PI3K/Akt-PAK1信号通路在表皮生长因子诱导乳腺癌细胞迁移中作用机制的研究
|
摘要
以往的研究证实,EGF是人类乳腺癌细胞迁移过程中起着关键趋化作用的诱导因子,EGF能促进胞内ROS的产生。另一方面,ROS可以促进恶性肿瘤细胞的迁移,但目前ROS在恶性肿瘤细胞迁移中的分子调节机制尚不清楚。本研究在建立体外EGF诱导MDA-MB-231乳腺癌细胞迁移模型的基础上,研究了ROS和PI3K/Akt-PAK1信号通路在EGF诱导的MDA-MB-231细胞迁移中作用的可能机制,以期为深入阐明恶性肿瘤浸润和转移机制提供理论依据。
本研究发现:
1、EGF能明显促进MDA-MB-231细胞内ROS的产生,而ROS生成阻断剂NAC则能显著抑制EGF所诱导的ROS生成。
2、分别使用特异性化学阻断剂预处理细胞,或瞬时转染负显性突变Rac1、Akt、PAK1质粒,或siRNA干扰Akt表达后,通过细胞划痕实验,证实ROS、Rac1、PI3K/Akt和PAK1参与EGF诱导的MDA-MB-231细胞迁移。
3、因为EGF能诱导Rac1、PI3K/Akt和PAK1的活化,瞬时转染负显性突变体Rac1 T17N能有效抑制EGF引起的PI3K/Akt及PAK1活化,PI3K特异性抑制剂LY294002和siRNA干扰Akt均可以显著地降低PAK1磷酸化水平,结果证明EGF诱导的MDA-MB-231细胞迁移中存在着Rac1→PI3K/Akt→PAK1信号调控途径。因为ROS生成阻断剂NAC能明显抑制EGF诱导的PI3K/Akt及PAK1磷酸化,结果提示ROS中介PI3K/Akt和PAK1激活过程。
综上所述,我们第一次发现Rac1-PI3K/Akt-PAK1信号通路中介EGF诱导的MDA-MB-231细胞迁移;在此信号通路中,ROS中介EGF诱导的PI3K/Akt和PAK1活化。
Epidermal growth factor (EGF) plays an important role in human breast cancer cell migration. EGF can increase intracellular ROS production, but the ROS sensitivity of migration and of the signaling pathways leading to migration are largely unknown. Previous studies have shown that activated Rac1, PI3K/Akt and PAK1 contribute to progression, invasion, and maintenance of the malignant phenotype in human cancers, so we supposed they all might participate in ROS-dependent regulation of EGF-induced breast cancer cell migration. In MDA-MB-231 breast cancer cells with high metastatic ability, we reported that EGF promoted migration compared with nonstimulated cells, with a maximum increase at 10ng/mL. Pretreatment with the ROS inhibitor NAC siginificantly attenuated migration. Moreover, preincubated with the PI3K inhibitor LY294002 or siRNA Akt or dominant negative forms of Rac1 T17N, SRα-Akt (T308A/S473A) and PAK1 K299R all obviously decreased cell migration in response to EGF. Phosphorylation of PI3K/Akt and PAK1 (Thr423) were attenuated by ROS inhibitor, but Rac1 regulated EGF-stimulated ROS production. PI3K/Akt activated PAK1 at Thr423, and EGF stimulated PI3K/Akt and PAK1 kinase activity through a Rac1-dependent mechanism. Taken together, these finding suggest that EGF-induced MDA-MB-231 cell migration is ROS dependent and identify the PI3K/Akt/PAK1 signaling pathway as an essential ROS-sensitive mediator of migration.
本研究发现:
1、EGF能明显促进MDA-MB-231细胞内ROS的产生,而ROS生成阻断剂NAC则能显著抑制EGF所诱导的ROS生成。
2、分别使用特异性化学阻断剂预处理细胞,或瞬时转染负显性突变Rac1、Akt、PAK1质粒,或siRNA干扰Akt表达后,通过细胞划痕实验,证实ROS、Rac1、PI3K/Akt和PAK1参与EGF诱导的MDA-MB-231细胞迁移。
3、因为EGF能诱导Rac1、PI3K/Akt和PAK1的活化,瞬时转染负显性突变体Rac1 T17N能有效抑制EGF引起的PI3K/Akt及PAK1活化,PI3K特异性抑制剂LY294002和siRNA干扰Akt均可以显著地降低PAK1磷酸化水平,结果证明EGF诱导的MDA-MB-231细胞迁移中存在着Rac1→PI3K/Akt→PAK1信号调控途径。因为ROS生成阻断剂NAC能明显抑制EGF诱导的PI3K/Akt及PAK1磷酸化,结果提示ROS中介PI3K/Akt和PAK1激活过程。
综上所述,我们第一次发现Rac1-PI3K/Akt-PAK1信号通路中介EGF诱导的MDA-MB-231细胞迁移;在此信号通路中,ROS中介EGF诱导的PI3K/Akt和PAK1活化。
Epidermal growth factor (EGF) plays an important role in human breast cancer cell migration. EGF can increase intracellular ROS production, but the ROS sensitivity of migration and of the signaling pathways leading to migration are largely unknown. Previous studies have shown that activated Rac1, PI3K/Akt and PAK1 contribute to progression, invasion, and maintenance of the malignant phenotype in human cancers, so we supposed they all might participate in ROS-dependent regulation of EGF-induced breast cancer cell migration. In MDA-MB-231 breast cancer cells with high metastatic ability, we reported that EGF promoted migration compared with nonstimulated cells, with a maximum increase at 10ng/mL. Pretreatment with the ROS inhibitor NAC siginificantly attenuated migration. Moreover, preincubated with the PI3K inhibitor LY294002 or siRNA Akt or dominant negative forms of Rac1 T17N, SRα-Akt (T308A/S473A) and PAK1 K299R all obviously decreased cell migration in response to EGF. Phosphorylation of PI3K/Akt and PAK1 (Thr423) were attenuated by ROS inhibitor, but Rac1 regulated EGF-stimulated ROS production. PI3K/Akt activated PAK1 at Thr423, and EGF stimulated PI3K/Akt and PAK1 kinase activity through a Rac1-dependent mechanism. Taken together, these finding suggest that EGF-induced MDA-MB-231 cell migration is ROS dependent and identify the PI3K/Akt/PAK1 signaling pathway as an essential ROS-sensitive mediator of migration.
