Patrick John Casey (Secondary)
Enzyme Mechanisms, Membrane Biochemistry, Signal Transduction
C133 Lev Sci Res Ctr, Durham, NC 27708
Duke Box 3813, Durham, NC 27710
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. 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 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. We have also have a program to identify molecular targets of G12 proteins. We have linked the G12 proteins to cell-surface cadherins and to activation of the GTPase Rho, and have obtained evidence that activation of G12 impacts on the cellular processes of of adhesion and migration and that aberrant activation of G12 contributes to metastatic progression of breast and prostate cancer.
Ph.D., Brandeis University 1987
- Lau, HY, Ramanujulu, PM, Guo, D, Yang, T, Wirawan, M, Casey, PJ, Go, ML, and Wang, M."An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo." Cancer biology & therapy 15, no. 9 (September 2014): 1280-1291. Full Text
- Chia, CY, Kumari, U, and Casey, PJ. "Breast cancer cell invasion mediated by Gα12 signaling involves expression of interleukins-6 and -8, and matrix metalloproteinase-2."Journal of molecular signaling 9 (2014): 6-. Full Text
- Hultman, R, Kumari, U, Michel, N, and Casey, PJ. "Gαz regulates BDNF-induction of axon growth in cortical neurons." Mol Cell Neurosci 58 (January 2014): 53-61. Full Text Link to Item
- Kimple, ME, Neuman, JC, Linnemann, AK, and Casey, PJ. "Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes." Experimental & molecular medicine 46 (2014): e102-. (Review) Full Text
- Cushman, I, Cushman, SM, Potter, PM, and Casey, PJ. "Control of RhoA methylation by carboxylesterase I." J Biol Chem 288, no. 26 (June 28, 2013): 19177-19183. Full Text Link to Item