Overview
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.
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.
Current Appointments & Affiliations
James B. Duke Distinguished Professor of Pharmacology and Cancer Biology
·
2002 - Present
Pharmacology & Cancer Biology,
Basic Science Departments
Professor of Pharmacology and Cancer Biology
·
1999 - Present
Pharmacology & Cancer Biology,
Basic Science Departments
Professor of Biochemistry
·
1999 - Present
Biochemistry,
Basic Science Departments
Member of the Duke Cancer Institute
·
1990 - Present
Duke Cancer Institute,
Institutes and Centers
Recent Publications
Gα13 Promotes Clonogenic Growth by Increasing Tolerance to Oxidative Metabolic Stress in Prostate Cancer Cells.
Journal Article Int J Mol Sci · May 20, 2025 The oncogenic role of the G12 family in many human solid cancers has been extensively studied, primarily through the effects of constitutively active mutants of these proteins on cell migration and invasion. However, these mutations are not seen in cancers ... Full text Link to item CiteFostering Global Research Collaborations: An Update on Duke-NUS Medical School, the Duke University and National University of Singapore Partnership.
Journal Article Acad Med · February 26, 2025 PROBLEM: Navigating the complexities of international research collaborations is a challenge. This article provides a detailed examination of the international collaboration between Duke University and the National University of Singapore to establish the ... Full text Link to item CiteRAB4A is a master regulator of cancer cell stemness upstream of NUMB-NOTCH signaling.
Journal Article Cell Death Dis · October 27, 2024 Cancer stem cells (CSCs) are a group of specially programmed tumor cells that possess the characteristics of perpetual cell renewal, increased invasiveness, and often, drug resistance. Hence, eliminating CSCs is a major challenge for cancer treatment. Unde ... Full text Link to item CiteRecent Grants
Cancer Biology Training Grant
Inst. Training Prgm or CMEMentor · Awarded by National Cancer Institute · 1993 - 2016G(alpha)Z signaling in insulin secretion and glucose tolerance
ResearchMentor · Awarded by National Institutes of Health · 2008 - 2010Nonclassical signaling of the androgen receptor polyproline domain
ResearchCollaborator · Awarded by National Institutes of Health · 2009 - 2010View All Grants
Education, Training & Certifications
Brandeis University ·
1987
Ph.D.