21. Pacheco A, Chernoff J. Group I p21-activated kinases: emerging roles in immune function and viral pathogenesis. Int J Biochem Cell Biol 2010;42:13-16
22. Vadlamudi RK, Kumar R. p21-Activated kinase 1: an emerging therapeutic target. Cancer Treat Res 2004;119:77-88
23. Kreis P, Barnier JV. PAK signalling in neuronal physiology. Cell signal 2009;21:384-393
24. Su AI, Wiltshire T, Batalov S, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 2004;101:6062-6067
25. Burbelo PD, Kozak CA, Finegold AA, et al. Cloning, central nervous system expression and chromosomal mapping of the mouse PAK-1 and PAK-3 genes. Gene 1999;232:209-215
26. Clerk A, Sugden PH. Activation of p21-activated protein kinase alpha (alpha PAK) by hyperosmotic shock in neonatal ventricular myocytes. FEBS Lett 1997;403:23-25
27. Dharmawardhane S, Brownson D, Lennartz M, Bokoch GM. Localization of p21-activated kinase 1 (PAK1) to pseudopodia, membrane ruffles, and phagocytic cups in activated human neutrophils. J Leukoc Biol 1999;66:521-527
28. Kageyama K, Sakihara S, Suda T. Regulation and role of p21-activated kinase 3 by corticotropin-releasing factor in mouse pituitary. Regul Pept 2009;152:88-94
29. Abo A, Qu J, Cammarano MS, et al. PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia. EMBO J 1998;17:6527-6540
30. Callow MG, Clairvoyant F, Zhu S, et al. Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. J Biol Chem 2002;277:550-558
31. Qu J, Li X, Novitch BG, et al. PAK4 kinase is essential for embryonic viability and for proper neuronal development. Mol Cell Biol 2003;23:7122-7133
32. Li X, Minden A. Targeted disruption of the gene for the PAK5 kinase in mice. Mol Cell Biol 2003;23:7134-7142
33. Nekrasova T, Jobes ML, Ting JH, et al. Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion. Dev Biol 2008;322:95-108
34. Pandey A, Dan I, Kristiansen TZ, et al. Cloning and characterization of PAK5, a novel member of mammalian p21-activated kinase-II subfamily that is predominantly expressed in brain. Oncogene 2002;21:3939-3948
35. Yang F, Li X, Sharma M, et al. Androgen receptor specifically interacts with a novel p21-activated kinase, PAK6. J Biol Chem 2001;276:15345-15353
36. Reddy SD, Ohshiro K, Rayala SK, Kumar R. MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions. Cancer Res 2008;68:8195-8200
37. Knaus UG, Bokoch GM. The p21Rac/ Cdc42-activated kinases (PAKs). Int J Biochem Cell Biol 1998;30:857-862
38. Lei M, Lu W, Meng W, et al. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell 2000;102:387-397
39. Knaus UG, Wang Y, Reilly AM, et al. Structural requirements for PAK activation by Rac GTPases. J Biol Chem 1998;273:21512-21518
40. Manser E, Loo TH, Koh CG, et al. PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. Mol cell 1998;1:183-192
41. Bagrodia S, Taylor SJ, Jordon KA, et al. A novel regulator of p21-activated kinases. J Biol Chem 1998;273:23633-23636
42. Walter BN, Huang Z, Jakobi R, et al. Cleavage and activation of p21-activated protein kinase gamma-PAK by CPP32 (caspase 3). Effects of autophosphorylation on activity. J Biol Chem 1998;273:28733-28739 (Pubitemid 28507560)
43. Wang J, Frost JA, Cobb MH, Ross EM. Reciprocal signaling between heterotrimeric G proteins and the p21-stimulated protein kinase. J Biol Chem 1999;274:31641-31647
44. Mitsios N, Saka M, Krupinski J, et al. A microarray study of gene and protein regulation in human and rat brain following middle cerebral artery occlusion. BMC Neurosci 2007;8:93
45. Gatti A, Huang Z, Tuazon PT, Traugh JA. Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation. J Biol Chem 1999;274:8022-8028
46. Chong C, Tan L, Lim L, Manser E. The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity. J Biol Chem 2001;276:17347-17353
47. Thompson G, Owen D, Chalk PA, Lowe PN. Delineation of the Cdc42/ Rac-binding domain of p21-activated kinase. Biochemistry 1998;37:7885-7891
48. Roig J, Traugh JA. Cytostatic p21 G protein-activated protein kinase gamma-PAK. Vitam Horm 2001;62:167-198
49. Pirruccello M, Sondermann H, Pelton JG, et al. A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. J Mol Biol 2006;361:312-326
50. King CC, Gardiner EM, Zenke FT, et al. p21-Activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). J Biol Chem 2000;275:41201-41209
