Casey, Patrick J

Research Interests:

Research in this laboratory focuses on the area of transmembrane signaling mediated through guanine nucleotide-binding regulatory proteins (G proteins). Many of these signaling pathways are involved in control of cell growth; this property is highlighted by discoveries over the past decade that mutations in G proteins can lead to cell transformation. There are two major areas of research ongoing in the lab. The first is 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. We are studying the enzymes that catalyze these modifications 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) and a specific methyltransferase termed Icmt have become major targets in the development of anti-cancer therapeutics.

The second general area of research involves 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. Gz exhibits several biochemical properties that suggest that this protein controls a unique signaling pathway, and we have recently linked Gz to control of important aspects of pancreatic beta-cell function. Another major program is to identify molecular targets of G12 proteins. We have linked the G12 proteins to cellular processes of adhesion and migration via cell-surface cadherins and the Rho GTPase, and have obtained evidence that additional effectors of G12 proteins may be important in metastatic progression of cancer accompanying aberrant activation of these G protein.

Selected Publications:

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., Stemmle, L.N., Madden, J.F., Fields, T.A, Daaka, Y. & Casey, P.J. (2006) A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J. Biol. Chem. 281:26483-26490.

Peterson, Y.K., Weinbaum, C.A. & Casey, P.J. (2006) A novel protein geranylgeranyltransferase-I inhibitor with high potency, selectivity and cellular activity. J. Biol. Chem. 281:12445-12450.

Stemmle, L.N., Fields, T.A. & Casey, P.J. (2006) The RGS domain of Axin selectively interacts with Ga12 but not Ga13. Mol. Pharmacol. 70:1461-1468.

Baron, R.A., Otto, J.C., Rudolph, J. & Casey, P.J. (2007) Time-dependent inhibition of isoprenylcysteine carboxylmethyltransferase by indole-based small molecules. Biochemistry, 46:544-560.

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.

Rao, P.V., Peterson, Y.K., Inoue, T. & Casey, P.J. (2008) Pharmacological inhibition of protein geranylgeranyltransferase type I increases aqueous humor outflow through the trabecular meshwork. Invest Ophthalmol Vis Sci., 49:2964-2971.

Wang, M., Tan, W., Zhou, J., Leow, J., Go, M., Lee, H.S. & Casey P.J. (2008) A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J. Biol. Chem., 283:18678-18684.

Juneja, J. & Casey, P.J. (2009) Role of G12 proteins in oncogenesis and metastasis. Brit. J. Pharmacol., 158:32-40.

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.