The emerging importance of group II PAKs

Biochemical Journal

Volumn 425, Issue 3, 2010, Pages 465-473

  Wells, Claire M ^a   Jones, Gareth E ^b  

^a KING'S COLLEGE LONDON   (United Kingdom)

^b KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Actin cytoskeleton; Cancer; Inflammatory response; Knockout mouse study; Neurological disorder; p21 activated kinase (PAK)

Indexed keywords

ACTIN CYTOSKELETON; CELL SURVIVAL; CELLULAR FUNCTION; CYTOSKELETAL DYNAMICS; DISEASE PROGRESSION; GENE TRANSCRIPTIONS; GTPASES; HORMONE SIGNALLING; INFLAMMATORY RESPONSE; INTRACELLULAR PROCESS; NEURITE OUTGROWTH; NEUROLOGICAL DISORDERS; P-21 ACTIVATED KINASE;

ENZYME ACTIVITY; MAMMALS; PRESSURE EFFECTS; TRANSCRIPTION;

PROTEINS;

ALPHA SYNUCLEIN; ANDROGEN RECEPTOR; CCAAT ENHANCER BINDING PROTEIN; COFILIN; ESTROGEN RECEPTOR ALPHA; LIM KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE KINASE 6; MITOGEN ACTIVATED PROTEIN KINASE P38; NCK PROTEIN; P21 ACTIVATED KINASE; P21 ACTIVATED KINASE 1; P21 ACTIVATED KINASE 2; P21 ACTIVATED KINASE 3; P21 ACTIVATED KINASE 4; P21 ACTIVATED KINASE 5; P21 ACTIVATED KINASE 6; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BAD; PROTEIN CDC42; RAC PROTEIN; RAC1 PROTEIN; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; APOPTOSIS; BRAIN ATROPHY; CELL SURVIVAL; CELLULAR DISTRIBUTION; DEMENTIA; DISEASE COURSE; DROSOPHILA MELANOGASTER; EMBRYO DEVELOPMENT; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME LOCALIZATION; ENZYME REGULATION; ENZYME STRUCTURE; GENE MUTATION; GENETIC TRANSCRIPTION; HUMAN; INFLAMMATION; NEOPLASM; NERVE CELL PLASTICITY; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; XENOPUS; ZEBRA FISH;

ACTINS; ANIMALS; CCAAT-ENHANCER-BINDING PROTEINS; CYTOSKELETON; DISEASE PROGRESSION; HUMANS; INFLAMMATION; MICE; MICE, KNOCKOUT; MODELS, BIOLOGICAL; NEOPLASMS; NERVOUS SYSTEM DISEASES; P21-ACTIVATED KINASES; PROTEIN STRUCTURE, TERTIARY; TRANSCRIPTION, GENETIC;

MAMMALIA;

EID: 74349102008     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BJ20091173     Document Type: Review

References (96)

1. Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., Parsons, J. T. and Horwitz, A. R. (2003) Cell migration: integrating signals from front to back. Science 302, 1704-1709
2. Arias-Romero, L. E. and Chernoff, J. (2008) A tale of two Paks. Biol. Cell 100, 97-108
3. Jaffer, Z. M. and Chernoff, J. (2002) p21-activated kinases: three more join the Pak. Int. J. Biochem. Cell Biol. 34, 713-717
4. Kumar, R., Gururaj, A. E. and Barnes, C. J. (2006) p21-activated kinases in cancer. Nat. Rev. Cancer 6, 459-471
5. Zhao, Z. S., Manser, E. and Lim, L. (2000) Interaction between PAK and Nck: a template for Nck targets and role of PAK autophosphorylation. Mol. Cell. Biol. 20, 3906-3917
6. Wu, X. and Frost, J. A. (2006) Multiple Rho proteins regulate the subcellular targeting of PAK5. Biochem. Biophys. Res. Commun. 351, 328-335
7. Eswaran, J., Lee, W. H., Debreczeni, J. E., Filippakopoulos, P., Turnbull, A., Fedorov, O., Deacon, S. W., Peterson, J. R. and Knapp, S. (2007) Crystal structures of the p21-activated kinases PAK4, PAK5, and PAK6 reveal catalytic domain plasticity of active group II PAKs. Structure 15, 201-213
8. Rennefahrt, U. E., Deacon, S. W., Parker, S. A., Devarajan, K., Beeser, A., Chernoff, J., Knapp, S., Turk, B. E. and Peterson, J. R. (2007) Specificity profiling of Pak kinases allows identification of novel phosphorylation sites. J. Biol. Chem. 282, 15667-15678
9. Callow, M. G., Zozulya, S., Gishizky, M. L., Jallal, B. and Smeal, T. (2005) PAK4 mediates morphological changes through the regulation of GEF-H1. J. Cell Sci. 118, 1861-1872
10. Zhang, H., Li, Z., Viklund, E. K. and Stromblad, S. (2002) p21-activated kinase 4 interacts with integrin αvβ5 and regulates αvβ5-mediated cell migration. J. Cell Biol. 158, 1287-1297
11. Abo, A., Qu, J., Cammarano, M. S., Dan, C., Fritsch, A., Baud, V., Belisle, B. and Minden, A. (1998) PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia. EMBO J. 17, 6527-6540
12. Ching, Y. P., Leong, V. Y., Wong, C. M. and Kung, H. F. (2003) Identification of an autoinhibitory domain of p21-activated protein kinase 5. J. Biol. Chem. 278, 33621-33624
13. Dan, C., Nath, N., Liberto, M. and Minden, A. (2002) PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells. Mol. Cell. Biol. 22, 567-577
14. Ahmed, T., Shea, K., Masters, J. R., Jones, G. E. and Wells, C. M. (2008) A PAK4-LIMK1 pathway drives prostate cancer cell migration downstream of HGF. Cell. Signalling 20, 1320-1328
15. Lu, Y., Pan, Z. Z., Devaux, Y. and Ray, P. (2003) p21-activated protein kinase 4 (PAK4) interacts with the keratinocyte growth factor receptor and participates in keratinocyte growth factor-mediated inhibition of oxidant-induced cell death. J. Biol. Chem. 278, 10374-10380
16. Wells, C. M., Abo, A. and Ridley, A. J. (2002) PAK4 is activated via PI3K in HGF-stimulated epithelial cells. J. Cell Sci. 115, 3947-3956
17. Schrantz, N., da Silva Correia, J., Fowler, B., Ge, Q., Sun, Z. and Bokoch, G. M. (2004) Mechanism of p21-activated kinase 6-mediated inhibition of androgen receptor signaling. J. Biol. Chem. 279, 1922-1931
18. Pandey, A., Dan, I., Kristiansen, T. Z., Watanabe, N. M., Voldby, J., Kajikawa, E., Khosravi-Far, R., Blagoev, B. and Mann, M. (2002) Cloning and characterization of PAK5, a novel member of mammalian p21-activated kinase-II subfamily that is predominantly expressed in brain. Oncogene 21, 3939-3948
19. Parrini, M. C., Lei, M., Harrison, S. C. and Mayer, B. J. (2002) Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1. Mol. Cell 9, 73-83
20. Qu, J., Cammarano, M. S., Shi, Q., Ha, K. C., de Lanerolle, P. and Minden, A. (2001) Activated PAK4 regulates cell adhesion and anchorage-independent growth. Mol. Cell. Biol. 21, 3523-3533
