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.

Kaplan, D.D, Meigs, T.E., Kelly, P. & Casey, P.J. (2004) A role for ß-catenin in establishment of a bipolar mitotic spindle. J. Biol. Chem. 279:10829-10832.

Winter-Vann, A.M., Baron, R.A., Wong, W., Dela Cruz, J., York, J.D., Gooden, D., Bergo, M.O., Young, S.G., Toone, E.J. & Casey, P.J. (2005) A small molecule inhibitor of isoprenylcysteine carboxylmethyltransferase with antitumor activity in cancer cells. Proc. Natl. Acad. Sci. 102:4336-4341.

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.

Meigs, T.E., Juneja, J., Kaplan, D.D., DeMarco, C.T., Stemmle, L.N. & Casey, P.J. (2005) Selective uncoupling of Ga12 from Rho-mediated signaling. J. Biol. Chem., 280:18049-18055.

Pagliarini, D.J., Wiley, S.E., Kimple, M.E., Dixon, J.R., Kelly, P., Casey, P.J. & Dixon, J.E. (2005) Regulation of ATP production and insulin secretion by a novel mitochondrial phosphatase. Mol. Cell, 19:197-207.

Kimple , M.E. , Nixon, A.B., Kelly, P., Bailey, C.L., Fields, T.A. & Casey, P.J. (2005) A role for Gz in pancreatic islet beta-cell biology. J. Biol. Chem. 280:31708-31713.

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

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.

Stemmle, L.N., Fields, T.A. & Casey, P.J. (2006) The RGS domain of axin selectively interacts with Gα12 but not Gα13. Mol. Pharmacol., 70:1461-1468.

Sjogren, A.M., et al (2007) A.deficiency of GGTase-I reduces tumor formation and improves survival in mice with K-Ras-induced lung cancer. J. Clin. Invest., 117:1294-1304.

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. in press.