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Faculty Affairs: Faculty Interests Database Jeffrey L. Benovic, PhD

Biochemistry & Molecular Biology
Thomas Jefferson University
Jefferson Medical College

Professor and Chair, Dept. of Biochemistry & Molecular Biology

Leader, Cancer Cell Biology & Signaling Program, Kimmel Cancer Center


Mailing Address Contact Information
233 S 10th Street
Philadelphia, Pennsylvania 19107
United States 		Phone: 215-503-4607
Fax: 215-503-5393
benovic@mail.jci.tju.edu
Qualifications
B.S. in Biochemistry, 1976, Pennsylvania State University
Ph.D. in Biochemistry, 1986, Duke University

National Institutes of Health Research Training grant award, 1981-1984
Howard Hughes Medical Institute Research Fellow, 1987-1989
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.
Keywords
G protein-coupled receptor, arrestin, protein kinase, phosphorylation, signal transduction, chemokine receptors, X ray crystallography, adaptation, C. elegans, cancer biology
Publications
  • Selected Publications (2000-present)
  • Mundell, S. J. and Benovic, J. L. Selective regulation of endogenous G protein-coupled receptors by arrestins in HEK293 cells. J. Biol. Chem. 275:12900-12908, 2000.
  • Santini, F., Penn, R.B., Gagnon, A.W., Benovic, J.L., and Keen, J.H. Selective recruitment of arrestin-3 to clathrin coated pits upon stimulation of G protein-coupled receptors. J. Cell Science 113:2463-70, 2000.
  • Carman, C. V., Barak, L. S., Chen, C., Liu-Chen, L.-Y., Onorato, J. J., Kennedy, S. P., Caron, M. G., and Benovic, J. L. Mutational analysis of G-beta/gamma and phospholipid interaction with G protein-coupled receptor kinase 2. J. Biol. Chem. 275: 10443-10452, 2000.
  • Mundell, S.J., Matharu, A.-L., Kelly, E., and Benovic, J.L. Arrestin isoforms dictate differential kinetics of A2B adenosine receptor trafficking. Biochemistry 39:12828-12836, 2000.
  • Parent, J.-L., Labrecque, P., and Benovic, J. L. Role of the differentially spliced carboxyl-terminus in thromboxane A2 receptor trafficking: Identification of a distinct motif for tonic internalization. J. Biol. Chem. 276: 7079-7085, 2001.
  • Penn, R. B., Pascual, R. M., Kim, Y.-M., Mundell, S. J., Krymskaya, V.P., Panettieri, R. and Benovic, J. L. Arrestin specificity for GPCRs in human airway smooth muscle. J. Biol. Chem. 276: 32648-32656, 2001.
  • Marchese, A. and Benovic, J. L. Agonist-promoted ubiquitination of the G-protein-coupled receptor CXCR4 mediates lysosomal sorting. J Biol Chem. 276: 45509-45512, 2001.
  • Milano, S.K., Pace, H.C., Kim, Y.-M., Brenner, C., and Benovic, J.L. Scaffolding functions of arrestin-2 revealed by crystal structure and mutagenesis. Biochemistry 41: 3321-3328, 2002.
  • Gurevich, E.V., Benovic, J.L., and Gurevich, V.V. Arrestin2 and arrestin3 are differentially expressed in the rat brain during postnatal development. Neuroscience 109: 421-436, 2002.
  • Kim, Y.M., Barak, L.S., Caron, M.G., and Benovic, J.L. Regulation of arrestin-3 phosphorylation by casein kinase II. J. Biol. Chem. 277: 16837-16846, 2002.
  • Pao, C. and Benovic, J. Phosphorylation-independent desensitization of G protein-coupled receptors? Science's STKE (2002), http://stke.sciencemag.org/cgi/content/full/sigtrans;2002/ 153/pe42