51. Dharmawardhane S, Sanders LC, Martin SS, et al. Localization of p21-activated kinase 1 (PAK1) to pinocytic vesicles and cortical actin structures in stimulated cells. J Cell Biol 1997;138:1265-1278
52. Wu X, Frost JA. Multiple Rho proteins regulate the subcellular targeting of PAK5. Biochem Biophys Res Commun 2006;351:328-335
53. Aronheim A, Broder YC, Cohen A, et al. Chp, a homologue of the GTPase Cdc42Hs, activates the JNK pathway and is implicated in reorganizing the actin cytoskeleton. Curr Biol 1998;8:1125-1128
54. Neudauer CL, Joberty G, Tatsis N, Macara IG. Distinct cellular effects and interactions of the Rho-family GTPase TC10. Curr Biol 1998;8:1151-1160
55. Tao W, Pennica D, Xu L, et al. Wrch-1, a novel member of the Rho gene family that is regulated by Wnt-1. Genes Dev 2001;15:1796-1807
56. Daniels RH, Zenke FT, Bokoch GM. alphaPix stimulates p21-activated kinase activity through exchange factor-dependent and -independent mechanisms. J Biol Chem 1999;274:6047-6050
57. Feng Q, Albeck JG, Cerione RA, Yang W. Regulation of the Cool/Pix proteins: key binding partners of the Cdc42/Rac targets, the p21-activated kinases. J Biol Chem 2002;277:5644-5650
58. Stockton R, Reutershan J, Scott D, et al. Induction of vascular permeability: beta PIX and GIT1 scaffold the activation of extracellular signal-regulated kinase by PAK. Mol Biol Cell 2007;18:2346-2355
59. Matsuda C, Kameyama K, Suzuki A, et al. Affixin activates Rac1 via betaPIX in C2C12 myoblast. FEBS Lett 2008;582:1189-1196
60. Bokoch GM, Reilly AM, Daniels RH, et al. A GTPase-independent mechanism of p21-activated kinase activation. Regulation by sphingosine and other biologically active lipids. J Biol Chem 1998;273:8137-8144
61. Galisteo ML, Chernoff J, Su YC, et al. The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1. J Biol Chem 1996;271:20997-21000
62. Puto LA, Pestonjamasp K, King CC, Bokoch GM. p21-Activated kinase 1 (PAK1) interacts with the Grb2 adapter protein to couple to growth factor signaling. J Biol Chem 2003;278:9388-9393
63. Zhou GL, Zhuo Y, King CC, et al. Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration. Mol Cell Biol 2003;23:8058-8069
64. McManus MJ, Boerner JL, Danielsen AJ, et al. An oncogenic epidermal growth factor receptor signals via a p21-activated kinase-caldesmon-myosin phosphotyrosine complex. J Biol Chem 2000;275:35328-35334
65. Bagheri-Yarmand R, Mandal M, Taludker AH, et al. Etk/Bmx tyrosine kinase activates Pak1 and regulates tumorigenicity of breast cancer cells. J Biol Chem 2001;276:29403-29409
66. Westphal RS, Coffee RL Jr, Marotta A, et al. Identification of kinase-phosphatase signaling modules composed of p70 S6 kinase-protein phosphatase 2A (PP2A) and p21-activated kinase-PP2A. J Biol Chem 1999;274:687-692
67. Koh CG, Tan EJ, Manser E, Lim L. The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family. Curr Biol 2002;12:317-321
68. Brzeska H, Szczepanowska J, Matsumura F, Korn ED. Rac-induced increase of phosphorylation of myosin regulatory light chain in HeLa cells. Cell Motil Cytoskeleton 2004;58:186-199
69. Leberer E, Dignard D, Harcus D, et al. The protein kinase homologue Ste20p is required to link the yeast pheromone response G-protein betagamma subunits to downstream signalling components. EMBO J 1992;11:4815-4824
70. Wu C, Lytvyn V, Thomas DY, Leberer E. The phosphorylation site for Ste20p-like protein kinases is essential for the function of myosin-I in yeast. J Biol Chem 1997;272:30623-30626
71. Zhang H, Webb DJ, Asmussen H, et al. A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci 2005;25:3379-3388
72. Sanders LC, Matsumura F, Bokoch GM, de Lanerolle P. Inhibition of myosin light chain kinase by p21-activated kinase. Science 1999;283:2083-2085
73. Bernard O. Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol 2007;39:1071-1076
74. Po'uha ST, Shum MS, Goebel A, et al. LIM-kinase 2, a regulator of actin dynamics, is involved in mitotic spindle integrity and sensitivity to microtubule-destabilizing drugs. Oncogene 2010;29:597-607
75. Vadlamudi RK, Li F, Adam L, et al. Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1. Nat Cell Biol 2002;4:681-690
