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The Molecular Functions of RalBP1 in Lung Cancer  

Lee, Seunghyung (Department of Anatomy & Cell Biology and The Sol Sherry Thrombosis Research Center Temple University School of Medicine)
Abstract
RalBP1 is an ATP-dependent non-ABC transporter, responsible for the major transport function in many cells including many cancer cell lines, causing efflux of glutathione-electrophile conjugates of both endogenous metabolites and environmental toxins. RalBP1 is expressed in most human tissues, and is over-expressed in non-small cell lung cancer cell lines and in many other tumor types. Blockade of RalBP1 by various approaches has been shown to increase sensitivity to radiation and chemotherapeutic drugs, leading to cell apoptosis. In xenograft tumor models in mice, RalBP1 blockade or depletion results in complete and sustained regression across many cancer cell types including lung cancer cells. In addition to its transport function, RalBP1 has many other cellular and physiological functions, based on its domain structure which includes a unique Ral-binding domain and a RhoGAP catalytic domain, as well as docking sites for multiple signaling proteins. Additionally, RalBP1 is also important for stromal cell function in tumors, as it was recently shown to be required for efficient endothelial cell function and angiogenesis in solid tumors. In this review, we discuss the cellular and physiological functions of RalBP1 in normal and lung cancer cells.
Keywords
RalBP1; Tumorigenesis; Lung cancer; R-Ras; RhoGAP;
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1 Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol. 1999. 39: 361-398.   DOI   ScienceOn
2 Awasthi S, Cheng J, Singhal SS, Saini MK, Pandya U, Pikula S, Bandorowicz-Pikula J, Singh SV, Zimniak P, Awasthi YC. Novel function of human RLIP76: ATP-dependent transport of glutathione conjugates and doxorubicin. Biochemistry. 2000. 39: 9327-9334.   DOI
3 Awasthi S, Cheng JZ, Singhal SS, Pandya U, Sharma R, Singh SV, Zimniak P, Awasthi YC. Functional reassembly of ATPdependent xenobiotic transport by the N- and C-terminal domains of RLIP76 and identification of ATP binding sequences. Biochemistry. 2001. 40: 4159-4168.   DOI
4 Awasthi S, Sharma R, Yang Y, Singhal SS, Pikula S, Bandorowicz-Pikula J, Zimniak P, Awasthi YC. Transport functions and physiological significance of 76 kDa Ral-binding GTPase activating protein (RLIP76). Acta Biochim Pol. 2002. 49: 855-867.
5 Awasthi S, Singhal SS, Awasthi YC, Martin B, Woo JH, Cunningham CC, Frankel AE. RLIP76 and Cancer. Clin Cancer Res. 2008. 14: 4372-4377.   DOI   ScienceOn
6 Awasthi S, Singhal SS, Sharma R, Zimniak P, Awasthi YC. Transport of glutathione conjugates and chemotherapeutic drugs by RLIP76 (RALBP1): a novel link between G-protein and tyrosine kinase signaling and drug resistance. Int J Cancer. 2003. 106: 635-646.   DOI
7 Awasthi S, Singhal SS, Singhal J, Cheng J, Zimniak P, Awasthi YC. Role of RLIP76 in lung cancer doxorubicin resistance: II. Doxorubicin transport in lung cancer by RLIP76. Int J Oncol. 2003. 22: 713-720.
8 Awasthi S, Singhal SS, Singhal J, Yang Y, Zimniak P, Awasthi YC. Role of RLIP76 in lung cancer doxorubicin resistance: III. Anti-RLIP76 antibodies trigger apoptosis in lung cancer cells and synergistically increase doxorubicin cytotoxicity. Int J Oncol. 2003. 22: 721-732.
9 Singhal SS, Awasthi YC, Awasthi S. Regression of melanoma in a murine model by RLIP76 depletion. Cancer Res. 2006. 66: 2354-2360.   DOI   ScienceOn
10 Singhal SS, Roth C, Leake K, Singhal J, Yadav S, Awasthi S. Regression of prostate cancer xenografts by RLIP76 depletion. Biochem Pharmacol. 2009. 77: 1074-1083.   DOI   ScienceOn
11 Singhal SS, Singhal J, Sharma R, Singh SV, Zimniak P, Awasthi YC, Awasthi S. Role of RLIP76 in lung cancer doxorubicin resistance: I. The ATPase activity of RLIP76 correlates with doxorubicin and 4-hydroxynonenal resistance in lung cancer cells. Int J Oncol. 2003. 22: 365-375.