引文
[1] D. Max Parkin, Freddie Bray, J. Ferlay and Paola Pisani. Global Cancer Statistics, 2002. CA Cancer J. Clin., 2005, 55(2): 74-108
[2] Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward, Taylor Murray, Jiaquan Xu and Michael J. Thun. Cancer Statistics, 2007. CA Cancer J. Clin., 2007, 57(1): 43-66
[3] Isaiah J. Fidler. Critical determinants of metastasis. Seminars in Cancer Biology, 2002, 12(2): 89–96
[4] Nicola Normanno, Antonella De Luca, Caterina Bianco, Luigi Strizzi, Mario Mancino, Monica R. Maiello, Adele Carotenuto, Gianfranco De Feo, Francesco Caponigro, David S. Salomon. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 2006, 366(1): 2-16
[5] Elizabeth S. Henson, Spencer B. Gibson. Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: Implications for cancer therapy. Cellular Signalling, 2006, 18(12): 2089-2097
[6] Fortunato Ciardiello and Giampaolo Tortora. EGFR Antagonists in Cancer Treatment. The New England Journal of Medicine, 2008, 358(11): 1160-1174
[7] Jacqueline M. Lafky a, Jason A. Wilken b, Andre T. Baron c,d, Nita J. Maihle. Clinical implications of the ErbB/epidermal growth factor (EGF) receptor family and its ligands in ovarian cancer. Biochimica et Biophysica Acta. 2008, 1785(2): 232-265
[8] Stephen Johnston, Maureen Trudeau, Bella Kaufman, Hamouda Boussen, Kimberley Blackwell, Patricia LoRusso, Donald P. Lombardi, Slim Ben Ahmed, Dennis L. Citrin, Michelle L. DeSilvio, Jennifer Harris, Ron E. Westlund,Vanessa Salazar, Tal Z. Zaks, Neil L. Spector. Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy. Journal of Clinical Oncology, 2008, 26(7): 1066-1072
[9] Jeyanthy Eswaran1, Meera Soundararajan1, Rakesh Kumar2,3 and Stefan Knapp. UnPAKing the class differences among p21-activated kinases. Cell, 2008, 33(8): 394-403
[10] Victor L. J. Tybulewicz and Robert B. Henderson. Rho family GTPases and their regulators in lymphocytes. Nature Reviews Immunology, 2009, 9(9): 630-644
[11] E.E. Bosco, J. C. Mulloy and Y. Zheng. Rac1 GTPase: a“Rac”of all trades. Cellular and Molecular Life Sciences, 2009, 66(3):370-374
[12] Francisco M. Vega, Anne J. Ridley. Rho GTPases in cancer cell biology. FEBS Letters, 2008, 582(14):2093-2101
[13] Zeng-qiang Yuan, Donghwa Kim, Satoshi Kaneko, Melissa Sussman, Gary M. Bokoch, Gary D. Kruh, Santo V. Nicosia, Joseph R. Testa, and Jin Q. Cheng. ArgBP2γInteracts with Akt and p21-activated Kinase-1 and Promotes Cell Survival. The Journal of Biological Chemistry, 2005, 280(22): 21483–21490
[14] Hisashi Ishida, Kui Li, MinKyung Yi, and Stanley M. Lemon. p21-activated Kinase 1 is activated through the mammalian target of rapamycin/p70S6 kinase pathway and regulates the replication of hepatitis C virus in human hepatoma cells. The Journal of Biological Chemistry, 2007, 282(16): 11836–11848
[15] In Duk Jung, Jangsoon Lee, Kyung Bok Lee, Chang Gyo Park, Yong Kee Kim, Dong Wan Seo, Dongeun Park, Hyang Woo Lee, Jeung-Whan Han and Hoi Young Lee. Activation of p21-activated kinase 1 is required for lysophosphatidic acid-induced focal adhesion kinase phosphorylation and cellmotility in human melanoma A2058 cells. European journal of biochemistry/FEBS, 2004, 271(8): 1557–1565
[16] Ling-Zhi Liu, Xiao-Wen Hu, Chang Xia, Jie He, Qiong Zhou, Xianglin Shi, Jing Fang, Bing-Hua Jiang. Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1αexpression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radical Biology and Medicine, 2006, 41(10): 1521–1533
[17] Yanan Huo, Wen-Ya Qiu, Qing Pan, Yu-Feng Yao, Kuiyi Xing, Marjorie F. Lou. Reactive oxygen species (ROS) are essential mediators in epidermal growth factor (EGF)-stimulated corneal epithelial cell proliferation, adhesion,migration, and wound healing. Experimental Eye Research, 2009, 89(6): 876-886
[18] I-Chung Lo, Jun-Ming Shih and Meei Jyh Jiang. Reactive oxygen species and ERK1/2 mediate monocyte chemotactic protein-1-stimulated smooth muscle cell migration. Journal of Biomedical Science, 2005, 12(2): 377–388
[19] David S. Weber, Yoshihiro Taniyama, Petra Rocic, Puvi N. Seshiah, Melissa A. Dechert, William T. Gerthoffer and Kathy K. Griendling. Phosphoinositide -Dependent Kinase 1 and p21-Activated Protein Kinase Mediate Reactive Oxygen Species–Dependent Regulation of Platelet-Derived Growth Factor–Induced Smooth Muscle Cell Migration. Circulation Research, 2004, 94(9): 1219-1226
[20] Elethia A. Woolfolk, Satoru Eguchi, Haruhiko Ohtsu, Hidekatsu Nakashima, Hikaru Ueno, William T. Gerthoffer, and Evangeline D. Motley. Angiotensin II-induced activation of p21-activated kinase 1 requires Ca2+ and protein kinase Cδin vascular smooth muscle cells. Am J Physiol Cell Physiol, 2005, 289(5):1286–1294
[21] Rania Harfouche, Nelly A. Abdel-Malak, Ralf P. Brandes, Aly Karsan, Kaikobad Irani, and Sabah N. A. Hussain. Roles of reactive oxygen species in angiopoietin-1/tie-2 receptor signaling. The FASEB Journal, 2005, 19(12):1728-30
[22] Ji-Hee Kim, Hee-Jun Na, Chun-Ki Kim, Ji-Yoon Kim, Kwon-Soo Ha, Hansoo Lee, Hun-Taeg Chung, Ho Jeong Kwon, Young-Guen Kwon, Young-Myeong Kim. The non-provitamin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathways: Role of H2O2 in NF-κB activation. Free Radical Biology & Medicine, 2008, 45(6): 885–896
[23] Hu-Nan SUN, Sun-Uk KIM, Mi-Sook LEE, Sang-Keun KIM, Jin-Man KIM, Mijung YIM, Dae-Yeul YU, and Dong-Seok LEE. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of phosphoinositide 3-kinase and p38 mitogen-activated protein kinase signal pathways is required for lipopolysaccharide-induced microglial phagocytosis. Biol Pharm Bull, 2008, 31(9): 1711—1715