  • Bhattacharya, M., Anborgh, P. H., Babwah, A. V., Dale, L. B., Dobransky, T., Benovic, J. L., Feldman, R.D., Verdi, J. M., Rylett, R.J., and Ferguson, S.S.G. beta-Arrestins regulate a Ral-GDS-Ral effector pathway that mediates cytoskeletal reorganization. Nat. Cell Biol. 4: 547-555, 2002.
  • Kim, Y.M. and Benovic, J. L. Differential roles of arrestin-2 interaction with clathrin and AP2 in G protein-coupled receptor trafficking. J. Biol. Chem. J. Biol. Chem. 277: 30760-30768, 2002.
  • DeGraff, J.L., Gurevich, V.V., and Benovic, J.L. The third intracellular loop of alpha-2-adrenergic receptors determines subtype specificity of arrestin interaction. J. Biol. Chem. 277: 43247-43252, 2002.
  • Marchese, A., Chen, C., Kim, Y.-M., and Benovic, J.L. The ins and outs of G protein-coupled receptor trafficking. Trends Biochem. Sci. 28: 369-376, 2003.
  • Marchese, A., Raiborg, C., Santini, F., Keen, J.H., Stenmark, H., and Benovic, J.L. The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4. Developmental Cell 5: 709-722, 2003.
  • Noble, B., Kallal, L.A., Pausch, M.H., and Benovic, J.L. Development of a yeast bioassay to characterize G protein-coupled receptor kinases: Identification of an N-terminal region essential for receptor phosphorylation. J. Biol. Chem. 278: 47466-47476, 2003.
  • Luo, J., and Benovic, J.L. G protein-coupled receptor kinase interaction with Hsp90 mediates kinase maturation. J. Biol. Chem. 278: 50908-50914, 2003.
  • Vishnivetskiy, S.A., Hosey, M.M., Benovic, J.L., and Gurevich, V.V. Mapping the arrestin-receptor interface: Structural elements responsible for receptor specificity of arrestin proteins. J. Biol. Chem. 279: 1262-1268, 2004.
  • Gurevich, E.V., Benovic, J.L., and Gurevich, V.V. Arrestin2 expression selectively increases during neural differentiation. J. Neurochem. 91: 1404-1416, 2004.
  • Day, P.W., Tesmer, J.J.G., Sterne-Marr, R., Freeman, L.C., Benovic, J.L., and Wedegaertner, P.B. Characterization of the GRK2 binding site of G-alpha-q. J. Biol. Chem. 279: 53643-53652, 2004.
  • Iwata, K., Luo, J., Penn, R.B., and Benovic, J.L. Bimodal regulation of the human H1 histamine receptor by GRK2. J. Biol. Chem. 280: 2197-2204, 2005.
  • Hardy, A.R., Conley, P.B., Luo, J., Benovic, J.L., Poole, A.W., and Mundell, S.J. P2Y1 and P2Y12 receptors for ADP desensitize by distinct kinase-dependent mechanisms. Blood 105: 3552-3560, 2005.
  • Naik, S., Billington, C.K., Pascual, R.M., Deshpande, D.A., Stefano, F.P., Kohout, T.A., Eckman, D.M., Benovic, J.L., and Penn, R.B. Regulation of cysteinyl leukotriene type 1 receptor internalization and signaling. J. Biol. Chem. 280: 8722-8732, 2005.
  • Pao, C.S. and Benovic, J.L. Structure/function analysis of alpha-2A-adrenergic receptor interaction with G protein-coupled receptor kinase 2. J. Biol. Chem. 280: 11052-11058, 2005.
  • Palmitessa, A., Hess, H.A., Bany, I.A., Kim, Y.-M., Koelle, M.R., and Benovic, J.L. C. elegans arrestin regulates neural G protein signaling and olfactory adaptation and recovery. J. Biol. Chem. 280: 24649-24662, 2005.
  • Milano, S.K., Kim, Y.-M., Stefano, F., Benovic, J.L. and Brenner, C. Phosphoinositide-dependent regulation of arrestin oligomerization and function. J. Biol. Chem. 281: 9812-9823, 2006.
  • Lodowski, D.T., Tesmer, V.M., Benovic, J.L., and Tesmer, J.J.G. Crystal structure of G protein-coupled receptor kinase 6 defines the conserved molecular features of the GRK family. J. Biol. Chem. 281:16785-16793, 2006.
