Patrick John Casey, Ph.D.

Director of the Center for Chemical Biology

James B. Duke Professor of Pharmacology&Cancer Biology

Department:
Pharmacology&Cancer Biology

Email:
casey006mcdukeedu

Mailing Address:
Box 3813, DUMC
Durham, NC 27710

Telephone:
919-613-8613

Training:
Ph.D., Brandeis University

Last Updated:
November 24, 2005

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.  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 ishighlighted 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.

Publications:
2003 -- Pubmed # 14609943 -- Taylor JS, Reid TS, Terry KL, Casey PJ, Beese LS. Structure of mammalian protein geranylgeranyltransferase type-I. EMBO J. 2003 Nov 17;22(22):5963-74.

2003 -- Pubmed # 12750467 -- Winter-Vann AM, Kamen BA, Bergo MO, Young SG, Melnyk S, James SJ, Casey PJ. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6529-34.

2002 -- Pubmed # 11882662 -- Nixon AB, Grenningloh G, Casey PJ. The interaction of RGSZ1 with SCG10 attenuates the ability of SCG10 to promote microtubule disassembly. J Biol Chem. 2002 May 17;277(20):18127-33.

2002 -- Pubmed # 11976333 -- Meigs TE, Fedor-Chaiken M, Kaplan DD, Brackenbury R, Casey PJ. Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin. J Biol Chem. 2002 Jul 5;277(27):24594-600.

2002 -- Pubmed # 12374986 -- Long SB, Casey PJ, Beese LS. Reaction path of protein farnesyltransferase at atomic resolution. Nature. 2002 Oct 10;419(6907):645-50.

2002 -- Pubmed # 12198116 -- Meng J, Casey PJ. Activation of Gz attenuates Rap1-mediated differentiation of PC12 cells. J Biol Chem. 2002 Nov 8;277(45):43417-24.

2002 -- Pubmed # 12186880 -- Digits JA, Pyun HJ, Coates RM, Casey PJ. Stereospecificity and kinetic mechanism of human prenylcysteine lyase, an unusual thioether oxidase. J Biol Chem. 2002 Oct 25;277(43):41086-93.

2002 -- Pubmed # 11739732 -- Bergo MO, Ambroziak P, Gregory C, George A, Otto JC, Kim E, Nagase H, Casey PJ, Balmain A, Young SG. Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol Cell Biol. 2002 Jan;22(1):171-81.

2001 -- Pubmed # 11546809 -- Kaplan DD, Meigs TE, Casey PJ. Distinct regions of the cadherin cytoplasmic domain are essential for functional interaction with Galpha 12 and beta-catenin. J Biol Chem. 2001 Nov 23;276(47):44037-43.

2001 -- Pubmed # 11136230 -- Meigs TE, Fields TA, McKee DD, Casey PJ. Interaction of Galpha 12 and Galpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta -catenin release. Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):519-24.

2001 -- Pubmed # 11121396 -- Bergo MO, Leung GK, Ambroziak P, Otto JC, Casey PJ, Gomes AQ, Seabra MC, Young SG. Isoprenylcysteine carboxyl methyltransferase deficiency in mice. J Biol Chem. 2001 Feb 23;276(8):5841-5.

2001 -- Pubmed # 11443111 -- Burgon PG, Lee WL, Nixon AB, Peralta EG, Casey PJ. Phosphorylation and nuclear translocation of a regulator of G protein signaling (RGS10). J Biol Chem. 2001 Aug 31;276(35):32828-34.

1999 -- Otto, J. C., Kim, E., Young, S.G & Casey, P.J. (1999) Cloning and characterization of Rce1, a mammalian prenyl protein protease. J. Biol. Chem. 274:8379-8382.