[24] Keun Young Hwang, Young Taek Oh, Hana Yoon, Jinhwa Lee, Hocheol Kimd, Wonchae Choe, Insug Kang. Baicalein suppresses hypoxia-induced HIF-1 protein accumulation and activation through inhibition of reactive oxygen species and PI3-kinase/Akt pathway in BV2 murine microglial cells. Neuroscience Letters, 2008, 444(3): 264-269
[25] Kevin P. Mollen, Carol A. McCloskey, Hiroyuki Tanaka, Jose M. Prince, Ryan M. Levy, Brian S. Zuckerbraun, and Timothy R. Billiar. Hypoxia activates c-Jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes. Shock, 2007, 28(3): 270-277
[26] Patrizia Dentelli, Arturo Rosso, Annarita Zeoli, Roberto Gambino, Luigi Pegoraro, Gianfranco Pagano, Rita Falcioni, and Maria Felice Brizzi. Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production andβ4 Integrin Expression. The Journal of Biological Chemistry, 2007, 282(36): 26101–26110
[27] Nicola′s Tobar, Mo′nica Ca′ceres, Juan F. Santiba′n?ez, Patricio C. Smith, Jorge Mart?′nez. RAC1 activity and intracellular ROS modulate the migratory potential of MCF-7 cells through a NADPH oxidase and NFκB-dependent mechanism. Cancer Letters, 2008, 267(1): 125–132
[28] Maitrayee Sundaresan, Zu-Xi Yu, Victor J. Ferrans, David J. Sulciner, J. Silvio Gutkind, Kaikobad Irani, Pascal J. Goldschmidt-Clermont, and Toren Finkel. Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. Biochem J, 1996, 318(2): 379-382
[29] Geho DH, Bandle RW, Clair T, Liotta LA. Physiological mechanisms of tumor-cell invasion and migration. Physiology, 2005, 20: 194-200
[30] Huber MA, Kraut N, Beug H. Molecular requirements for epithelial– mesenchymal transition during tumor progression. Current Opinion in Cell Biology, 2005, 17(5): 548–558
[31] Wen-Sheng Wu. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev, 2006, 25(4): 695–705
[32] Tomasz P. Rygiel, Alexander E. Mertens, Kristin Strumane, Rob van der Kammen and John G. Collard. The Rac activator Tiam1 prevents keratinocyte apoptosis by controlling ROS-mediated ERK phosphorylation. The Journal of Cell Science, 2008, 121(8): 1183-1192
[33] Jie Wang and Jing Yi. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biology and Therapy, 2008, 7(12): 1875-1884
[34] Rakesh Kumar, Anupama E. Gururaj and Christopher J. Barnes. p21-activated kinases in cancer. Nature (Rev Cancer), 2006, 6(6): 459-471
[35] Anupama E Gururaj, Suresh K Rayala and Rakesh Kumar. P21-activated kinase signalling in breast cancer. Breast Cancer Research, 2005, 7(1): 5-12
[36] M.C. Parrini, M. Matsuda and J. de Gunzburg. Spatiotemporal regulation of the Pak1 kinase. Biochemical Society Transactions, 2005, 33(4): 646-648
[37] V. Craig Jordan. Pak up your breast tumor and grow ! Journal of National Cancer Institute, 2006, 98(10): 657-659
[38] Shubha Bagrodia and Richard A. Cerione. PAK to the future. trends in Cell Biology, 1999, 9(9): 350-355
[39] Luis E. Arias-Romero and Jonathan Chernoff. A tale of two Paks. Biology of the Cell, 2008, 100(2): 97-108
[40] Bettina Dummler, Kazufumi Ohshiro, Rakesh Kumar, Jeffrey Field. Pak protein kinases and their role in cancer. Cancer and Metastasis Reviews, 2009, 28(1-2): 51–63
[41] Poonam R. Molli, Da-Qiang Li, Murray Brion, Suresh K. Rayala, and Rakesh Kumar. PAK Signaling in Oncogenesis. Oncogene, 2009, 28(28): 2545–2555
[42] Ratna K. Vadlamudi and Rakesh Kumar. p21-activated kinases in human cancer. Cancer and Metastasis Reviews, 2003, 22(4): 385–393
[43] Maiko Higuchi, Keisuke Onishi, Chikako Kikuchi and Yukiko Gotoh. Scaffolding function of PAK in the PDK1–Akt pathway. Nature Cell Biology, 2008, 10(11): 1356– 1364
[44] Violaine Delorme, Matthias Machacek, Ce′line DerMardirossian, Karen L. Anderson, Torsten Wittmann, Dorit Hanein, Clare Waterman-Storer, Gaudenz Danuser, and Gary M. Bokoch. Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actinnetworks. Developmental Cell, 2007, 13(5): 646-662
[45] Luraynne C. Sanders, Fumio Matsumura, Gary M. Bokoch, Primal de Lanerolle. Inhibition of Myosin Light Chain Kinase by PAK1 Kinase. Science, 1999, 283(5410): 2083-2085
[46] Vadlamudi RK, Bagheri-Yarmand R, Yang Z, Balasenthil S, Nguyen D, Sahin AA, den Hollander P, Kumar R. Dynein light chain1,a p21-activated kinase1-interacting substrate, promotes cancerous phenotypes. Cancer Cell, 2004, 5(6): 575-585
[47] Ji Luo, Brendan D. Manning, and Lewis C. Cantley. Targeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell, 2003, 4(4): 257-262
[48] M. Osaki, M. Oshimura and H. Ito. PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis, 2004, 9(6): 667–676
[49] TF Franke. PI3K/Akt: getting it right matters. Oncogene, 2008, 27(50): 6473–6488
[50] Lewis C. Cantley. The Phosphoinositide 3-Kinase Pathway. Science, 2002, 296 (5573): 1655-1657
[51] Kai Mao, Satoru Kobayashi, Zahara M. Jaffer, Yuan Huang, Paul Volden, Jonathan Chernoff, Qiangrong Liang. Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. Journal of Molecular and Cellular Cardiology, 2008, 44(2): 429-434
[52] Nandini Dey, Hal E. Crosswell, Pradip De, Ramon Parsons, Qiong Peng, Jing Dong Su, and Donald L. Durden. The Protein Phosphatase Activity of PTEN regulates Src family kinases and controls glioma migration. Cancer Research, 2008, 68(6):1862-1871
[53] M Ozaki, S Haga, HQ Zhang1, K Irani and S Suzuki. Inhibition ofhypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon Rac1. Cell Death and Differentiation, 2003, 10(5): 508–515
[54] Kun Jiang, Bin Zhong, Connie Ritchey, Danielle L. Gilvary, Elizabeth Hong-Geller, Sheng Wei, and Julie Y. Djeu. Regulation of Akt-dependent cell survival by Syk and Rac. Blood, 2003, 101(1): 236-244
[55] Ryo Fukuyama, Takashi Fujita, Yasutaka Azuma, Akihiko Hirano, Hiromichi Nakamuta, Masao Koida, and Toshihisa Komori. Statins inhibit osteoblast migration by inhibiting Rac-Akt signaling. Biochemical and Biophysical Research Communications, 2004, 315 (3): 636–642