12 Singhal SS, Singhal J, Yadav S, Dwivedi S, Boor PJ, Awasthi YC, Awasthi S. Regression of lung and colon cancer xenografts by depleting or inhibiting RLIP76 (Ral-binding protein 1). Cancer Res. 2007. 67: 4382-4389.   DOI   ScienceOn
13 Singhal SS, Singhal J, Yadav S, Sahu M, Awasthi YC, Awasthi S. RLIP76: a target for kidney cancer therapy. Cancer Res. 2009. 69: 4244-4251.   DOI   ScienceOn
14 Singhal SS, Yadav S, Drake K, Singhal J, Awasthi S. Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1. J Biol Chem. 2008. 283: 19714-19729.   DOI   ScienceOn
15 Singhal SS, Yadav S, Singhal J, Awasthi YC, Awasthi S. Mitogenic and drug-resistance mediating effects of PKCalpha require RLIP76. Biochem Biophys Res Commun. 2006. 348: 722-727.   DOI
16 Singhal SS, Yadav S, Singhal J, Drake K, Awasthi YC, Awasthi S. The role of PKCalpha and RLIP76 in transport-mediated doxorubicin-resistance in lung cancer. FEBS Lett. 2005. 579: 4635-4641.   DOI
17 Singhal SS, Yadav S, Singhal J, Zajac E, Awasthi YC, Awasthi S. Depletion of RLIP76 sensitizes lung cancer cells to doxorubicin. Biochem Pharmacol. 2005. 70: 481-488.   DOI   ScienceOn
18 Singhal SS, Wickramarachchi D, Yadav S, Singhal J, Leake K, Vatsyayan R, Chaudhary P, Lelsani P, Suzuki S, Yang S, Awasthi YC, Awasthi S. Glutathione-conjugate transport by RLIP76 is required for clathrin-dependent endocytosis and chemical carcinogenesis. Mol Cancer Ther. 2011. 10: 16-28.
19 Stuckler D, Singhal J, Singhal SS, Yadav S, Awasthi YC, Awasthi S. RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer. Cancer Res. 2005. 65: 991-998.
20 Srivastava SK, Hu X, Xia H, Bleicher RJ, Zaren HA, Orchard JL, Awasthi S, Singh SV. ATP-dependent transport of glutathione conjugate of 7beta, alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene in murine hepatic canalicular plasma membrane vesicles. Biochem J. 1998. 332: 799-805.   DOI
21 Takaya A, Ohba Y, Kurokawa K, Matsuda M. RalA activation at nascent lamellipodia of epidermal growth factor-stimulated Cos7 cells and migrating Madin-Darby canine kidney cells. Mol Biol Cell. 2004. 15: 2549-2557.   DOI
22 Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst. 2000. 92: 1295-1302.   DOI   ScienceOn
23 Awasthi S, Singhal SS, Srivastava SK, Zimniak P, Bajpai KK, Saxena M, Sharma R, Ziller SA 3rd, Frenkel EP, Singh SV. Adenosine triphosphate-dependent transport of doxorubicin, daunomycin, and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein. J Clin Invest. 1994. 93: 958-965.   DOI
24 Awasthi YC, Singhal SS, Gupta S, Ahmad H, Zimniak P, Radominska A, Lester R, Sharma R. Purification and characterization of an ATPase from human liver which catalyzes ATP hydrolysis in the presence of the conjugates of bilirubin bile acids and glutathione. Biochem Biophys Res Commun. 1991. 175: 1090-1096.   DOI   ScienceOn
25 Bauer B, Mirey G, Vetter IR, Garcia-Ranea JA, Valencia A, Wittinghofer A, Camonis JH, Cool RH. Effector recognition by the small GTP-binding proteins Ras and Ral. J Biol Chem. 1999. 274: 17763-17770.   DOI
26 Burridge K. Crosstalk between Rac and Rho. Science. 1999. 283: 2028-2029.   DOI
27 Cantor SB, Urano T, Feig LA. Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases. Mol Cell Biol. 1995. 15: 4578-4584.   DOI
28 Cheng JZ, Sharma R, Yang Y, Singhal SS, Sharma A, Saini MK, Singh SV, Zimniak P, Awasthi S, Awasthi YC. Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress. J Biol Chem. 2001. 276: 41213-41223.   DOI   ScienceOn
29 Fillatre J, Delacour D, Van Hove L, Bagarre T, Houssin N, Soulika M, Veitaia RA, Moreau J. Dynamics of the subcellular localization of RalBP1/RLIP through the cell cycle: the role of targeting signals and of protein-protein interactions. FASEB J. 2012. 26: 2164-2174.   DOI
30 Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin L. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007. 2: 706-714.   DOI   ScienceOn
