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James B. Duke Professor of Pharmacology and Cancer Biology
Professor of Biochemistry
Duke University School of Medicine
Durham, NC 27710
Research in this laboratory focuses on the area of transmembrane signaling mediated through guanine nucleotide-binding regulatory proteins (G proteins). There are two major areas of research ongoing in the lab. The first involves the covalent modification of G proteins by isoprenoid lipids and the role this modification, termed protein prenylation, plays in the membrane targeting and function of G proteins. Prenylation plays a crucial role oncogenic transformation by one class of G proteins, the Ras proteins. The enzymes that catalyze these modifications have been isolated and cloned and are being used to develop in vitro systems to both define the enzymes' structures and molecular mechanisms and elucidate the role of prenylation in G protein function. The importance of this work is highlighted by the fact that several of these enzymes, most notably protein farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase-1), a prenyl protein-specific protease termed Rce1, and a specific methyltransferase termed Icmt have become major targets in the development of anti-cancer therapeutics. The second general area of research is identification of the signaling pathways controlled by specific types of G proteins. One such protein, termed Gz, exhibits very limited tissue distribution that includes primarily neuronal and neuroendocrine cells, and we have recently linked Gz to two distinct pathways using molecular genetic and biochemical approaches. One of these pathways impacts significantly on insulin secretion from pancreatic beta-cells, and we have shown that down-regulation of Gz function impairs the ability of select hormones modulate insulin secretion in beta-cells. We also have a program to identify molecular targets of G12 proteins. This is the least understood of all G protein families, but evidence has been accumulating that the two members of this family play critical roles in cell growth and development. We are studying the biological consequences of interactions of G12 proteins with cell-surface cadherins and regulators of Rho proteins, and have obtained evidence that these interactions, along with aberrant activation of G12, are an important component in metastasis of several types of cancer.
Winter-Vann, A.M. & Casey, P.J. (2005) Post-prenylation processing enzymes as targets for development of anti-cancer therapeutics. Nature Rev. Cancer 5:405-412.
Kelly, P., Moeller, B.J., Booden, M.A., Kasbohm, E.A., Madden, J.F., Der, C.J., Daaka, Y, Dewhirst, M.W., Fields, T.A. & Casey, P.J. (2006) The G12 family of heterotrimeric G-proteins promotes cancer invasion and metastasis. Proc. Natl. Acad. Sci. 103:8173-8178.
Kelly, P., Casey, P.J. & Meigs T.E. (2007) Biologic functions of the G12 subfamily of heterotrimeric G proteins: Growth, migration, and metastasis. Biochemistry 46:6677-6687.
Kimple, M.E., Joseph, J.W., Bailey, C.L., Fueger, P.T., Hendry, I.A., Newgard, C.B. & Casey, P.J. (2008) Gαz negatively regulates insulin secretion and glucose clearance. J. Biol. Chem. 283:4560-4567.
Bailey, C.R., Kelly, P. & Casey, P.J. (2009) Activation of Rap1 promotes prostate cancer metastasis. Cancer Res., 69:4962-4968.
Cushman, I. & Casey, P.J. (2009) Role of Icmt-catalyzed methylation in Rho signaling and migration. J. Biol. Chem, 284:27964-27973.
Wang, M., Tan, W., Coolman, B., Zhou, J., Liu, S., & Casey, P.J. (2010) Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth in hepatocellular carcinoma. Oncogene 29(35):4959-4970.
Go, M.L., Leow, J., Gorla, S.K., Schueller, A., Wang, M. & Casey, P.J. (2010) Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase. J. Med. Chem, 53:6838-6850.
Forrester, M.T, Hess, D.T., Thompson, J.W., Hultman, R, Moseley, M.A., Stamler, J.S. & Casey, P.J. (2011) Site-specific analysis of protein S-acylation by Resin-Assisted Capture (Acyl-RAC). J. Lipid Res., 52:393-398.
Juneja, J., Cushman, I. & Casey, P.J. (2011) G12 signaling through c-Jun NH2-terminal kinase promotes breast cancer cell invasion. PLoS One, 6(11): e26085.
Zhu, W.L., Hossain, M.S., Guo, D.Y., Liu, S., Tong, H., Khakpoor, A., Casey, P.J. & Wang M. (2011) A role for the Rac3 GTPase in autophagy regulation. J. Biol. Chem., 286:35291-35298.
Kimple, M.E., Moss, J.B, Brar, H.K., Rosa, T.C., Newgard, C.B. & Casey, P.J. (2012) Deletion of Gαz protects against diet-induced glucose intolerance via expansion of β-cell mass. J. Biol. Chem, in press.