76. Vadlamudi RK, Li F, Barnes CJ, et al. p41-Arc subunit of human Arp2/ 3 complex is a p21-activated kinase-1-interacting substrate. EMBO Rep 2004;5:154-160
77. Ayala I, Baldassarre M, Giacchetti G, et al. Multiple regulatory inputs converge on cortactin to control invadopodia biogenesis and extracellular matrix degradation. J Cell Sci 2008;121:369-378
78. Morita T, Mayanagi T, Yoshio T, Sobue K. Changes in the balance between caldesmon regulated by p21-activated kinases and the Arp2/ 3 complex govern podosome formation. J Biol Chem 2007;282:8454-8463
79. Acconcia F, Barnes CJ, Singh RR, et al. Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase. Proc Natl Acad Sci USA 2007;104:6782-6787
80. Wittmann T, Bokoch GM, Waterman-Storer CM. Regulation of microtubule destabilizing activity of Op18/stathmin downstream of Rac1. J Biol Chem 2004;279:6196-6203
81. Vadlamudi RK, Barnes CJ, Rayala S, et al. p21-Activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor B. Mol Cell Biol 2005;25:3726-3736
82. Menzel N, Melzer J, Waschke J, et al. The Drosophila p21-activated kinase Mbt modulates DE-cadherin-mediated cell adhesion by phosphorylation of Armadillo. Biochem J 2008;416:231-241
83. Hashimoto S, Tsubouchi A, Mazaki Y, Sabe H. 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 2001;276:6037-6045
84. Weis SM. Evaluating integrin function in models of angiogenesis and vascular permeability. Methods Enzymol 2007;426:505-528
85. Mammoto A, Mammoto T, Ingber DE. Rho signaling and mechanical control of vascular development. Curr Opin Hematol 2008;15:228-234
86. Kiosses WB, Daniels RH, Otey C, et al. A role for p21-activated kinase in endothelial cell migration. J Cell Biol 1999;147:831-844
87. Guo F, Debidda M, Yang L, et al. Genetic deletion of Rac1 GTPase reveals its critical role in actin stress fiber formation and focal adhesion complex assembly. J Biol Chem 2006;281:18652-18659
88. Zhou GL, Tucker DF, Bae SS, et al. Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. J Biol Chem 2006;281:36443-36453
89. Orr AW, Stockton R, Simmers MB, et al. Matrix-specific p21-activated kinase activation regulates vascular permeability in atherogenesis. J Cell Biol 2007;176:719-727
90. Tan W, Palmby TR, Gavard J, et al. An essential role for Rac1 in endothelial cell function and vascular development. FASEB J 2008;22:1829-1838
91. Galan Moya EM, Le Guelte A, Gavard J. PAKing up to the endothelium. Cell Signal 2009;21:1727-1737
92. Alavi A, Hood JD, Frausto R, et al. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 2003;301:94-96
93. Connolly JO, Simpson N, Hewlett L, Hall A. Rac regulates endothelial morphogenesis and capillary assembly. Mol Biol Cell 2002;13:2474-2485
94. Kiosses WB, Hood J, Yang S, et al. A dominant-negative p65 PAK peptide inhibits angiogenesis. Circ Res 2002;90:697-702
95. Stoletov KV, Gong C, Terman BI. Nck and Crk mediate distinct VEGF-induced signaling pathways that serve overlapping functions in focal adhesion turnover and integrin activation. Exp Cell Res 2004;295:258-268
96. Nakatsu MN, Hughes CC. An optimized three-dimensional in vitro model for the analysis of angiogenesis. Methods Enzymol 2008;443:65-82
97. Koh W, Sachidanandam K, Stratman AN, et al. Formation of endothelial lumens requires a coordinated PKCepsilon-, Src-, Pak- and Raf-kinase-dependent signaling cascade downstream of Cdc42 activation. J Cell Sci 2009;122:1812-1822
98. Kamei M, Saunders WB, Bayless KJ, et al. Endothelial tubes assemble from intracellular vacuoles in vivo. Nature 2006;442:453-456
99. Abraham S, Yeo M, Montero-Balaguer M, et al. VE-Cadherin-mediated cell-cell interaction suppresses sprouting via signaling to MLC2 phosphorylation. Curr Biol 2009;19:668-674
100. Lampugnani MG, Dejana E. Adherens junctions in endothelial cells regulate vessel maintenance and angiogenesis. Thromb Res 2007;120(Suppl 2):S1-6
101. Mehta D, Rahman A, Malik AB. Protein kinase C-alpha signals rho-guanine nucleotide dissociation inhibitor phosphorylation and rho activation and regulates the endothelial cell barrier function. J Biol Chem 2001;276:22614-22620
102. Gavard J, Gutkind JS. VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 2006;8:1223-1234