[56] Elisabeth M. Genot, Celile Arrieumerlou, Gregory Ku, Boudewijn M. T. Burgering, Arthur Weiss, and Ijsbrand M. Kramer. The T-Cell Receptor Regulates Akt (Protein Kinase B) via a Pathway Involving Rac1 and Phosphatidylinositide 3-Kinase. Molecular and Cellular Biology, 2000, 20(15): 5469-5478
[57] Yehoshua C. Levine, Gordon K. Li, and Thomas Michel. Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells. Journal of Biological Chemistry, 2007, 282(28): 20351–20364
[58] Kirstine Roepstorff, Izabela Rasmussen, Makoto Sawada, Cristophe Cudre-Maroux, Patrick Salmon, Gary Bokoch, Bo van Deurs, and Frederik Vilhardt. Stimulus-dependent Regulation of the Phagocyte NADPH Oxidase by a VAV1, Rac1, and PAK1 Signaling Axis. Journal of Biological Chemistry, 2008, 283(12): 7983–7993
[1] Rakesh Kumar, Anupama E. Gururaj and Christopher J. Barnes. p21-activated kinases in cancer. Nature (Rev Cancer), 2006, 6(6): 459-471
[2] Wang RA, Vadlamudi RK, Bagheri-Yarmand R, Beuvink I, Hynes NE, Kumar R. Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands. Journal of Cell Biology, 2003, 161(3): 583–592
[3] Wang RA, Zhang H, Balasenthil S, Medina D, Kumar R. PAK1 hyperactivation is sufficient for mammary gland tumor formation. Oncogene, 2006, 25(20): 2931–2936
[4] Celine Van den Broeke, Maria Radu, Jonathan Chernoff, and Herman W. Favoreel. An emerging role for p21-activated kinases (Paks) in viral infections. Trends Cell Biol, 2010, 20(3): 160-169
[5] Hofmann C, Shepelev M, Chernoff J. The genetics of Pak. Journal of Cell Science, 2004, 117(19): 4343–4354
[6] Poonam R. Molli, Da-Qiang Li, Murray Brion, Suresh K. Rayala, and Rakesh Kumar. PAK Signaling in Oncogenesis. Oncogene, 2009, 28(28): 2545–2555
[7] Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem, 2003, 72: 743–781
[8] Jaffer, Z.M. and Chernoff, J. p21-activated kinases: three more join the Pak. Int J Biochem Cell Biol, 2002, 34(7): 713–717
[9] Li X, Liu F, Li F. PAK as a therapeutic target in gastric cancer. Expert Opin Ther Targets, 2010, 14(4): 419-433
[10] Sophie Cotteret, Zahara M. Jaffer, Alexander Beeser, and Jonathan Chernoff.p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol Cell Biol, 2003, 23(16): 5526–5539
[11] Yang F, Li X, Sharma M, Zarnegar M, Lim B, Sun Z. Androgen receptor specifically interacts with a novel p21-activated kinase, PAK6. J Biol Chem, 2001, 276(18): 15345–15353
[12] Callow MG, Clairvoyant F, Zhu S, Schryver B, Whyte DB, Bischoff JR, Jallal B, Smeal T. Requirement for PAK4 in the anchorageindependent growth of human cancer cell lines. J Biol Chem, 2002, 277(1): 550–558
[13] Pandey A, Dan I, Kristiansen TZ, Watanabe NM, Voldby J, Kajikawa E, Khosravi-Far R, Blagoev B, Mann M. 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
[14] 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
[15] Meng J, Meng Y, Hanna A, Janus C, Jia Z. Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. J Neurosci, 2005, 25(28): 6641–6650
[16] Qu J, Li X, Novitch BG, Zheng Y, Kohn M, Xie JM, Kozinn S, Bronson R, Beg AA, Minden A. PAK4 kinase is essential for embryonic viability and for proper neuronal development. Mol Cell Biol, 2003, 23(20): 7122–7133
[17] Bettina Dummler, Kazufumi Ohshiro, Rakesh Kumar, Jeffrey Field. Pak protein kinases and their role in cancer. Cancer and Metastasis Reviews, 2009, 28(1-2): 51–63
[18] Arias-Romero, L.E. and Chernoff, J. A tale of two Paks. Biol Cell, 2008, 100(2): 97–108
[19] Balasenthil S, Sahin AA, Barnes CJ, Wang RA, Pestell RG, Vadlamudi RK, Kumar R. p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. J Biol Chem, 2004, 279(2): 1422–1428
[20] Soosairajah J, Maiti S, Wiggan O, Sarmiere P, Moussi N, Sarcevic B, Sampath R, Bamburg JR, Bernard O. Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. EMBO J, 2005, 24(3): 473–486
[21] Nowicki M, Kosacka J, Brossmer R, Spanel-Borowski K, Borlak J. The myelin-associated glycoprotein inhibitor BENZ induces outgrowth and survival of rat dorsal root ganglion cell cultures. J Neurosci Res, 2007, 85(14): 3053–3063
[22] 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
[23] Zhang H, Li Z, Viklund EK, Str?mblad S. P21-activated kinase 4 interacts with integrinαvβ5 and regulatesαvβ5-mediated cell migration. J Cell Biol, 2002, 158(7): 1287–1297
[24] Zenke FT, Krendel M, DerMardirossian C, King CC, Bohl BP, Bokoch GM. 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
[25] 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
[26] Zegers MM, Forget MA, Chernoff J, Mostov KE, ter Beest MB, Hansen SH. Pak1 and PIX regulate contact inhibition during epithelial wound healing. EMBO J, 2003, 22(16): 4155–4165
[27] Zhang H, Webb DJ, Asmussen H, Niu S, Horwitz AF. A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci, 2005, 25(13): 3379–3388
[28] Nodé-Langlois R, Muller D, Boda B. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. J Cell Sci, 2006, 119(23): 4986–4993
[29] Barac A, Basile J, Vázquez-Prado J, Gao Y, Zheng Y, Gutkind JS. 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
[30] Callow MG, Zozulya S, Gishizky ML, Jallal B, Smeal T. PAK4 mediates morphological changes through the regulation of GEF-H1. J Cell Sci, 2005, 118(9): 1861–1872
[31] Gnesutta, N. and Minden, A. Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4. Mol Cell Biol, 2003, 23(21): 7838–7848
[32] 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
[33] 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
[34] Jung, J.H. and Traugh, J.A. Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141. J Biol Chem, 2005, 280(48): 40025–40031