21. Lee, S. R., Ramos, S. M., Ko, A., Masiello, D., Swanson, K. D., Lu, M. L. and Balk, S. P. (2002) AR and ER interaction with a p21-activated kinase (PAK6). Mol. Endocrinol. 16, 85-99
22. Kaur, R., Liu, X., Gjoerup, O., Zhang, A., Yuan, X., Balk, S. P., Schneider, M. C. and Lu, M. L. (2005) Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. J. Biol. Chem. 280, 3323-3330
23. Eswaran, J., Soundararajan, M. and Knapp, S. (2009) Targeting group II PAKs in cancer and metastasis. Cancer Metastasis Rev. 28, 209-217
24. Huang, Y., Mikami, F., Jono, H., Zhang, W., Weng, X., Koga, T., Xu, H., Yan, C., Kai, H. and Li, J. D. (2007) Opposing roles of PAK2 and PAK4 in synergistic induction of MUC5AC mucin by bacterium NTHi and EGF. Biochem. Biophys. Res. Commun. 359, 691-696
25. Melzig, J., Rein, K. H., Schafer, U., Pfister, H., Jackle, H., Heisenberg, M. and Raabe, T. (1998) A protein related to p21-activated kinase (PAK) that is involved in neurogenesis in the Drosophila adult central nervous system. Curr. Biol. 8, 1223-1226
26. Nekrasova, T., Jobes, M. L., Ting, J. H., Wagner, G. C. and Minden, A. (2008) Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion. Dev. Biol. 322, 95-108
27. Menzel, N., Melzer, J., Waschke, J., Lenz, C., Wecklein, H., Lochnit, G., Drenckhahn, D. and Raabe, T. (2008) The Drosophila p21-activated kinase Mbt modulates DE-cadherin-mediated cell adhesion by phosphorylation of Armadillo. Biochem. J. 416, 231-241
28. Faure, S., Cau, J., de Santa Barbara, P., Bigou, S., Ge, Q., Delsert, C. and Morin, N. (2005) Xenopus p21-activated kinase 5 regulates blastomeres' adhesive properties during convergent extension movements. Dev. Biol. 277, 472-492
29. Luo, T., Xu, Y., Hoffman, T. L., Zhang, T., Schilling, T. and Sargent, T. D. (2007) Inca: a novel p21-activated kinase-associated protein required for cranial neural crest development. Development 134, 1279-1289
30. Liu, J., Fraser, S. D., Faloon, P. W., Rollins, E. L., Vom Berg, J., Starovic-Subota, O., Laliberte, A. L., Chen, J. N., Serluca, F. C. and Childs, S. J. (2007) A βPix-Pak2a signaling pathway regulates cerebral vascular stability in zebrafish. Proc. Natl. Acad. Sci. U.S.A. 104, 13990-13995
31. Li, X. and Minden, A. (2003) Targeted disruption of the gene for the PAK5 kinase in mice. Mol. Cell. Biol. 23, 7134-7142
32. Cotteret, S., Jaffer, Z. M., Beeser, A. and Chernoff, J. (2003) p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol. Cell. Biol. 23, 5526-5539
33. Cotteret, S. and Chernoff, J. (2006) Nucleocytoplasmic shuttling of Pak5 regulates its antiapoptotic properties. Mol. Cell. Biol. 26, 3215-3230
34. Yang, F., Li, X., Sharma, M., Zarnegar, M., Lim, B. and Sun, Z. (2001) Androgen receptor specifically interacts with a novel p21-activated kinase, PAK6. J. Biol. Chem. 276, 15345-15353
35. Trivedi, A. K., Bararia, D., Christopeit, M., Peerzada, A. A., Singh, S. M., Kieser, A., Hiddemann, W., Behre, H. M. and Behre, G. (2007) Proteomic identification of C/EBP-DBD multiprotein complex: JNK1 activates stem cell regulator C/EBPα by inhibiting its ubiquitination. Oncogene 26, 1789-1801
36. Dammer, E. B. and Sewer, M. B. (2008) Phosphorylation of CtBP1 by cAMP-dependent protein kinase modulates induction of CYP17 by stimulating partnering of CtBP1 and 2. J. Biol. Chem. 283, 6925-6934
37. Kumar, V., Carlson, J. E., Ohgi, K. A., Edwards, T. A., Rose, D. W., Escalante, C. R., Rosenfeld, M. G. and Aggarwal, A. K. (2002) Transcription corepressor CtBP is an NAD+-regulated dehydrogenase. Mol. Cell 10, 857-869