  • Mundell, S.J., Luo, J., Benovic, J.L., Conley, P.B., and Poole, A.W. Distinct Clathrin-Coated Pits Sort Different G Protein-Coupled Receptor Cargo. Traffic 7: 1420-1431, 2006.
  • Parameswaran, N., Pao, C.S., Leonhard, K.S., Kang, D.S., Kratz, M., Ley, S.C., and Benovic, J.L. Arrestin-2 and G protein-coupled receptor kinase 5 interact with NFkappa B1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages. J. Biol. Chem. 281: 34159-34170, 2006.
  • Jiang, X., Benovic, J.L, Wedegaertner, P.B. Plasma membrane and nuclear localization of G protein-coupled receptor kinase 6A. Mol. Biol. Cell 18: 2960-2969, 2007.
  • Bhandari, D., Trejo, J., Benovic, J.L., and Marchese, A. Arrestin-2 interacts with the ubiquitin-protein isopeptide ligase Atrophin-Interacting Protein 4 and mediates endosomal sorting of the chemokine receptor CXCR4. J. Biol. Chem. 282: 36971-36979, 2007.
  • Moore, C.A.C., Milano, S.K., and Benovic, J.L. Regulation of receptor trafficking by GRKs and arrestins. Annu. Rev. Physiol. 69, 451-482, 2007.
  • Busillo, J.M., and Benovic, J.L. Regulation of CXCR4 signaling. Biochim Biophys Acta. 1768: 952-963, 2007.
  • Ahmed, M.A., Bychkov, E., Gurevich, V.V., Benovic, J.L., and Gurevich, E.V. Altered expression and subcellular distribution of GRK subtypes in the dopamine-depleted rat basal ganglia is not normalized by L-DOPA treatment. J. Neurochem. 104: 1622-1636, 2008.
  • Ahmed, M.R., Gurevich, V.V., Dalby, K.N., Benovic, J.L., and Gurevich, E. Haloperidol and clozapine differentially affect the expression of arrestins, receptor kinases, and ERK activation. J. Pharmacol. Exp. Ther. 325: 276-283, 2008.
  • Penn, R.B., and Benovic, J.L Regulation of heterotrimeric G-protein signaling in airway smooth muscle. Proc. Am. Thorac. Soc. 5: 47-57, 2008.
  • Luo, J., Busillo, J.M., and Benovic, J.L. M3 muscarinic acetylcholine receptor-mediated signaling is regulated by distinct mechanisms. Mol. Pharm. 74: 338-347, 2008.
  • Yang, M., He, R.L., Benovic, J.L., and Ye, R.D. beta-arrestin1 interacts with the G protein subunits beta1gamma2 and promotes beta1gamma2-dependent Akt signaling for NF-kB activation. Biochem. J. 17: 287-296, 2009.
  • Lakshmikanthan, V., Zou, L., Michal, A., Kim, J.I., Benovic, J.L., and Daaka, Y. Identification of beta-arrestin2 as a corepressor of androgen receptor signaling in prostate cancer. Proc. Natl. Acad. Sci. USA 106: 9379-9384, 2009.
  • Zhu, C., Huang, H., Hua, R., Li, G., Yang, D., Luo, J., Zhang, C., Shi, L., Benovic, J.L., and Zhou, N. Molecular and functional characterization of adipokinetic hormone receptor and its peptide ligands in Bombyx mori. FEBS Lett. 583: 1463-1468, 2009.
  • Kern, R.C., Kang, D.S., and Benovic, J.L. Arrestin2/clathrin interaction is regulated by key N- and C-terminal regions in arrestin2. Biochemistry 48: 7190-7200, 2009.
  • Pao, C.S., Barker, B., and Benovic, J.L. Role of the amino terminus of G protein-coupled receptor kinase 2 in receptor phosphorylation. Biochemistry 48: 7325-7333, 2009.
  • Barthet, G., Carrat, G., Cassier, E., Barker, B., Gaven, F., Pillot, M., Framery, B., Pellissier, L.P., Augier, J., Kang, D.S., Claeysen, S., Reiter, E., Banères, J.L., Benovic, J.L., Marin, P., Bockaert, J., and Dumuis, A. beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT(4) receptor signalling. EMBO J. 28: 2706-2718, 2009.