103. Stockton RA, Schaefer E, Schwartz MA. p21-Activated kinase regulates endothelial permeability through modulation of contractility. J Biol Chem 2004;279:46621-46630
104. Buchner DA, Su F, Yamaoka JS, et al. pak2a mutations cause cerebral hemorrhage in redhead zebrafish. Proc Natl Acad Sci USA 2007;104:13996-14001
105. Hinoki A, Kimura K, Higuchi S, et al. p21-Activated kinase 1 participates in vascular remodeling in vitro and in vivo. Hypertension 2010;55:161-165
106. Yi C, Wilker EW, Yaffe MB, et al. Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2. Cancer Res 2008;68:7932-7937
107. Siu MK, Wong ES, Chan HY, et al. Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion. Int J Cancer 2010;127:21-31
108. Wang RA, Zhang H, Balasenthil S, et al. PAK1 hyperactivation is sufficient for mammary gland tumor formation. Oncogene 2006;25:2931-2936
109. Bostner J, Skoog L, Fornander T, et al. Estrogen receptor-alpha phosphorylation at serine 305, nuclear p21-activated kinase 1 expression, and response to tamoxifen in postmenopausal breast cancer. Clin Cancer Res 2010;16:1624-1633
110. Bostner J, Ahnstrom Waltersson M, Fornander T, et al. Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer. Oncogene 2007;26:6997-7005
111. Liu F, Li X, Wang C, et al. Downregulation of p21-activated kinase-1 inhibits the growth of gastric cancer cells involving cyclin B1. Int J Cancer 2009;125:2511-2519
112. Kandel ES, Hay N. The regulation and activities of the multifunctional serine/ threonine kinase Akt/PKB. Exp Cell Res 1999;253:210-229
113. Weinberg RA. The biology of cancer. Garland Science, New York; 2007
114. Tang Y, Chen Z, Ambrose D, et al. Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts. Mol Cell Biol 1997;17:4454-4464
115. Nheu T, He H, Hirokawa Y, et al. PAK is essential for RAS-induced upregulation of cyclin D1 during the G1 to S transition. Cell Cycle 2004;3:71-74
116. Hirokawa Y, Tikoo A, Huynh J, et al. A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer J 2004;10:20-26
117. Dadke D, Fryer BH, Golemis EA, Field J. Activation of p21-activated kinase 1-nuclear factor kB signaling by Kaposi's sarcoma-associated herpes virus G protein-coupled receptor during cellular transformation. Cancer Res 2003;63:8837-8847
118. Chen J, Siddiqui A. Hepatitis B virus X protein stimulates the mitochondrial translocation of Raf-1 via oxidative stress. J Virol 2007;81:6757-6760
119. Vadlamudi RK, Adam L, Wang RA, et al. Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem 2000;275:36238-36244
120. Wang R-A, Mazumdar A, Vadlamudi RK, Kumar R. P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary epithelium. EMBO J 2002;21:5437-5447
121. Deacon K, Mistry P, Chernoff J, et al. p38 Mitogen-activated protein kinase mediates cell death and p21-activated kinase mediates cell survival during chemotherapeutic drug-induced mitotic arrest. Mol Biol Cell 2003;14:2071-2087
122. Jakobi R, Moertl E, Koeppel MA. p21-Activated protein kinase gamma-PAK suppresses programmed cell death of BALB3T3 fibroblasts. J Biol Chem 2001;276:16624-16634
123. Menard RE, Jovanovski AP, Mattingly RR. Active p21-activated kinase 1 rescues MCF10A breast epithelial cells from undergoing anoikis. Neoplasia 2005;7:638-645
124. Schurmann A, Mooney AF, Sanders LC, et al. p21-Activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis. Mol Cell Biol 2000;20:453-461
125. Jin S, Zhuo Y, Guo W, Field J. p21-Activated kinase 1 (Pak1)-dependent phosphorylation of Raf-1 regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association. J Biol Chem 2005;280:24698-24705
126. Tang Y, Zhou H, Chen A, et al. The Akt proto-oncogene links Ras to Pak and cell survival signals. J Biol Chem 2000;275:9106-9109
127. Friedland JC, Lakins JN, Kazanietz MG, et al. alpha6beta4 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-kB-dependent resistance to apoptosis in 3D mammary acini. J Cell Sci 2007;120:3700-3712
128. Zahir N, Lakins JN, Russell A, et al. Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkB to mediate anchorage-independent survival of mammary tumors. J Cell Biol 2003;163:1397-1407
129. Bachelder RE, Ribick MJ, Marchetti A, et al. P53 inhibits alpha6beta4 integrin survival signaling by promoting the caspase 3-dependent cleavage of Akt/ PKB. J Cell Biol 1999;147:1063-1072