31 Hu Y, Mivechi NF. HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo. J Biol Chem. 2003. 278: 17299-17306.   DOI
32 Goldfinger LE, Ptak C, Jeffery ED, Shabanowitz J, Hunt DF, Ginsberg MH. RLIP76 (RalBP1) is an R-Ras effector that mediates adhesion-dependent Rac activation and cell migration. J Cell Biol. 2006. 174: 877-888.   DOI
33 Goldfinger LE, Ptak C, Jeffery ED, Shabanowitz J, Han J, Haling JR, Sherman NE, Fox JW, Hunt DF, Ginsberg MH. An experimentally derived database of candidate Ras-interacting proteins. J Proteome Res. 2007. 6: 1806-1811.   DOI   ScienceOn
34 Herlevsen MC, Theodorescu D. Mass spectroscopic phosphoprotein mapping of Ral binding protein 1 (RalBP1/Rip1/RLIP76). Biochem Biophys Res Commun. 2007. 362: 56-62.   DOI
35 Issaq SH, Lim KH, Counter CM. Sec5 and Exo84 foster oncogenic ras-mediated tumorigenesis. Mol Cancer Res. Feb 2010. 8: 223-231.   DOI
36 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. Sep-Oct 2010. 60: 277-300.   DOI
37 Jilkina O, Bhullar RP. A serine kinase associates with 1 the RAL GTPase and phosphorylates RAL-interacting protein 1. Biochim Biophys Acta. 2006. 1763: 948-957.   DOI
38 Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH. Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. J Biol Chem. 1995. 270: 22473-22477.   DOI   ScienceOn
39 Jullien-Flores V, Mahe Y, Mirey G, Leprince C, Meunier-Bisceuil B, Sorkin A, Camonis JH. RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: involvement of the Ral pathway in receptor endocytosis. J Cell Sci. 2000. 113: 2837-2844.
40 Kariya K, Koyama S, Nakashima S, Oshiro T, Morinaka K, Kikuchi A. Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by mitotic phosphorylation. J Biol Chem. 2000. 275: 18399-18406.   DOI
41 Male H, Patel V, Jacob MA, Borrego-Diza E, Wang K, Young DA, Wise AL, Huang C, Van Veldhuizen P, O'Brien-Ladner A, Williamson SK, Taylor SA, Tawfik O, Esfandyari T, Farassati F. Inhibition of RalA signaling pathway in treatment of nonsmall cell lung cancer. Lung Cancer. 2012. 77: 252-259.   DOI
42 Kashatus DF, Lim KH, Brady DC, Pershing NL, Cox AD, Counter CM. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol. 2011. 13: 1108-1115.   DOI   ScienceOn
43 Lebreton S, Boissel L, Iouzalen N, Moreau J. RLIP mediates downstream signalling from RalB to the actin cytoskeleton during Xenopus early development. Mech Dev. 2004. 121: 1481-1494.   DOI
44 Lim KH, Baines AT, Fiordalisi JJ, Shipitsin M, Feig LA, Cox AD, Der CJ, Counter CM. Activation of RalA is critical for Rasinduced tumorigenesis of human cells. Cancer Cell. 2005. 7: 533-545.   DOI
45 Nakashima S, Morinaka K, Koyama S, Ikeda M, Kishida M, Okawa K, Iwamatsu A, Kishida S, Kikuchi A. Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors. EMBO J. 1999. 18: 3629-3642.   DOI   ScienceOn
46 Park SH, Weinberg RA. A putative effector of Ral has homology to Rho/Rac GTPase activating proteins. Oncogene. 1995. 11: 2349-2355.
47 Riaz SP, Luchtenborg M, Coupland VH, Spicer J, Peake MD, Moller H. Trends in incidence of small cell lung cancer and all lung cancer. Lung Cancer. 2012. 75: 280-284.   DOI
48 Rosse C, L'Hoste S, Offner N, Picard A, Camonis J. RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to phosphorylate epsin during the switch off of endocytosis in mitosis. J Biol Chem. 2003. 278: 30597-30604.   DOI
49 Sharma R, Gupta S, Singh SV, Medh RD, Ahmad H, LaBelle EF, Awasthi YC. Purification and characterization of dinitrophenylglutathione ATPase of human erythrocytes and its expression in other tissues. Biochem Biophys Res Commun. 1990. 171: 155-161.   DOI   ScienceOn
50 Sharma R, Singhal SS, Wickramarachchi D, Awasthi YC, Awasthi S. RLIP76 (RALBP1)-mediated transport of leukotriene C4 (LTC4) 1 in cancer cells: implications in drug resistance. Int J Cancer. 2004. 112: 934-942.   DOI   ScienceOn