  • Kang D.S., Kern, R.C., Puthenveedu, M.A., von Zastrow, M., Williams, J.C., and Benovic, J.L. Structure of an arrestin-2/clathrin complex reveals a novel clathrin binding domain that modulates receptor trafficking. J. Biol. Chem. 284: 29860-29872, 2009.
  • Patial, S., Luo, J., Porter, K.J., Benovic, J.L., and Parameswaran, N. G-protein coupled receptor kinases mediate TNFalpha-induced NFkappB signaling via direct interaction with and phosphorylation of IkBalpha. Biochem. J. 425: 169-178, 2010.
  • Busillo, J.M., Armando, S., Sengupta, R., Meucci, O., Bouvier, M., and Benovic, J.L. Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling. J. Biol. Chem. 285: 7805-7817, 2010.
  • Shankar, H. Michal, A., Kern, R.C., Kang, D.S., Gurevich, V.V., and Benovic, J.L. Non-visual arrestins are constitutively associated with the centrosome and regulate centrosome function. J. Biol. Chem. 285: 8316-8329, 2010.
  • Mundell, S., Matharu, A.L., Nisar, S., Palmer, T., Benovic, J., and Kelly, E. Deletion of the distal COOH-terminus of the A2B adenosine receptor switches internalization to an arrestin- and clathrin-independent pathway and inhibits recycling. Br. J. Pharmacol. 159: 518-533, 2010.
  • Palmitessa, A. and Benovic, J.L. Arrestin and the multi-PDZ domain containing protein MPZ-1 interact with phosphatase and tensin homolog (PTEN) and regulate C. elegans longevity. J. Biol. Chem. 285: 15187-15200, 2010.
  • Li, G., Shi, Y., Zhang, Y., Wu, K., Luo, J., Sun, Y., Lu, J., Benovic, J.L., and Zhou, N. Internalisation of the human nicotinic acid receptor GPR109A is regulated by Gi, GRK2 and arrestin3. J. Biol. Chem. 285: 22605-22618, 2010.
  • Sosa, M.S., Lopez-Haber, C., Yang, C., Wang, H., Lemmon, M.A., Busillo, J.M., Luo, J., Benovic, J.L., Klein-Szanto, A., Yagi, H., Gutkind, J.S., Parsons, R.E., and Kazanietz, M.G. Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Mol. Cell 40: 877-879, 2010.
  • Chen, X., Mei, L., Yan, J., Fan, Y., Yang, W., Luo, J., Hong, K., Wang, Z., Chen, X., Lu, J., Benovic, J.L., and Zhou, N. Structural determinants in the second intracellular loop of the human cannabinoid CB1 receptor mediate selective coupling to Gs and Gi. Br. J. Pharmacol. 161: 1817-1834, 2010.
  • Huang, H., He, X., Deng, X., Li, G., Ying, G., Sun, Y., Shi, L., Benovic, J.L., and Zhou, N. Bombyx adipokinetic hormone receptor activates extracellular signal-regulated kinase 1 and 2 via G protein-dependent PKA and PKC but beta-arrestin-independent pathways. Biochemistry 49: 10862-10872, 2010.
  • Michal, A.M., Tran, T.H., Ryder, A., Liu, C., Rimm, D.L., Rui, H., and Benovic, J.L. Differential expression of arrestins is a predictor of breast cancer progression and survival. Breast Cancer Res Treat, in press.
  • Barker, B.L., and Benovic, J. L. G protein-coupled receptor kinase 5 phosphorylation of Hip regulates internalization of the chemokine receptor CXCR4. Biochemistry 50: 6933-6941, 2011.
  • Bychkov, E.R., Ahmed, M.R., Gurevich, V.V., Benovic, J.L., and Gurevich E.V. Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder. Neurobiol. Dis., in press.

Last Updated by KT Ferrera: Tuesday, June 5, 2012 3:40:40 PM

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