130. Bradley EW, Ruan MM, Oursler MJ. PAK1 is a novel MEK-independent raf target controlling expression of the IAP survivin in M-CSF-mediated osteoclast survival. J Cell Physiol 2008;217:752-758
131. Pennati M, Folini M, Zaffaroni N. Targeting survivin in cancer therapy. Expert Opin Ther Targets 2008;12:463-476
132. Rowe RG, Weiss SJ. Breaching the basement membrane: who, when and how? Trends Cell Biol 2008;18:560-574
133. Murphy G, Nagase H. Progress in matrix metalloproteinase research. Mol Aspects Med 2008;29:290-308
134. Li Q, Mullins SR, Sloane BF, Mattingly RR. p21-Activated kinase 1 coordinates aberrant cell survival and pericellular proteolysis in a three-dimensional culture model for premalignant progression of human breast cancer. Neoplasia 2008;10(4):314-329
135. Zhou L, Yan C, Gieling RG, et al. Tumor necrosis factor-alpha induced expression of matrix metalloproteinase-9 through p21-activated kinase-1. BMC Immunol 2009;10:15
136. Noël A, Jost M, Maquoi E. Matrix metalloproteinases at cancer tumor-host interface. Semin Cell Dev Biol 2008;19:52-60
137. Kandel ES, Lu T, Wan Y, et al. Mutagenesis by reversible promoter insertion to study the activation of NF-kB. Proc Natl Acad Sci USA 2005;102:6425-6430
138. McPhie DL, Coopersmith R, Hines-Peralta A, et al. DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci 2003;23:6914-6927
139. Allen KM, Gleeson JG, Bagrodia S, et al. PAK3 mutation in nonsyndromic X-linked mental retardation. Nat Genet 1998;20:25-30
140. Zhao L, Ma Q-L, Calon F, et al. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci 2006;9(2):234-242
141. Kreis P, Barnier J-V. PAK signalling in neuronal physiology. Cell signal 2009;21(3):384-393
142. Boda B, Alberi S, Nikonenko I, et al. The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. J Neurosci 2004;24:10816-10825
143. Ma Q-L, Yang F, Calon F, et al. p21-Activated kinase-aberrant activation and translocation in alzheimer disease pathogenesis. J Biol Chem 2008;283:14132-14143
144. Hayashi ML, Choi SY, Rao BS, et al. Altered cortical synaptic morphology and impaired memory consolidation in forebrain-specific dominant-negative PAK transgenic mice. Neuron 2004;42:773-787
145. Hayashi ML, Rao BS, Seo JS, et al. Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proc Natl Acad Sci USA 2007;104:11489-11494
146. Luo S, Mizuta H, Rubinsztein DC. p21-Activated kinase 1 promotes soluble mutant huntingtin self-interaction and enhances toxicity. Hum Mol Genet 2008;17:895-905
147. Eriguchi M, Mizuta H, Luo S, et al. alpha Pix enhances mutant huntingtin aggregation. J Neurol Sci 2010;290:80-85
148. Van den Broeke C, Radu M, Chernoff J, Favoreel HW. An emerging role for p21-activated kinases (Paks) in viral infections. Trends Cell Biol 2010;20:160-169
149. Leis J, Johnson S, Collins LS, Traugh JA. Effects of phosphorylation of avian retrovirus nucleocapsid protein pp12 on binding of viral RNA. J Biol Chem 1984;259:7726-7732
150. Fu X, Phillips N, Jentoft J, et al. Site-specific phosphorylation of avian retrovirus nucleocapsid protein pp12 regulates binding to viral RNA. Evidence for different protein conformations. J Biol Chem 1985;260:9941-9947
151. Sawai ET, Baur A, Struble H, et al. Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes. Proc Natl Acad Sci USA 1994;91:1539-1543
152. Nunn MF, Marsh JW. Human immunodeficiency virus type 1 Nef associates with a member of the p21-activated kinase family. J Virol 1996;70:6157-6161
153. Fackler OT, Lu X, Frost JA, et al. p21-Activated kinase 1 plays a critical role in cellular activation by Nef. Mol Cell Biol 2000;20:2619-2627
154. Arora VK, Molina RP, Foster JL, et al. Lentivirus Nef specifically activates Pak2. J Virol 2000;74:11081-11087
155. Renkema GH, Manninen A, Mann DA, et al. Identification of the Nef-associated kinase as p21-activated kinase 2. Curr Biol 1999;9:1407-1410
156. Foster J, Garcia JV. HIV-1 Nef: at the crossroads. Retrovirology 2008;5:84
157. Schindler M, Rajan D, Specht A, et al. Association of Nef with p21-activated kinase 2 is dispensable for efficient human immunodeficiency virus type 1 replication and cytopathicity in ex vivo-infected human lymphoid tissue. J Virol 2007;81:13005-13014
