PAK as a therapeutic target in gastric cancer

Expert Opinion on Therapeutic Targets

Volumn 14, Issue 4, 2010, Pages 419-433

  Li, Xiaodong ^a   Liu, Funan ^a   Li, Feng ^a  

^a CHINA MEDICAL UNIVERSITY   (China)

Author keywords

Gastric cancer; Inhibitor; PAK; Therapeutic target

Indexed keywords

1 [2,3 DIHYDRO 1 (2' METHYLPHENACYL) 2 OXO 5 PHENYL 1H 1,4 BENZODIAZEPIN 3 YL] 3 (3 METHYLPHENYL)UREA; 2 AMINO N [4 [5 (2 PHENANTHRENYL) 3 TRIFLUOROMETHYL 1H PYRAZOL 1 YL]PHENYL]ACETAMIDE; 4 AMINO 7 TERT BUTYL 5 (4 METHYLPHENYL)PYRAZOLO[3,4 D]PYRIMIDINE; CEP 1347; CGP 74514A; CRIPAK; CURCUMIN; CYCLIN DEPENDENT KINASE 5; ENZYME INHIBITOR; IPA 3; K 252A; MERLIN; NISCHARIN; P 110C; P21 ACTIVATED KINASE; P21 ACTIVATED KINASE INHIBITOR; POPX 1 2; PROTEIN P35; PURVALAROL; STAUROSPORINE; SU 11652; SU 9516; UNCLASSIFIED DRUG;

CANCER CELL; CANCER INVASION; CELL GROWTH; DNA FLANKING REGION; DOWNSTREAM PROCESSING; ENZYME ACTIVATION; EPITHELIUM CELL; HUMAN; MESENCHYME; METASTASIS; NEOPLASM; REGULATORY MECHANISM; REVIEW; STOMACH CANCER;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL PROLIFERATION; ENZYME INHIBITORS; HUMANS; NEOPLASM METASTASIS; P21-ACTIVATED KINASES; STOMACH NEOPLASMS;

EID: 77949545968     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728221003642019     Document Type: Review

References (134)