[35] Pirruccello M, Sondermann H, Pelton JG, Pellicena P, Hoelz A, Chernoff J,Wemmer DE, Kuriyan J. A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. J. Mol. Biol. 2006, 361(2): 312–326
[36] Rudel, T. and Bokoch, G.M. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science, 1997, 276(5318): 1571–1574
[37] Cammarano MS, Nekrasova T, Noel B, Minden A. Pak4 induces premature senescence via a pathway requiring p16INK4/p19ARF and mitogen-activated protein kinase signaling. Mol Cell Biol, 2005, 25(21): 9532–9542
[38] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell, 2010, 141(1): 39-51
[39] Robert R. Langley and Isaiah J. Fidler. Tumor cell-organ microenvironment ctions in the pathogenesis of cancer metastasis. Endocrine Rev, 2007, 28 (3): 21 intera297-3
[40] Daniel J. Hicklin, Lee M. Ellis. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol, 2005, 23(5): 1011-1027
[41] Tuomas Tammela, Berndt Enholm, Kari Alitalo, Karri Paavonen. The biology of vascular endothelial growth factors. Cardiovasc Res, 2005, 65(3): 550-563
[42] Ratna K. Vadlamudi and Rakesh Kumar. p21-activated kinases in human cancer. Cancer and Metastasis Reviews, 2003, 22(4): 385–393
[43] Kiosses WB, Hood J, Yang S, Gerritsen ME, Cheresh DA, Alderson N, Schwartz MA. A dominant-negative p65 PAK peptide inhibits angiogenesis. Circ Res, 2002, 90(6): 697–702
[44] Kumar, R. and Vadlamudi, R.K. Emerging functions of p21-activated kinases in human cancer cells. J Cell Physio, 2002, 193(2): 133–144
[45] Misra UK, Deedwania R, Pizzo SV. Binding of activatedα2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J Biol Chem, 2005, 280(28): 26278–26286
[46] Tran, N.H. and Frost, J.A. Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition. J Biol Chem, 2003, 278(13): 11221–11226
[47] Rousseau S, Dolado I, Beardmore V, Shpiro N, Marquez R, Nebreda AR, Arthur JS, Case LM, Tessier-Lavigne M, Gaestel M, Cuenda A, Cohen P. CXCL12 and C5a trigger cell migration via a PAK1/2-p38αMAPK–MAPKAP–K2–HSP27 pathway. Cell Signal, 2006, 18(11): 1897–1905
[48] Rayala, S.K. and Kumar, R. Sliding p21-activated kinase 1 to nucleus impacts tamoxifen sensitivity. Biomed Pharmacother, 2007, 61(7): 408–411
[49] Garber, K. The second wave in kinase cancer drugs. Nat Biotechnol, 2006, 24(2): 127–130
[50] Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol, 2005, 23(3): 329–336
[51] Eswaran J, Soundararajan M, Kumar R, Knapp S. UnPAKing the class differences among p21-activated kinases. Cell, 2008, 33(8): 394-403
[52] Deacon SW, Beeser A, Fukui JA, Rennefahrt UE, Myers C, Chernoff J, Peterson JR. An isoform-selective, small-molecule inhibitor targets theautoregulatory mechanism of p21-activated kinase. Chem Biol, 2008, 15(4): 322–331
[53] Bokoch, G.M. PAK’n It In: identification of a selective PAK inhibitor. Chem Biol, 2008, 15(4): 305–306
[2] Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward, Taylor Murray, Jiaquan Xu and Michael J. Thun. Cancer Statistics, 2007. CA Cancer J. Clin., 2007, 57(1): 43-66
[3] Isaiah J. Fidler. Critical determinants of metastasis. Seminars in Cancer Biology, 2002, 12(2): 89–96
[4] Nicola Normanno, Antonella De Luca, Caterina Bianco, Luigi Strizzi, Mario Mancino, Monica R. Maiello, Adele Carotenuto, Gianfranco De Feo, Francesco Caponigro, David S. Salomon. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 2006, 366(1): 2-16
[5] Elizabeth S. Henson, Spencer B. Gibson. Surviving cell death through epidermal growth factor (EGF) signal transduction pathways: Implications for cancer therapy. Cellular Signalling, 2006, 18(12): 2089-2097
[6] Fortunato Ciardiello and Giampaolo Tortora. EGFR Antagonists in Cancer Treatment. The New England Journal of Medicine, 2008, 358(11): 1160-1174
[7] Jacqueline M. Lafky a, Jason A. Wilken b, Andre T. Baron c,d, Nita J. Maihle. Clinical implications of the ErbB/epidermal growth factor (EGF) receptor family and its ligands in ovarian cancer. Biochimica et Biophysica Acta. 2008, 1785(2): 232-265
[8] Stephen Johnston, Maureen Trudeau, Bella Kaufman, Hamouda Boussen, Kimberley Blackwell, Patricia LoRusso, Donald P. Lombardi, Slim Ben Ahmed, Dennis L. Citrin, Michelle L. DeSilvio, Jennifer Harris, Ron E. Westlund,Vanessa Salazar, Tal Z. Zaks, Neil L. Spector. Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy. Journal of Clinical Oncology, 2008, 26(7): 1066-1072
[9] Jeyanthy Eswaran1, Meera Soundararajan1, Rakesh Kumar2,3 and Stefan Knapp. UnPAKing the class differences among p21-activated kinases. Cell, 2008, 33(8): 394-403
[10] Victor L. J. Tybulewicz and Robert B. Henderson. Rho family GTPases and their regulators in lymphocytes. Nature Reviews Immunology, 2009, 9(9): 630-644
[11] E.E. Bosco, J. C. Mulloy and Y. Zheng. Rac1 GTPase: a“Rac”of all trades. Cellular and Molecular Life Sciences, 2009, 66(3):370-374
[12] Francisco M. Vega, Anne J. Ridley. Rho GTPases in cancer cell biology. FEBS Letters, 2008, 582(14):2093-2101
[13] Zeng-qiang Yuan, Donghwa Kim, Satoshi Kaneko, Melissa Sussman, Gary M. Bokoch, Gary D. Kruh, Santo V. Nicosia, Joseph R. Testa, and Jin Q. Cheng. ArgBP2γInteracts with Akt and p21-activated Kinase-1 and Promotes Cell Survival. The Journal of Biological Chemistry, 2005, 280(22): 21483–21490
[14] Hisashi Ishida, Kui Li, MinKyung Yi, and Stanley M. Lemon. p21-activated Kinase 1 is activated through the mammalian target of rapamycin/p70S6 kinase pathway and regulates the replication of hepatitis C virus in human hepatoma cells. The Journal of Biological Chemistry, 2007, 282(16): 11836–11848