158. Lang SM, Iafrate AJ, Stahl-Hennig C, et al. Association of simian immunodeficiency virus Nef with cellular serine/threonine kinases is dispensable for the development of AIDS in rhesus macaques. Nat Med 1997;3:860-865
159. Dharmawardhane S, Schurmann A, Sells MA, et al. Regulation of macropinocytosis by p21-activated kinase-1. Mol Biol Cell 2000;11:3341-3352
160. Amstutz B, Gastaldelli M, Kalin S, et al. Subversion of CtBP1-controlled macropinocytosis by human adenovirus serotype 3. EMBO J 2008;27:956-969
161. Mercer J, Helenius A. Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science 2008;320:531-535
162. Van den Broeke C, Radu M, Deruelle M, et al. Alphaherpesvirus US3-mediated reorganization of the actin cytoskeleton is mediated by group A p21-activated kinases. Proc Natl Acad Sci USA 2009;106:8707-8712
163. Smith SD, Jaffer ZM, Chernoff J, Ridley AJ. PAK1-mediated activation of ERK1/2 regulates lamellipodial dynamics. J Cell Sci 2008;121:3729-3736
164. Li Z, Hannigan M, Mo Z, et al. Directional sensing requires Gbetagamma-mediated PAK1 and PIXalpha-dependent activation of Cdc42. Cell 2003;114:215-227
165. Rudrabhatla RS, Sukumaran SK, Bokoch GM, Prasadarao NV. Modulation of myosin light-chain phosphorylation by p21-activated kinase 1 in Escherichia coli invasion of human brain microvascular endothelial cells. Infect Immun 2003;71:2787-2797
166. Allen JD, Jaffer ZM, Park S-J, et al. p21-Activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics. Blood 2009;113:2695-2705
167. Frost JA, Khokhlatchev A, Stippec S, et al. Differential effects of PAK1-activating mutations reveal activity-dependent and -independent effects on cytoskeletal regulation. J Biol Chem 1998;273:28191-28198
168. Higuchi M, Onishi K, Kikuchi C, Gotoh Y. Scaffolding function of PAK in the PDK1-Akt pathway. Nat Cell Biol 2008;10:1356-1364
169. He H, Hirokawa Y, Manser E, et al. Signal therapy for ras-induced cancers in combination of ag 879 and pp1, specific inhibitors for erbb2 and src family kinases, that block pak activation. Cancer J 2001;7:191-202
170. Maruta H, He H, Tikoo A, Nur-e- Kamal M. Cytoskeletal tumor suppressors that block oncogenic RAS signaling. Ann NY Acad Sci 1999;886:48-57
171. Thullberg M, Gad A, Beeser A, et al. The kinase-inhibitory domain of p21-activated kinase 1 (PAK1) inhibits cell cycle progression independent of PAK1 kinase activity. Oncogene 2007;26:1820-1828
172. Gartel AL, Kandel ES. RNA interference in cancer. Biomol Eng 2006;23:17-34
173. Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008;26:127-132
174. Porchia LM, Guerra M, Wang YC, et al. 2-amino-N-{4-[5-(2-phenanthrenyl)- 3- (trifluoromethyl)-1H-pyrazol-1-yl]- phenyl} acetamide (OSU-03012), a celecoxib derivative, directly targets p21-activated kinase. Mol Pharmacol 2007;72:1124-1131
175. Nheu TV, He H, Hirokawa Y, et al. The k252a derivatives, inhibitors for the pak/ mlk kinase family, selectively block the growth of ras transformants. Cancer J 2002;8:328-336
176. Maksimoska J, Feng L, Harms K, et al. Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes. J Am Chem Soc 2008;130:15764-15765
177. Deacon SW, Beeser A, Fukui JA, et al. An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase. Chem Biol 2008;15:322-331
178. Viaud J, Peterson JR. An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently. Mol Cancer Ther 2009;8:2559-2565
179. Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interference- based therapeutics. Nature 2009;457:426-433
180. Birukova AA, Alekseeva E, Cokic I, et al. Cross talk between paxillin and Rac is critical for mediation of barrier-protective effects by oxidized phospholipids. Am J Physiol 2008;295:L593-602
181. Banerjee M, Worth D, Prowse DM, Nikolic M. Pak1 phosphorylation on t212 affects microtubules in cells undergoing mitosis. Curr Biol 2002;12:1233-1239
182. Thiel DA, Reeder MK, Pfaff A, et al. Cell cycle-regulated phosphorylation of p21-activated kinase 1. Curr Biol 2002;12:1227-1232
183. Adam L, Vadlamudi R, Kondapaka SB, et al. Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase. J Biol Chem 1998;273:28238-28246 (Pubitemid 28496122)
