Jeffrey L. Benovic, PhD

Contact Dr. Benovic

900 Walnut Street

Philadelphia, PA 19107

(215) 503-4607
(215) 923-1098 fax

How Does Dysfunctional Regulation of Signaling Contribute to Disease?

My research focuses on understanding G protein-coupled receptor (GPCR) signaling. GPCRs regulate a variety of biological functions including neurotransmission, sensory perception, and chemotaxis, and have been implicated in many diseases including cancer and various neuronal disorders. We hope to understand the mechanisms involved in regulating GPCR signaling and how dysregulation contributes to disease. Current efforts are focused in four major areas.

Understanding signaling networks: We are characterizing the role of GPCR kinases (GRKs) and arrestins in regulating GPCR signaling and localization. GRKs and arrestins play an important role in regulating GPCR function via direct interaction as well as their ability to serve as adaptor proteins. We hope to better understand the mechanisms involved in these processes using strategies such as RNA interference and proteomic analysis.

Role of CXCR4 in cancer: We are characterizing the mechanisms that mediate cancer metastasis with a primary focus on the chemokine receptor CXCR4. CXCR4 is overexpressed in 23 cancers including breast, colon, and prostate and contributes to the ability of these cancers to metastasize. We are characterizing 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.

Understanding the mechanisms of chemosensation: We are using C. elegans as a model organism to gain insight into the process of chemosensation. C. elegans express~1500 GPCRs, 2 GRKs (GRK-1 and GRK-2) and a single arrestin (ARR-1). Our initial analysis suggests that ARR-1 and GRK-1 play important roles in regulating behaviors such as egg laying, fertility, and longevity while GRK-2 plays an essential role in chemosensation.

Structural analysis of signaling complexes: We are focusing on the structural analysis of GRKs, arrestins, GPCRs and various protein complexes. These studies are focused on understanding protein function and protein/protein interactions using X ray crystallography and other biophysical approaches. We hope to understand the interfaces and dynamics of these protein-protein complexes and use this information to regulate these interactions.

Publications

Most recent Peer-reviewed Publications

1. β-Arrestins and G protein-coupled receptor trafficking
2. Identification of phosphorylation sites in the COOH-terminal tail of the μ-opioid receptor
3. G-protein-coupled receptors signal victory
4. Identification and characterization of distinct c-terminal domains of the human hydroxycarboxylic acid receptor-2 that are essential for receptor export, constitutive activity, desensitization, and internalization
5. G protein-coupled receptor kinase 5 phosphorylates nucleophosmin and regulates cell sensitivity to polo-like kinase 1 inhibition
6. Structural domains required for Caenorhabditis elegans G protein-coupled receptor kinase 2 (GRK-2) function in Vivo
7. G protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression
8. Suppression of G-protein-coupled receptor kinase 3 expression is a feature of classical GBM that is required for maximal growth
9. Differential expression of arrestins is a predictor of breast cancer progression and survival
10. Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder
11. G protein-coupled receptor kinase 5 phosphorylation of hip regulates internalization of the chemokine receptor CXCR4
12. Bombyx adipokinetic hormone receptor activates extracellular signal-regulated kinase 1 and 2 via G protein-dependent PKA and PKC but β-arrestin-independent pathways
13. Identification of the Rac-GEF P-Rex1 as an Essential Mediator of ErbB Signaling in Breast Cancer
14. Internalization of the human nicotinic acid receptor GPR109A is regulated by Gi, GRK2, and arrestin3
15. Arrestin and the multi-PDZ domain-containing protein MPZ-1 interact with phosphatase and tensin homolog (PTEN) and regulate Caenorhabditis elegans longevity
16. Non-visual arrestins are constitutively associated with the centrosome and regulate centrosome function
17. Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling
18. Deletion of the distal COOH-terminus of the A 2B adenosine receptor switches internalization to an arrestin- and clathrin-independent pathway and inhibits recycling
19. G-protein-coupled-receptor kinases mediate TNFα-induced NF-κB signalling via direct interaction with and phosphorylation of IκBα
20. Structure of an arrestin2-clathrin complex reveals a novel clathrin binding domain that modulates receptor trafficking

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