[15] In Duk Jung, Jangsoon Lee, Kyung Bok Lee, Chang Gyo Park, Yong Kee Kim, Dong Wan Seo, Dongeun Park, Hyang Woo Lee, Jeung-Whan Han and Hoi Young Lee. Activation of p21-activated kinase 1 is required for lysophosphatidic acid-induced focal adhesion kinase phosphorylation and cellmotility in human melanoma A2058 cells. European journal of biochemistry/FEBS, 2004, 271(8): 1557–1565
[16] Ling-Zhi Liu, Xiao-Wen Hu, Chang Xia, Jie He, Qiong Zhou, Xianglin Shi, Jing Fang, Bing-Hua Jiang. Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1αexpression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radical Biology and Medicine, 2006, 41(10): 1521–1533
[17] Yanan Huo, Wen-Ya Qiu, Qing Pan, Yu-Feng Yao, Kuiyi Xing, Marjorie F. Lou. Reactive oxygen species (ROS) are essential mediators in epidermal growth factor (EGF)-stimulated corneal epithelial cell proliferation, adhesion,migration, and wound healing. Experimental Eye Research, 2009, 89(6): 876-886
[18] I-Chung Lo, Jun-Ming Shih and Meei Jyh Jiang. Reactive oxygen species and ERK1/2 mediate monocyte chemotactic protein-1-stimulated smooth muscle cell migration. Journal of Biomedical Science, 2005, 12(2): 377–388
[19] David S. Weber, Yoshihiro Taniyama, Petra Rocic, Puvi N. Seshiah, Melissa A. Dechert, William T. Gerthoffer and Kathy K. Griendling. Phosphoinositide -Dependent Kinase 1 and p21-Activated Protein Kinase Mediate Reactive Oxygen Species–Dependent Regulation of Platelet-Derived Growth Factor–Induced Smooth Muscle Cell Migration. Circulation Research, 2004, 94(9): 1219-1226
[20] Elethia A. Woolfolk, Satoru Eguchi, Haruhiko Ohtsu, Hidekatsu Nakashima, Hikaru Ueno, William T. Gerthoffer, and Evangeline D. Motley. Angiotensin II-induced activation of p21-activated kinase 1 requires Ca2+ and protein kinase Cδin vascular smooth muscle cells. Am J Physiol Cell Physiol, 2005, 289(5):1286–1294
[21] Rania Harfouche, Nelly A. Abdel-Malak, Ralf P. Brandes, Aly Karsan, Kaikobad Irani, and Sabah N. A. Hussain. Roles of reactive oxygen species in angiopoietin-1/tie-2 receptor signaling. The FASEB Journal, 2005, 19(12):1728-30
[22] Ji-Hee Kim, Hee-Jun Na, Chun-Ki Kim, Ji-Yoon Kim, Kwon-Soo Ha, Hansoo Lee, Hun-Taeg Chung, Ho Jeong Kwon, Young-Guen Kwon, Young-Myeong Kim. The non-provitamin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathways: Role of H2O2 in NF-κB activation. Free Radical Biology & Medicine, 2008, 45(6): 885–896
[23] Hu-Nan SUN, Sun-Uk KIM, Mi-Sook LEE, Sang-Keun KIM, Jin-Man KIM, Mijung YIM, Dae-Yeul YU, and Dong-Seok LEE. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent activation of phosphoinositide 3-kinase and p38 mitogen-activated protein kinase signal pathways is required for lipopolysaccharide-induced microglial phagocytosis. Biol Pharm Bull, 2008, 31(9): 1711—1715
[24] Keun Young Hwang, Young Taek Oh, Hana Yoon, Jinhwa Lee, Hocheol Kimd, Wonchae Choe, Insug Kang. Baicalein suppresses hypoxia-induced HIF-1 protein accumulation and activation through inhibition of reactive oxygen species and PI3-kinase/Akt pathway in BV2 murine microglial cells. Neuroscience Letters, 2008, 444(3): 264-269
[25] Kevin P. Mollen, Carol A. McCloskey, Hiroyuki Tanaka, Jose M. Prince, Ryan M. Levy, Brian S. Zuckerbraun, and Timothy R. Billiar. Hypoxia activates c-Jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes. Shock, 2007, 28(3): 270-277
[26] Patrizia Dentelli, Arturo Rosso, Annarita Zeoli, Roberto Gambino, Luigi Pegoraro, Gianfranco Pagano, Rita Falcioni, and Maria Felice Brizzi. Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production andβ4 Integrin Expression. The Journal of Biological Chemistry, 2007, 282(36): 26101–26110
[27] Nicola′s Tobar, Mo′nica Ca′ceres, Juan F. Santiba′n?ez, Patricio C. Smith, Jorge Mart?′nez. RAC1 activity and intracellular ROS modulate the migratory potential of MCF-7 cells through a NADPH oxidase and NFκB-dependent mechanism. Cancer Letters, 2008, 267(1): 125–132
[28] Maitrayee Sundaresan, Zu-Xi Yu, Victor J. Ferrans, David J. Sulciner, J. Silvio Gutkind, Kaikobad Irani, Pascal J. Goldschmidt-Clermont, and Toren Finkel. Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. Biochem J, 1996, 318(2): 379-382
[29] Geho DH, Bandle RW, Clair T, Liotta LA. Physiological mechanisms of tumor-cell invasion and migration. Physiology, 2005, 20: 194-200
[30] Huber MA, Kraut N, Beug H. Molecular requirements for epithelial– mesenchymal transition during tumor progression. Current Opinion in Cell Biology, 2005, 17(5): 548–558
[31] Wen-Sheng Wu. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev, 2006, 25(4): 695–705
[32] Tomasz P. Rygiel, Alexander E. Mertens, Kristin Strumane, Rob van der Kammen and John G. Collard. The Rac activator Tiam1 prevents keratinocyte apoptosis by controlling ROS-mediated ERK phosphorylation. The Journal of Cell Science, 2008, 121(8): 1183-1192
[33] Jie Wang and Jing Yi. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biology and Therapy, 2008, 7(12): 1875-1884
[34] Rakesh Kumar, Anupama E. Gururaj and Christopher J. Barnes. p21-activated kinases in cancer. Nature (Rev Cancer), 2006, 6(6): 459-471
[35] Anupama E Gururaj, Suresh K Rayala and Rakesh Kumar. P21-activated kinase signalling in breast cancer. Breast Cancer Research, 2005, 7(1): 5-12
[36] M.C. Parrini, M. Matsuda and J. de Gunzburg. Spatiotemporal regulation of the Pak1 kinase. Biochemical Society Transactions, 2005, 33(4): 646-648
[37] V. Craig Jordan. Pak up your breast tumor and grow ! Journal of National Cancer Institute, 2006, 98(10): 657-659
[38] Shubha Bagrodia and Richard A. Cerione. PAK to the future. trends in Cell Biology, 1999, 9(9): 350-355
[39] Luis E. Arias-Romero and Jonathan Chernoff. A tale of two Paks. Biology of the Cell, 2008, 100(2): 97-108