1. Coburn NG. Lymph nodes and gastric cancer. J Surg Oncol 2009;99(4):199-206
2. Choi IJ. Gastric cancer screening and diagnosis. Korean J Gastroenterol 2009;54(2):67-76
3. Karpeh MS Jr, Brennan MF. Gastric carcinoma. Ann Surg Oncol 1998;5(7):650-656
4. Hundahl SA, Phillips JL, Menck HR. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the "different disease" hypothesis. Cancer 2000;88(4):921-932
5. Maconi G, Manes G, Porro GB. Role of symptoms in diagnosis and outcome of gastric cancer. World J Gastroenterol 2008;14(8):1149-1155
6. Anagnostopoulos G, Sakorafas GH, Kostopoulos P, et al. Early (mucosal) gastric cancer with synchronous osteosclerotic bone metastases: a case report. Eur J Cancer Care (Engl) 2009: published online 26 August 2009, doi: 10.1111/j.1365-2354.2007.00847.x
7. Lazar D, Taban S, Sporea I, et al. Gastric cancer: correlation between clinicopathological factors and survival of patients (III). Rom J Morphol Embryol 2009;50(3):369-379
8. Report of the 10th annual meeting of the Chinese Society of Clinical Oncology. 2007. Available from: http://www.heart51. com/article/2007-09-39/ 181191048360367.html [Last accessed 25 January 2010]
9. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58(2):71-96
10. 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
11. Sells MA, Knaus UG, Bagrodia S, et al. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr Biol 1997;7(3):202-210
12. Sells MA, Boyd JT, Chernoff J. p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. J Cell Biol 1999;145(4):837-849
13. Jaffer ZM, Chernoff J. p21-activated kinases: three more join the Pak. Int J Biochem Cell Biol 2002;34(7):713-717
14. Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem 2003;72:743-781
15. Pirruccello M, Sondermann H, Pelton JG, et al. A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. J Mol Biol 2006;361(2):312-326
16. Lei M, Lu W, Meng W, et al. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell 2000;102(3):387-397
17. Vignal E, De Toledo M, Comunale F, et al. Characterization of TCL, a new GTPase of the rho family related to TC10 andCcdc42. J Biol Chem 2000;275(46):36457-36464
18. 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(20):1125-1128
19. 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(14):1796-1807
20. Bagheri-Yarmand R, Vadlamudi RK, Wang RA, et al. Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. J Biol Chem 2000;275(50):39451-39457
21. 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(24):8837-8847
22. 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(6):1265-1278
23. 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
24. Menard RE, Mattingly RR. Cell surface receptors activate p21-activated kinase 1 via multiple Ras and PI3-kinase-dependent pathways. Cell Signal 2003;15(12):1099-1109
25. Schmitz HP, Lorberg A, Heinisch JJ. Regulation of yeast protein kinase C activity by interaction with the small GTPase Rho1p through its amino-terminal HR1 domain. Mol Microbiol 2002;44(3):829-840
26. Teo M, Manser E, Lim L. Identification and molecular cloning of a p21cdc42/ rac1-activated serine/threonine kinase that is rapidly activated by thrombin in platelets. J Biol Chem 1995;270(44):26690-26697
27. Tsakiridis T, Taha C, Grinstein S, Klip A. Insulin activates a p21-activated kinase in muscle cells via phosphatidylinositol 3-kinase. J Biol Chem 1996;271(33):19664-19667
28. 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(52):41201-41209
29. Howe AK, Juliano RL. Regulation of anchorage-dependent signal transduction by protein kinase A and p21-activated kinase. Nat Cell Biol 2000;2(9):593-600
30. 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(13):9106-9109
31. Benner GE, Dennis PB, Masaracchia RA. Activation of an S6/H4 kinase (PAK 65) from human placenta by intramolecular and intermolecular autophosphorylation. J Biol Chem 1995;270(36):21121-21128
32. 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(6663):191-195
33. Thompson G, Owen D, Chalk PA, Lowe PN. Delineation of the Cdc42/Rac-binding domain of p21-activated kinase. Biochemistry 1998;37(21):7885-7891
34. Zhao ZS, Manser E, Chen XQ, et al. A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1. Mol Cell Biol 1998;18(4):2153-2163
35. 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(12):8022-8028
36. Morreale A, Venkatesan M, Mott HR, et al. Structure of Cdc42 bound to the GTPase binding domain of PAK. Nat Struct Biol 2000;7(5):384-388
37. 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(20):17347-17353
38. Hofmann C, Shepelev M, Chernoff J. The genetics of Pak. J Cell Sci 2004;117(Pt 19):4343-4354
39. Yang F, Li X, Sharma M, et al. Androgen receptor specifically interacts with a novel p21-activated kinase, PAK6. J Biol Chem 2001;276(18):15345-15353
40. 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(1):550-558
41. 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(24):3939-3948
42. Ching YP, Leong VY, Wong CM, Kung HF. Identification of an autoinhibitory domain of p21-activated protein kinase 5. J Biol Chem 2003;278(36):33621-33624
43. 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(22):6527-6540
44. Cotteret S, Jaffer ZM, Beeser A, Chernoff J. p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol Cell Biol 2003;23(16):5526-5539
45. Wu X, Frost JA. Multiple Rho proteins regulate the subcellular targeting of PAK5. Biochem Biophys Res Commun 2006;351(2):328-335
46. 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(2):201-213
47. Huang Z, Traugh JA, Bishop JM. Negative control of the Myc protein by the stress-responsive kinase Pak2. Mol Cell Biol 2004;24(4):1582-1594
48. Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature 2007;446(7132):153-158
49. 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(11):2511-2519
50. Li Z, Xu HM, Li F. Expression of PAK4 and its significance in gastric cancer. Chin J Oncol 2008;30(1):45-48
51. He H, Yim M, Liu KH, et al. Involvement of G proteins of the Rho family in the regulation of Bcl-2-like protein expression and caspase 3 activation by gastrins. Cell Signal 2008;20(1):83-93
52. Baek HY, Lim JW, Kim H. Interaction between the Helicobacter pylori CagA and alpha-Pix in gastric epithelial AGS cells. Ann NY Acad Sci 2007;1096:18-23
53. Basak C, Pathak SK, Bhattacharyya A, et al. NF-kB-and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages. J Biol Chem 2005;280(6):4279-4288
54. 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(1):71-74
55. 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
56. Frost JA, Swantek JL, Stippec S, et al. Stimulation of NFkB activity by multiple signaling pathways requires PAK1. J Biol Chem 2000;275(26):19693-19699
57. Friedland JC, Lakins JN, Kazanietz MG, et al. alpha6beta4 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-kappaB-dependent resistance to apoptosis in 3D mammary acini. J Cell Sci 2007;120(Pt 20):3700-3712
58. Liu Y, Xiao H, Tian Y, et al. The pak4 protein kinase plays a key role in cell survival and tumorigenesis in athymic mice. Mol Cancer Res 2008;6(7):1215-1224
59. 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(2):231-241
60. Wen X, Li X, Liao B, et al. Knockdown of p21-activated kinase 6 inhibits prostate cancer growth and enhances chemosensitivity to docetaxel. Urology 2009;73(6):1407-1411
61. 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(26):24698- 24705
62. Wu X, Carr HS, Dan I, et al. p21 activated kinase 5 activates Raf-1 and targets it to mitochondria. J Cell Biochem 2008;105(1):167-175
63. Huser M, Luckett J, Chiloeches A, et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J 2001;20(8):1940-1951
64. Mazumdar A, Kumar R. Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells. FEBS Lett 2003;535(1-3):6-10
65. Vadlamudi RK, Bagheri-Yarmand R, Yang Z, et al. Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes. Cancer Cell 2004;5(6):575-585
66. Jakobi R, Moertl E, Koeppel MA. p21-activated protein kinase gamma-PAK suppresses programmed cell death of BALB3T3 fibroblasts. J Biol Chem 2001;276(20):16624-16634
67. Li X, Minden A. PAK4 functions in tumor necrosis factor (TNF) alpha-induced survival pathways by facilitating TRADD binding to the TNF receptor. J Biol Chem 2005;280(50):41192-41200
68. Lu Y, Pan ZZ, Devaux Y, Ray P. 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 2003;278(12):10374-10380
69. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002;2(6):442-454
70. Batlle E, Sancho E, Franci C, et al. The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000;2(2):84-89
71. Blanco MJ, Moreno-Bueno G, Sarrio D, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 2002;21(20):3241-3246
72. Manser E, Huang HY, Loo TH, et al. Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes. Mol Cell Biol 1997;17(3):1129-1143
73. Sells MA. Pictures in cell biology. Pak1 kinase activity affects the character of cell morphology and movement. Trends Cell Biol 1999;9(9):350-355
74. 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(43):28191-28198
75. Rennefahrt UE, Deacon SW, Parker SA, et al. Specificity profiling of Pak kinases allows identification of novel phosphorylation sites. J Biol Chem 2007;282(21):15667-15678
76. 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(46):44417-44430
77. 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(3):1959-1965
78. McFawn PK, Shen L, Vincent SG, et al. Calcium-independent contraction and sensitization of airway smooth muscle by p21-activated protein kinase. Am J Physiol Lung Cell Mol Physiol 2003;284(5):L863-70
79. Van Eyk JE, Arrell DK, Foster DB, et al. Different molecular mechanisms for Rho family GTPase-dependent, Ca2+-independent contraction of smooth muscle. J Biol Chem 1998;273(36):23433-23439
80. 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(4):773-778
81. 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(3):712-716
82. 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(9):681-690
83. 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(18):18392-18400
84. 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(2):237-249
85. 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(5):253-259
86. Dan C, Kelly A, Bernard O, Minden A. Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin. J Biol Chem 2001;276(34):32115-32121
87. Sanders LC, Matsumura F, Bokoch GM, De Lanerolle P. Inhibition of myosin light chain kinase by p21-activated kinase. Science 1999;283(5410):2083-2085
88. Goeckeler ZM, Masaracchia RA, Zeng Q, et al. Phosphorylation of myosin light chain kinase by p21-activated kinase PAK2. J Biol Chem 2000;275(24):18366-18374
89. Alberts AS, Qin H, Carr HS, Frost JA. PAK1 negatively regulates the activity of the Rho exchange factor NET1. J Biol Chem 2005;280(13):12152-12161
90. 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(3):1677-1680
91. 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(2):154-160
92. Dermardirossian C, Schnelzer A, Bokoch GM. Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Mol Cell 2004;15(1):117-127
93. Chew TL, Masaracchia RA, Goeckeler ZM, Wysolmerski RB. Phosphorylation of non-muscle myosin II regulatory light chain by p21-activated kinase (gamma-PAK). J Muscle Res Cell Motil 1998;19(8):839-854