38. van de Wijngaart, D. J., van Royen, M. E., Hersmus, R., Pike, A. C., Houtsmuller, A. B., Jenster, G., Trapman, J. and Dubbink, H. J. (2006) Novel FXXFF and FXXMF motifs in androgen receptor cofactors mediate high affinity and specific interactions with the ligand-binding domain. J. Biol. Chem. 281, 19407-19416
39. Barac, A., Basile, J., Vazquez-Prado, J., Gao, Y., Zheng, Y. and Gutkind, J. S. (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
40. Qu, J., Cammarano, M. S., Shi, Q., Ha, K. C., de Lanerolle, P. and Minden, A. (2001) Activated PAK4 regulates cell adhesion and anchorage-independent growth. Mol. Cell. Biol. 21, 3523-3533
41. Sanders, L. C., Matsumura, F., Bokoch, G. M. and de Lanerolle, P. (1999) Inhibition of myosin light chain kinase by p21-activated kinase. Science 283, 2083-2085
42. Birkenfeld, J., Nalbant, P., Bohl, B. P., Pertz, O., Hahn, K. M. and Bokoch, G. M. (2007) GEF-H1 modulates localized RhoA activation during cytokinesis under the control of mitotic kinases. Dev. Cell. 12, 699-712
43. Krendel, M., Zenke, F. T. and Bokoch, G. M. (2002) Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nat. Cell Biol. 4, 294-301
44. Zenke, F. T., Krendel, M., DerMardirossian, C., King, C. C., Bohl, B. P. and Bokoch, G. M. (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
45. Birukova, A. A., Adyshev, D., Gorshkov, B., Bokoch, G. M., Birukov, K. G. and Verin, A. D. (2006) GEF-H1 is involved in agonist-induced human pulmonary endothelial barrier dysfunction. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L540-L548
46. Dan, C., Kelly, A., Bernard, O. and 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
47. DesMarais, V., Ghosh, M., Eddy, R. and Condeelis, J. (2005) Cofilin takes the lead. J. Cell Sci. 118, 19-26
48. Bailly, M. and Jones, G. E. (2003) Polarised migration: cofilin holds the front. Curr. Biol. 13, R128-R130
49. Condeelis, J. (2001) How is actin polymerization nucleated in vivo? Trends Cell Biol. 11, 288-293
50. Soosairajah, J., Maiti, S., Wiggan, O., Sarmiere, P., Moussi, N., Sarcevic, B., Sampath, R., Bamburg, J. R. and Bernard, O. (2005) Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. EMBO J. 24, 473-486
51. Mouneimne, G., Soon, L., DesMarais, V., Sidani, M., Song, X., Yip, S. C., Ghosh, M., Eddy, R., Backer, J. M. and Condeelis, J. (2004) Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation. J. Cell Biol. 166, 697-708
52. Finkelstein, E., Chang, W., Chao, P. H., Gruber, D., Minden, A., Hung, C. T. and Bulinski, J. C. (2004) Roles of microtubules, cell polarity and adhesion in electric-field-mediated motility of 3T3 fibroblasts. J. Cell Sci. 117, 1533-1545
53. Qu, J., Li, X., Novitch, B. G., Zheng, Y., Kohn, M., Xie, J. M., Kozinn, S., Bronson, R., Beg, A. A. and Minden, A. (2003) PAK4 kinase is essential for embryonic viability and for proper neuronal development. Mol. Cell. Biol. 23, 7122-7133
54. Lim, Y., Lim, S. T., Tomar, A., Gardel, M., Bernard-Trifilo, J. A., Chen, X. L., Uryu, S. A., Canete-Soler, R., Zhai, J., Lin, H. et al. (2008) PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J. Cell Biol. 180, 187-203
55. Small, J. V. and Kaverina, I. (2003) Microtubules meet substrate adhesions to arrange cell polarity. Curr. Opin. Cell Biol. 15, 40-47
56. Koh, W., Mahan, R. D. and Davis, G. E. (2008) Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling. J. Cell Sci. 121, 989-1001
57. Bryan, B., Kumar, V., Stafford, L. J., Cai, Y., Wu, G. and Liu, M. (2004) GEFT, a Rho family guanine nucleotide exchange factor, regulates neurite outgrowth and dendritic spine formation. J. Biol. Chem. 279, 45824-45832
58. Timm, T., Matenia, D., Li, X. Y., Griesshaber, B. and Mandelkow, E. M. (2006) Signaling from MARK to tau: regulation, cytoskeletal crosstalk, and pathological phosphorylation. Neurodegener. Dis. 3, 207-217