[40] Bettina Dummler, Kazufumi Ohshiro, Rakesh Kumar, Jeffrey Field. Pak protein kinases and their role in cancer. Cancer and Metastasis Reviews, 2009, 28(1-2): 51–63
[41] Poonam R. Molli, Da-Qiang Li, Murray Brion, Suresh K. Rayala, and Rakesh Kumar. PAK Signaling in Oncogenesis. Oncogene, 2009, 28(28): 2545–2555
[42] Ratna K. Vadlamudi and Rakesh Kumar. p21-activated kinases in human cancer. Cancer and Metastasis Reviews, 2003, 22(4): 385–393
[43] Maiko Higuchi, Keisuke Onishi, Chikako Kikuchi and Yukiko Gotoh. Scaffolding function of PAK in the PDK1–Akt pathway. Nature Cell Biology, 2008, 10(11): 1356– 1364
[44] Violaine Delorme, Matthias Machacek, Ce′line DerMardirossian, Karen L. Anderson, Torsten Wittmann, Dorit Hanein, Clare Waterman-Storer, Gaudenz Danuser, and Gary M. Bokoch. Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actinnetworks. Developmental Cell, 2007, 13(5): 646-662
[45] Luraynne C. Sanders, Fumio Matsumura, Gary M. Bokoch, Primal de Lanerolle. Inhibition of Myosin Light Chain Kinase by PAK1 Kinase. Science, 1999, 283(5410): 2083-2085
[46] Vadlamudi RK, Bagheri-Yarmand R, Yang Z, Balasenthil S, Nguyen D, Sahin AA, den Hollander P, Kumar R. Dynein light chain1,a p21-activated kinase1-interacting substrate, promotes cancerous phenotypes. Cancer Cell, 2004, 5(6): 575-585
[47] Ji Luo, Brendan D. Manning, and Lewis C. Cantley. Targeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell, 2003, 4(4): 257-262
[48] M. Osaki, M. Oshimura and H. Ito. PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis, 2004, 9(6): 667–676
[49] TF Franke. PI3K/Akt: getting it right matters. Oncogene, 2008, 27(50): 6473–6488
[50] Lewis C. Cantley. The Phosphoinositide 3-Kinase Pathway. Science, 2002, 296 (5573): 1655-1657
[51] Kai Mao, Satoru Kobayashi, Zahara M. Jaffer, Yuan Huang, Paul Volden, Jonathan Chernoff, Qiangrong Liang. Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. Journal of Molecular and Cellular Cardiology, 2008, 44(2): 429-434
[52] Nandini Dey, Hal E. Crosswell, Pradip De, Ramon Parsons, Qiong Peng, Jing Dong Su, and Donald L. Durden. The Protein Phosphatase Activity of PTEN regulates Src family kinases and controls glioma migration. Cancer Research, 2008, 68(6):1862-1871
[53] M Ozaki, S Haga, HQ Zhang1, K Irani and S Suzuki. Inhibition ofhypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon Rac1. Cell Death and Differentiation, 2003, 10(5): 508–515
[54] Kun Jiang, Bin Zhong, Connie Ritchey, Danielle L. Gilvary, Elizabeth Hong-Geller, Sheng Wei, and Julie Y. Djeu. Regulation of Akt-dependent cell survival by Syk and Rac. Blood, 2003, 101(1): 236-244
[55] Ryo Fukuyama, Takashi Fujita, Yasutaka Azuma, Akihiko Hirano, Hiromichi Nakamuta, Masao Koida, and Toshihisa Komori. Statins inhibit osteoblast migration by inhibiting Rac-Akt signaling. Biochemical and Biophysical Research Communications, 2004, 315 (3): 636–642
[56] Elisabeth M. Genot, Celile Arrieumerlou, Gregory Ku, Boudewijn M. T. Burgering, Arthur Weiss, and Ijsbrand M. Kramer. The T-Cell Receptor Regulates Akt (Protein Kinase B) via a Pathway Involving Rac1 and Phosphatidylinositide 3-Kinase. Molecular and Cellular Biology, 2000, 20(15): 5469-5478
[57] Yehoshua C. Levine, Gordon K. Li, and Thomas Michel. Agonist-modulated Regulation of AMP-activated Protein Kinase (AMPK) in Endothelial Cells. Journal of Biological Chemistry, 2007, 282(28): 20351–20364
[58] Kirstine Roepstorff, Izabela Rasmussen, Makoto Sawada, Cristophe Cudre-Maroux, Patrick Salmon, Gary Bokoch, Bo van Deurs, and Frederik Vilhardt. Stimulus-dependent Regulation of the Phagocyte NADPH Oxidase by a VAV1, Rac1, and PAK1 Signaling Axis. Journal of Biological Chemistry, 2008, 283(12): 7983–7993
[1] Rakesh Kumar, Anupama E. Gururaj and Christopher J. Barnes. p21-activated kinases in cancer. Nature (Rev Cancer), 2006, 6(6): 459-471
[2] Wang RA, Vadlamudi RK, Bagheri-Yarmand R, Beuvink I, Hynes NE, Kumar R. Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands. Journal of Cell Biology, 2003, 161(3): 583–592
[3] Wang RA, Zhang H, Balasenthil S, Medina D, Kumar R. PAK1 hyperactivation is sufficient for mammary gland tumor formation. Oncogene, 2006, 25(20): 2931–2936
[4] Celine Van den Broeke, Maria Radu, Jonathan Chernoff, and Herman W. Favoreel. An emerging role for p21-activated kinases (Paks) in viral infections. Trends Cell Biol, 2010, 20(3): 160-169
[5] Hofmann C, Shepelev M, Chernoff J. The genetics of Pak. Journal of Cell Science, 2004, 117(19): 4343–4354
[6] Poonam R. Molli, Da-Qiang Li, Murray Brion, Suresh K. Rayala, and Rakesh Kumar. PAK Signaling in Oncogenesis. Oncogene, 2009, 28(28): 2545–2555
[7] Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem, 2003, 72: 743–781
[8] Jaffer, Z.M. and Chernoff, J. p21-activated kinases: three more join the Pak. Int J Biochem Cell Biol, 2002, 34(7): 713–717
[9] Li X, Liu F, Li F. PAK as a therapeutic target in gastric cancer. Expert Opin Ther Targets, 2010, 14(4): 419-433
[10] Sophie Cotteret, Zahara M. Jaffer, Alexander Beeser, and Jonathan Chernoff.p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol Cell Biol, 2003, 23(16): 5526–5539
[11] Yang F, Li X, Sharma M, Zarnegar M, Lim B, Sun Z. Androgen receptor specifically interacts with a novel p21-activated kinase, PAK6. J Biol Chem, 2001, 276(18): 15345–15353
[12] Callow MG, Clairvoyant F, Zhu S, Schryver B, Whyte DB, Bischoff JR, Jallal B, Smeal T. Requirement for PAK4 in the anchorageindependent growth of human cancer cell lines. J Biol Chem, 2002, 277(1): 550–558
[13] Pandey A, Dan I, Kristiansen TZ, Watanabe NM, Voldby J, Kajikawa E, Khosravi-Far R, Blagoev B, Mann M. 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