184. Papakonstanti EA, Stournaras C. Association of PI-3 kinase with PAK1 leads to actin phosphorylation and cytoskeletal reorganization. Mol Biol Cell 2002;13:2946-2962
185. Weisz Hubsman M, Volinsky N, Manser E, et al. Autophosphorylation- dependent degradation of Pak1, triggered by the Rho-family GTPase, Chp. Biochem J 2007;404:487-497
186. Mira JP, Benard V, Groffen J, et al. Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway. Proc Natl Acad Sci USA 2000;97:185-189
187. Leisner TM, Liu M, Jaffer ZM, et al. Essential role of CIB1 in regulating PAK1 activation and cell migration. J Cell Biol 2005;170:465-476
188. Leeuw T, Wu C, Schrag JD, et al. Interaction of a G-protein beta-subunit with a conserved sequence in Ste20/PAK family protein kinases. Nature 1998;391:191-195
189. Lise MF, Srivastava DP, Arstikaitis P, et al. Myosin-Va-interacting protein, RILPL2, controls cell shape and neuronal morphogenesis via Rac signaling. J Cell Sci 2009;122:3810-3821
190. Talukder AH, Meng Q, Kumar R. CRIPak, a novel endogenous Pak1 inhibitor. Oncogene 2006;25:1311-1319
191. Xia C, Ma W, Stafford LJ, et al. Regulation of the p21-activated kinase (PAK) by a human Gbeta-like WD-repeat protein, hPIP1. Proc Natl Acad Sci USA 2001;98:6174-6179
192. Lightcap CM, Kari G, Arias-Romero LE, et al. Interaction with LC8 is required for Pak1 nuclear import and is indispensable for zebrafish development. PLoS One 2009;4(6):e6025
193. Ku GM, Yablonski D, Manser E, et al. A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT. EMBO J 2001;20:457-465
194. Turner CE, Brown MC, Perrotta JA, et al. Paxillin LD4 motif binds PAK and
195. Mazumdar A, Kumar R. Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells. FEBS Lett 2003;535:6-10
196. Frost JA, Xu S, Hutchison MR, et al. Actions of Rho family small G proteins and p21-activated protein kinases on mitogen-activated protein kinase family members. Mol Cell Biol 1996;16:3707-3713
197. Wang RA, Mazumdar A, Vadlamudi RK, Kumar R. P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary epithelium. EMBO J 2002;21:5437-5447
198. Li F, Adam L, Vadlamudi RK, et al. p21-activated kinase 1 interacts with and phosphorylates histone H3 in breast cancer cells. EMBO Rep 2002;3:767-773
199. Kissil JL, Johnson KC, Eckman MS, Jacks T. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J Biol Chem 2002;277:10394-10399
200. Zhao ZS, Lim JP, Ng YW, et al. The GIT-associated kinase PAK targets to the centrosome and regulates Aurora-A. Mol cell 2005;20:237-249
201. Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem 2005;280:16244-16253
202. Gallagher ED, Xu S, Moomaw C, et al. Binding of JNK/SAPK to MEKK1 is regulated by phosphorylation. J Biol Chem 2002;277:45785-45792
203. Zenke FT, Krendel M, DerMardirossian C, et al. p21-Activated kinase 1 phosphorylates and regulates 14-3-3 binding to GEF-H1, a microtubule-localized Rho exchange factor. J Biol Chem 2004;279:18392-18400
204. Goto H, Tanabe K, Manser E, et al. Phosphorylation and reorganization of vimentin by p21-activated kinase (PAK). Genes Cells 2002;7:91-97 (Pubitemid 34213355)
205. Daub H, Gevaert K, Vandekerckhove J, et al. Rac/Cdc42 and p65PAK regulate the microtubule-destabilizing protein stathmin through phosphorylation at serine 16. J Biol Chem 2001;276:1677-1680
206. Alberts AS, Qin H, Carr HS, Frost JA. PAK1 negatively regulates the activity of the Rho exchange factor NET1. J Biol Chem 2005;280:12152-12161
207. Foster DB, Shen LH, Kelly J, et al. Phosphorylation of caldesmon by p21-activated kinase. Implications for the Ca2+ sensitivity of smooth muscle contraction. J Biol Chem 2000;275:1959-1965
208. Takizawa N, Koga Y, Ikebe M. Phosphorylation of CPI17 and myosin binding subunit of type 1 protein phosphatase by p21-activated kinase. Biochem Biophys Res Commun 2002;297:773-778
209. Ohtakara K, Inada H, Goto H, et al. p21-Activated kinase PAK phosphorylates desmin at sites different from those for Rho-associated kinase. Biochem Biophys Res Commun 2000;272:712-716
210. Buscemi N, Foster DB, Neverova I, Van Eyk JE. p21-Activated kinase increases the calcium sensitivity of rat triton-skinned cardiac muscle fiber bundles via a mechanism potentially involving novel phosphorylation of troponin I. Circ Res 2002;91:509-516