59. Briggs, M. W. and Sacks, D. B. (2003) IQGAP proteins are integral components of cytoskeletal regulation. EMBO Rep. 4, 571-574
60. Chang, Y., Ceacareanu, B., Zhuang, D., Zhang, C., Pu, Q., Ceacareanu, A. C. and Hassid, A. (2006) Counter-regulatory function of protein tyrosine phosphatase 1B in platelet-derived growth factor- or fibroblast growth factor-induced motility and proliferation of cultured smooth muscle cells and in neointima formation. Arterioscler. Thromb. Vasc. Biol. 26, 501-507
61. Kaur, R., Yuan, X., Lu, M. L. and Balk, S. P. (2008) Increased PAK6 expression in prostate cancer and identification of PAK6 associated proteins. Prostate 68, 1510-1516
62. Elmore, S. (2007) Apoptosis: a review of programmed cell death. Toxicol. Pathol. 35, 495-516
63. Gnesutta, N., Qu, J. and Minden, A. (2001) The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis. J. Biol. Chem. 276, 14414-14419
64. Li, X. and Minden, A. (2005) PAK4 functions in tumor necrosis factor (TNF) α-induced survival pathways by facilitating TRADD binding to the TNF receptor. J. Biol. Chem. 280, 41192-41200
65. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. and Lowe, S. W. (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602
66. Cammarano, M. S., Nekrasova, T., Noel, B. and Minden, A. (2005) Pak4 induces premature senescence via a pathway requiring p16INK4/p19ARF and mitogen-activated protein kinase signaling. Mol. Cell. Biol. 25, 9532-9542
67. Lin, A. W., Barradas, M., Stone, J. C., van Aelst, L., Serrano, M. and Lowe, S. W. (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008-3019
68. Wu, X., Carr, H. S., Dan, I., Ruvolo, P. P. and Frost, J. A. (2008) p21 activated kinase 5 activates Raf-1 and targets it to mitochondria. J. Cell Biochem. 105, 167-175
69. Majewski, M., Nieborowska-Skorska, M., Salomoni, P., Slupianek, A., Reiss, K., Trotta, R., Calabretta, B. and Skorski, T. (1999) Activation of mitochondrial Raf-1 is involved in the antiapoptotic effects of Akt. Cancer Res. 59, 2815-2819
70. Callow, M. G., Clairvoyant, F., Zhu, S., Schryver, B., Whyte, D. B., Bischoff, J. R., Jallal, B. and Smeal, T. (2002) Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. J. Biol. Chem. 277, 550-558
71. Allen, K. M., Gleeson, J. G., Bagrodia, S., Partington, M. W., MacMillan, J. C., Cerione, R. A., Mulley, J. C. and Walsh, C. A. (1998) PAK3 mutation in nonsyndromic X-linked mental retardation. Nat. Genet. 20, 25-30
72. Gurniak, C. B., Perlas, E. and Witke, W. (2005) The actin depolymerizing factor n-cofilin is essential for neural tube morphogenesis and neural crest cell migration. Dev. Biol. 278, 231-241
73. Niehof, M. and Borlak, J. (2005) RSK4 and PAK5 are novel candidate genes in diabetic rat kidney and brain. Mol. Pharmacol. 67, 604-611
74. Morris, C. A. and Mervis, C. B. (2000) Williams syndrome and related disorders. Annu. Rev. Genomics Hum. Genet. 1, 461-484
75. Shults, C. W. (2006) Lewy bodies. Proc. Natl. Acad. Sci. U.S.A. 103, 1661-1668
76. Danzer, K. M., Schnack, C., Sutcliffe, A., Hengerer, B. and Gillardon, F. (2007) Functional protein kinase arrays reveal inhibition of p-21-activated kinase 4 by α-synuclein oligomers. J. Neurochem. 103, 2401-2407
77. Iwata, A., Maruyama, M., Kanazawa, I. and Nukina, N. (2001) α-Synuclein affects the MAPK pathway and accelerates cell death. J. Biol. Chem. 276, 45320-45329
78. Salminen, A., Suuronen, T. and Kaarniranta, K. (2008) ROCK, PAK, and Toll of synapses in Alzheimer's disease. Biochem. Biophys. Res. Commun. 371, 587-590
79. Matenia, D., Griesshaber, B., Li, X. Y., Thiessen, A., Johne, C., Jiao, J., Mandelkow, E. and 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
80. Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E. M. and Mandelkow, E. (1997) MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 89, 297-308
81. Gringel, A., Walz, D., Rosenberger, G., Minden, A., Kutsche, K., Kopp, P. and Linder, S. (2006) PAK4 and αPIX determine podosome size and number in macrophages through localized actin regulation. J. Cell. Physiol. 209, 568-579
82. Calle, Y., Anton, I. M., Thrasher, A. J. and Jones, G. E. (2008) WASP and WIP regulate podosomes in migrating leukocytes. J. Microsc. 231, 494-505
83. Calle, Y., Chou, H. C., Thrasher, A. J. and Jones, G. E. (2004) Wiskott-Aldrich syndrome protein and the cytoskeletal dynamics of dendritic cells. J. Pathol. 204, 460-469
84. Kim, J. H., Kim, H. N., Lee, K. T., Lee, J. K., Choi, S. H., Paik, S. W., Rhee, J. C. and Lowe, A. W. (2008) Gene expression profiles in gallbladder cancer: the close genetic similarity seen for early and advanced gallbladder cancers may explain the poor prognosis. Tumour Biol. 29, 41-49
85. Liu, Y., Xiao, H., Tian, Y., Nekrasova, T., Hao, X., Lee, H. J., Suh, N., Yang, C. S. and Minden, A. (2008) The pak4 protein kinase plays a key role in cell survival and tumorigenesis in athymic mice. Mol. Cancer Res. 6, 1215-1224
86. Chen, S., Auletta, T., Dovirak, O., Hutter, C., Kuntz, K., El-Ftesi, S., Kendall, J., Han, H., Von Hoff, D. D., Ashfaq, R. et al. (2008) Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification. Cancer Biol. Ther. 7, 1793-1802
87. Kimmelman, A. C., Hezel, A. F., Aguirre, A. J., Zheng, H., Paik, J. H., Ying, H., Chu, G. C., Zhang, J. X., Sahin, E., Yeo, G. et al. (2008) Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc. Natl. Acad. Sci. U.S.A. 105, 19372-19377
88. Mahlamaki, E. H., Kauraniemi, P., Monni, O., Wolf, M., Hautaniemi, S. and Kallioniemi, A. (2004) High-resolution genomic and expression profiling reveals 105 putative amplification target genes in pancreatic cancer. Neoplasia 6, 432-439
89. Begum, A., Imoto, I., Kozaki, K. I., Tsuda, H., Suzuki, E., Amagasa, T. and Inazawa, J. (2009) Identification of PAK4 as a putative target gene for amplification within 19q13.12-q13.2 in oral squamous-cell carcinoma. Cancer Sci. 100, 1908-1916
90. Giroux, V., Iovanna, J. and Dagorn, J. C. (2006) Probing the human kinome for kinases involved in pancreatic cancer cell survival and gemcitabine resistance. FASEB J. 20, 1982-1991
91. Parsons, D. W., Wang, T. L., Samuels, Y., Bardelli, A., Cummins, J. M., DeLong, L., Silliman, N., Ptak, J., Szabo, S., Willson, J. K. et al. (2005) Colorectal cancer: mutations in a signalling pathway. Nature 436, 792
92. Gong, W., An, Z., Wang, Y., Pan, X., Fang, W., Jiang, B. and Zhang, H. (2009) p21-activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration. Int. J. Cancer 125, 548-555
93. Wang, Y., Yu, Q., Cho, A. H., Rondeau, G., Welsh, J., Adamson, E., Mercola, D. and McClelland, M. (2005) Survey of differentially methylated promoters in prostate cancer cell lines. Neoplasia 7, 748-760
94. So, A., Gleave, M., Hurtado-Col, A. and Nelson, C. (2005) Mechanisms of the development of androgen independence in prostate cancer. World J. Urol. 23, 1-9
95. Lotan, T. L., Lyon, M., Huo, D., Taxy, J. B., Brendler, C., Foster, B. A., Stadler, W. and Rinker-Schaeffer, C. W. (2007) Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia. J. Pathol. 212, 386-394
96. Nakano, T., Tani, M., Ishibashi, Y., Kimura, K., Park, Y. B., Imaizumi, N., Tsuda, H., Aoyagi, K., Sasaki, H., Ohwada, S. and Yokota, J. (2003) Biological properties and gene expression associated with metastatic potential of human osteosarcoma. Clin. Exp. Metastasis 20, 665-674