[14] 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
[15] Meng J, Meng Y, Hanna A, Janus C, Jia Z. Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. J Neurosci, 2005, 25(28): 6641–6650
[16] Qu J, Li X, Novitch BG, Zheng Y, Kohn M, Xie JM, Kozinn S, Bronson R, Beg AA, Minden A. PAK4 kinase is essential for embryonic viability and for proper neuronal development. Mol Cell Biol, 2003, 23(20): 7122–7133
[17] Bettina Dummler, Kazufumi Ohshiro, Rakesh Kumar, Jeffrey Field. Pak protein kinases and their role in cancer. Cancer and Metastasis Reviews, 2009, 28(1-2): 51–63
[18] Arias-Romero, L.E. and Chernoff, J. A tale of two Paks. Biol Cell, 2008, 100(2): 97–108
[19] Balasenthil S, Sahin AA, Barnes CJ, Wang RA, Pestell RG, Vadlamudi RK, Kumar R. p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. J Biol Chem, 2004, 279(2): 1422–1428
[20] Soosairajah J, Maiti S, Wiggan O, Sarmiere P, Moussi N, Sarcevic B, Sampath R, Bamburg JR, Bernard O. Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. EMBO J, 2005, 24(3): 473–486
[21] Nowicki M, Kosacka J, Brossmer R, Spanel-Borowski K, Borlak J. The myelin-associated glycoprotein inhibitor BENZ induces outgrowth and survival of rat dorsal root ganglion cell cultures. J Neurosci Res, 2007, 85(14): 3053–3063
[22] 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
[23] Zhang H, Li Z, Viklund EK, Str?mblad S. P21-activated kinase 4 interacts with integrinαvβ5 and regulatesαvβ5-mediated cell migration. J Cell Biol, 2002, 158(7): 1287–1297
[24] Zenke FT, Krendel M, DerMardirossian C, King CC, Bohl BP, Bokoch GM. 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
[25] 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
[26] Zegers MM, Forget MA, Chernoff J, Mostov KE, ter Beest MB, Hansen SH. Pak1 and PIX regulate contact inhibition during epithelial wound healing. EMBO J, 2003, 22(16): 4155–4165
[27] Zhang H, Webb DJ, Asmussen H, Niu S, Horwitz AF. A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J Neurosci, 2005, 25(13): 3379–3388
[28] Nodé-Langlois R, Muller D, Boda B. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. J Cell Sci, 2006, 119(23): 4986–4993
[29] Barac A, Basile J, Vázquez-Prado J, Gao Y, Zheng Y, Gutkind JS. 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
[30] Callow MG, Zozulya S, Gishizky ML, Jallal B, Smeal T. PAK4 mediates morphological changes through the regulation of GEF-H1. J Cell Sci, 2005, 118(9): 1861–1872
[31] Gnesutta, N. and Minden, A. Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4. Mol Cell Biol, 2003, 23(21): 7838–7848
[32] 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
[33] 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
[34] Jung, J.H. and Traugh, J.A. Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141. J Biol Chem, 2005, 280(48): 40025–40031
[35] Pirruccello M, Sondermann H, Pelton JG, Pellicena P, Hoelz A, Chernoff J,Wemmer DE, Kuriyan J. A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. J. Mol. Biol. 2006, 361(2): 312–326
[36] Rudel, T. and Bokoch, G.M. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science, 1997, 276(5318): 1571–1574
[37] Cammarano MS, Nekrasova T, Noel B, Minden A. Pak4 induces premature senescence via a pathway requiring p16INK4/p19ARF and mitogen-activated protein kinase signaling. Mol Cell Biol, 2005, 25(21): 9532–9542
[38] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell, 2010, 141(1): 39-51
[39] Robert R. Langley and Isaiah J. Fidler. Tumor cell-organ microenvironment ctions in the pathogenesis of cancer metastasis. Endocrine Rev, 2007, 28 (3): 21 intera297-3
[40] Daniel J. Hicklin, Lee M. Ellis. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol, 2005, 23(5): 1011-1027
[41] Tuomas Tammela, Berndt Enholm, Kari Alitalo, Karri Paavonen. The biology of vascular endothelial growth factors. Cardiovasc Res, 2005, 65(3): 550-563
[42] Ratna K. Vadlamudi and Rakesh Kumar. p21-activated kinases in human cancer. Cancer and Metastasis Reviews, 2003, 22(4): 385–393
[43] Kiosses WB, Hood J, Yang S, Gerritsen ME, Cheresh DA, Alderson N, Schwartz MA. A dominant-negative p65 PAK peptide inhibits angiogenesis. Circ Res, 2002, 90(6): 697–702
[44] Kumar, R. and Vadlamudi, R.K. Emerging functions of p21-activated kinases in human cancer cells. J Cell Physio, 2002, 193(2): 133–144
[45] Misra UK, Deedwania R, Pizzo SV. Binding of activatedα2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J Biol Chem, 2005, 280(28): 26278–26286
[46] Tran, N.H. and Frost, J.A. Phosphorylation of Raf-1 by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition. J Biol Chem, 2003, 278(13): 11221–11226
[47] Rousseau S, Dolado I, Beardmore V, Shpiro N, Marquez R, Nebreda AR, Arthur JS, Case LM, Tessier-Lavigne M, Gaestel M, Cuenda A, Cohen P. CXCL12 and C5a trigger cell migration via a PAK1/2-p38αMAPK–MAPKAP–K2–HSP27 pathway. Cell Signal, 2006, 18(11): 1897–1905
[48] Rayala, S.K. and Kumar, R. Sliding p21-activated kinase 1 to nucleus impacts tamoxifen sensitivity. Biomed Pharmacother, 2007, 61(7): 408–411
[49] Garber, K. The second wave in kinase cancer drugs. Nat Biotechnol, 2006, 24(2): 127–130
[50] Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol, 2005, 23(3): 329–336
[51] Eswaran J, Soundararajan M, Kumar R, Knapp S. UnPAKing the class differences among p21-activated kinases. Cell, 2008, 33(8): 394-403
[52] Deacon SW, Beeser A, Fukui JA, Rennefahrt UE, Myers C, Chernoff J, Peterson JR. An isoform-selective, small-molecule inhibitor targets theautoregulatory mechanism of p21-activated kinase. Chem Biol, 2008, 15(4): 322–331
[53] Bokoch, G.M. PAK’n It In: identification of a selective PAK inhibitor. Chem Biol, 2008, 15(4): 305–306