94. Ramos E, Wysolmerski RB, Masaracchia RA. Myosin phosphorylation by human cdc42-dependent S6/H4 kinase/ gammaPAK from placenta and lymphoid cells. Recept Signal Transduct 1997;7(2):99-110
95. 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(9):3726-3736
96. Goto H, Tanabe K, Manser E, et al. Phosphorylation and reorganization of vimentin by p21-activated kinase (PAK). Genes Cells 2002;7(2):91-97
97. Guo D, Tan YC, Wang D, et al. A Rac-cGMP signaling pathway. Cell 2007;128(2):341-355
98. Callow MG, Zozulya S, Gishizky ML, et al. PAK4 mediates morphological changes through the regulation of GEF-H1. J Cell Sci 2005;118(Pt 9):1861-1872
99. Dan C, Nath N, Liberto M, Minden A. PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells. Mol Cell Biol 2002;22(2):567-577
100. Paliouras GN, Naujokas MA, Park M. Pak4, a novel Gab1 binding partner, modulates cell migration and invasion by the Met receptor. Mol Cell Biol 2009;29(11):3018-3032
101. Barac A, Basile J, Vazquez-Prado J, et al. Direct interaction of p21-activated kinase 4 with PDZ-RhoGEF, a G protein-linked Rho guanine exchange factor. J Biol Chem 2004;279(7):6182-6189
102. Li X, Ke Q, Li Y, et al. DGCR6L, a novel PAK4 interaction protein, regulates PAK4-mediated migration of human gastric cancer cell via LIMK1. Int J Biochem Cell Biol 2010;42(1):70-79
103. Zhang H, Li Z, Viklund EK, Stromblad S. P21-activated kinase 4 interacts with integrin alphavbeta5 and regulates alphavbeta5-mediated cell migration. J Cell Biol 2002;158(7):1287-1297
104. Block MR, Badowski C, Millon-Fremillon A, et al. Podosome-type adhesions and focal adhesions, so alike yet so different. Eur J Cell Biol 2008;87(8-9):491-506
105. 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(11):8454-8463
106. Gilliam AD, Watson SA, Henwood M, et al. A phase II study of G17DT in gastric carcinoma. Eur J Surg Oncol 2004;30(5):536-543
107. Murayama T, Matsumori Y, Iwata N, et al. Antiproliferative effect of a novel cholecystokinin-B/gastrin receptor antagonist, YM022. Jpn J Cancer Res 1996;87(7):743-750
108. 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(4):317-321
109. Zhan Q, Ge Q, Ohira T, et al. p21-activated kinase 2 in neutrophils can be regulated by phosphorylation at multiple sites and by a variety of protein phosphatases. J Immunol 2003;171(7):3785-3793
110. 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(11):6174-6179
111. Kissil JL, Wilker EW, Johnson KC, et al. Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol Cell 2003;12(4):841-849
112. Talukder AH, Meng Q, Kumar R. CRIPak, a novel endogenous Pak1 inhibitor. Oncogene 2006;25(9):1311-1319
113. Alahari SK, Reddig PJ, Juliano RL. The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK. EMBO J 2004;23(14):2777-2788
114. Chen S, Yin X, Zhu X, et al. The C-terminal kinase domain of the p34cdc2-related PITSLRE protein kinase (p110C) associates with p21-activated kinase 1 and inhibits its activity during anoikis. J Biol Chem 2003;278(22):20029-20036
115. 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(4):328-336
116. Roux PP, Dorval G, Boudreau M, et al. K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK. J Biol Chem 2002;277(51):49473-49480
117. 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(5):1124-1131
118. Cai XZ, Wang J, Li XD, et al. Curcumin suppresses proliferation and invasion in human gastric cancer cells by downregulation of PAK1 activity and cyclin D1 expression. Cancer Biol Ther 2009;8(14):1360-1368
119. 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(4):322-331
120. Carter JH, Douglass LE, Deddens JA, et al. Pak-1 expression increases with progression of colorectal carcinomas to metastasis. Clin Cancer Res 2004;10(10):3448-3456
121. Parsons DW, Wang TL, Samuels Y, et al. Colorectal cancer: mutations in a signalling pathway. Nature 2005;436(7052):792
122. Gong W, An Z, Wang Y, et al. P21-activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration. Int J Cancer 2009;125(3):548-555
123. Mahlamaki EH, Kauraniemi P, Monni O, et al. High-resolution genomic and expression profiling reveals 105 putative amplification target genes in pancreatic cancer. Neoplasia 2004;6(5):432-439
124. Chen S, Auletta T, Dovirak O, et al. Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification. Cancer Biol Ther 2008;7(11):1793-1803
125. Kimmelman AC, Hezel AF, Aguirre AJ, et al. Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc Natl Acad Sci USA 2008;105(49):19372-19377
126. Balasenthil S, Barnes CJ, Rayala SK, Kumar R. Estrogen receptor activation at serine 305 is sufficient to upregulate cyclin D1 in breast cancer cells. FEBS Lett 2004;567(2-3):243-247
127. 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(10):671-680
128. 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(3):985-992
129. Mao X, Orchard G, Lillington DM, et al. Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas. Blood 2003;101(4):1513-1519
130. Begum A, Imoto I, Kozaki K, et al. Identification of PAK4 as a putative target gene for amplification within 19q13.12-q13.2 in oral squamous-cell carcinoma. Cancer Sci 2009;100(10):1908-1916
131. Nikolic M, Chou MM, Lu W, et al. The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 1998;395(6698):194-198
132. Cau J, Faure S, Vigneron S, et al. Regulation of Xenopus p21-activated kinase (X-PAK2) by Cdc42 and maturation-promoting factor controls Xenopus oocyte maturation. J Biol Chem 2000;275(4):2367-2375
133. 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(3):191-202
134. Hirokawa Y, Levitzki A, Lessene G, et al. 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). Cancer Lett 2007;245(1-2):242-251