Jeffrey L. Benovic, PhD
Philadelphia, PA 19107
(215) 503-5393 fax
Most Recent Peer-reviewed Publications
- β-arrestin-biased signaling through the β
2-adrenergic receptor promotes cardiomyocyte contraction
- The αarrestin ARRDC3 regulates the endosomal residence time and intracellular signaling of the β2-adrenergic receptor
- Interdicting Gq activation in airway disease by receptor-dependent and receptor-independent mechanisms
- Atomic structure of GRK5 reveals distinct structural features novel for G protein-coupled receptor kinases
- Structural biology: Arresting developments in receptor signalling
PhD in Biochemistry, Duke University - 1986
Howard Hughes Medical Institute Research Fellow, 1987-1989
National Institutes of Health Research Training grant award, 1981-1984
Established Investigator, American Heart Association, 1994-1999
Editorial Board, Receptors and Signal Transduction, 1991-present
Editorial Board, Journal of Biological Chemistry, 1995-2000
Editorial Board, Molecular Pharmacology, 1998-present
Editorial Board, Molecular Endocrinology, 2002-2003
Editorial Board, Journal of Cell Biology, 2004-present
Editorial Board, Cell, 2009-present
Associate Editor, Biochemistry, 2001-present
Member, Publications Committee, ASBMB, 2011-2014
Member, American Association for the Advancement of Science
Member, American Society for Biochemistry and Molecular Biology
Member, American Society for Pharmacology and Experimental Therapeutics
Member, Southeastern Pennsylvania AHA Review Committee, 1991-1996
Member, NIH Pharmacology Study Section, 1996-2000
ISI Highly Cited Researcher in Biology and Biochemistry
NIH MERIT Award, 2006-2016
Expertise and Research Interests
G protein-coupled receptors (GPCRs), the largest family of proteins in the human genome, regulate a variety of biological functions including neurotransmission, sensory perception, chemotaxis, embryogenesis, development, and cell growth, differentiation, and apoptosis. GPCRs have been implicated in a number of diseases including cancer, HIV, hypertension, sensory defects, and various neuronal disorders, and are the target of ~50% of the drugs currently on the market. Research in the Benovic laboratory is focused on understanding the regulation of GPCR function with a primary emphasis on the role of GPCR kinases (GRKs) and arrestins. GRK phosphorylation of activated GPCRs and subsequent binding of arrestins functions to dynamically regulate receptor signaling and trafficking. Current research efforts are focused in four major areas.
1. Structural analysis of GRKs, arrestins, GPCRs and various protein complexes. These studies involve collaborations with a number of investigators and are focused on understanding protein function and protein/protein interactions using X ray crystallography and other biophysical approaches (analytical ultracentrifugation, surface plasmon resonance, isothermal titration calorimetry). We hope to understand the interaction surfaces and dynamics of these protein-protein complexes and use this information to modulate their formation.
2. Understand the role of GRKs and arrestins in regulating signaling networks and protein localization. GRKs and arrestin plan an important role in regulating GPCR function via direct interaction as well as via their ability to serve as scaffolding proteins. We hope to better understand the mechanisms involved in these processes using strategies such as RNAi and proteomic analysis.
3. Characterize the mechanisms that mediate cancer metastasis with a primary focus on dysregulation of the chemokine receptor CXCR4. CXCR4 has been implicated in a number of diseases including WHIM syndrome, HIV, and cancer. CXCR4 is overexpressed in breast, colon, and prostate cancer and contributes to the ability of these cancers to metastasize to tissues such as the bone, lung, and liver. At present, the mechanisms involved in CXCR4 overexpression and its role in metastasis are poorly understood. We are using various molecular, biochemical, and cellular strategies to better characterize the mechanisms that regulate CXCR4 expression and function in normal and cancer cells with a long-term goal of providing novel therapeutic strategies for preventing cancer metastasis.
4. Use C. elegans as a model to gain mechanistic insight into the process of chemosensation. C. elegans has served as a powerful model organism to study a wide variety of biological processes. The C. elegans genome encodes ~1200 GPCRs but only 2 GRKs (GRK-1 and GRK-2) and a single arrestin (ARR-1). While our initial analysis of ARR-1 in C. elegans suggests that it plays an important role in regulating behaviors such as egg laying, chemosensation, and adaptation, we currently know little about the mechanisms involved in ARR-1 function. Similarly, GRK-2 has been shown to play a positive role in chemosensation although the mechanism of this is currently unknown. We will use C. elegans as a model to further define the mechanisms involved in chemosensation.
G protein-coupled receptor, arrestin, protein kinase, phosphorylation, signal transduction, chemokine receptors, X ray crystallography, adaptation, C. elegans, cancer biology