211. Edwards DC, Sanders LC, Bokoch GM, Gill GN. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1999;1:253-259
212. Shin EY, Shin KS, Lee CS, et al. Phosphorylation of p85 betaPIX, 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 2002;277:44417-44430
213. DerMardirossian C, Schnelzer A, Bokoch GM. Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Mol Cell 2004;15:117-127
214. Vadlamudi RK, Manavathi B, Singh RR, et al. An essential role of Pak1 phosphorylation of SHARP in Notch signaling. Oncogene 2005;24:4591-4596
215. Liberali P, Kakkonen E, Turacchio G, et al. The closure of Pak1-dependent macropinosomes requires the phosphorylation of CtBP1/BARS. EMBO J 2008;27:970-981
216. Yang Z, Rayala S, Nguyen D, et al. Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res 2005;65:3179-3184
217. Gururaj A, Barnes CJ, Vadlamudi RK, Kumar R. Regulation of phosphoglucomutase 1 phosphorylation and activity by a signaling kinase. Oncogene 2004;23:8118-8127
218. Manavathi B, Rayala SK, Kumar R. Phosphorylation-dependent regulation of stability and transforming potential of ETS transcriptional factor ESE-1 by p21-activated kinase 1. J Biol Chem 2007;282:19820-19830
219. Wang RA, Vadlamudi RK, Bagheri-Yarmand R, et al. Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands. J Cell Biol 2003;161:583-592
220. Sakurada K, Kato H, Nagumo H, et al. Synapsin I is phosphorylated at Ser603 by p21-activated kinases (PAKs) in vitro and in PC12 cells stimulated with bradykinin. J Biol Chem 2002;277:45473-45479
221. Ahmed S, Prigmore E, Govind S, et al. Cryptic Rac-binding and p21(Cdc42Hs/ Rac)-activated kinase phosphorylation sites of NADPH oxidase component p67 (phox). J Biol Chem 1998;273:15693-15701
222. Shalom-Barak T, Knaus UG. A p21-activated kinase-controlled metabolic switch up-regulates phagocyte NADPH oxidase. J Biol Chem 2002;277:40659-40665
223. Ito M, Nishiyama H, Kawanishi H, et al. P21-Activated kinase 1: a new molecular marker for intravesical recurrence after transurethral resection of bladder cancer. J Urol 2007;178:1073-1079
224. Balasenthil S, Sahin AA, Barnes CJ, et al. p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. J Biol Chem 2004;279(2):1422-1428
225. Bekri S, Adelaide J, Merscher S, et al. Detailed map of a region commonly amplified at 11q13!q14 in human breast carcinoma. Cytogenet Cell Genet 1997;79:125-131
226. Holm C, Rayala S, Jirstrom K, et al. Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients. J Natl Cancer Inst 2006;98:671-680
227. Lundgren K, Holm K, Nordenskjold B, et al. Gene products of chromosome 11q and their association with CCND1 gene amplification and tamoxifen resistance in premenopausal breast cancer. Breast Cancer Res 2008;10:R81
228. Salh B, Marotta A, Wagey R, et al. Dysregulation of phosphatidylinositol 3-kinase and downstream effectors in human breast cancer. Int J Cancer 2002;98:148-154
229. Schraml P, Schwerdtfeger G, Burkhalter F, et al. Combined array comparative genomic hybridization and tissue microarray analysis suggest PAK1 at 11q13.5-q14 as a critical oncogene target in ovarian carcinoma. Am J Pathol 2003;163:985-992
230. Carter JH, Douglass LE, Deddens JA, et al. Pak-1 expression increases with progression of colorectal carcinomas to metastasis. Clin Cancer Res 2004;10:3448-3456
231. Aoki H, Yokoyama T, Fujiwara K, et al. Phosphorylated Pak1 level in the cytoplasm correlates with shorter survival time in patients with glioblastoma. Clin Cancer Res 2007;13:6603-6609
232. Ching Y-P, Leong VYL, Lee M-F, et al. P21-activated protein kinase is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving c-Jun NH2-terminal kinase activation and paxillin phosphorylation. Cancer Res 2007;67(8):3601-3608
233. Mao X, Onadim Z, Price EA, et al. Genomic alterations in blastic natural killer/extranodal natural killer-like T cell lymphoma with cutaneous involvement. J Invest Dermatol 2003;121:618-627
234. Brown LA, Kalloger SE, Miller MA, et al. Amplification of 11q13 in ovarian carcinoma. Genes Chromosomes Cancer 2008;47:481-489
235. O'sullivan GC, Tangney M, Casey G, et al. Modulation of p21-activated kinase 1 alters the behavior of renal cell carcinoma. Int J Cancer 2007;121:1930-1940