Thomas Jefferson University

Benovic, Jeffrey L

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jlb104

Jeffrey L. Benovic, PhD

Contact Dr. Benovic

900 Walnut Street
JHN 4th floor
Philadelphia, PA 19107

(215) 503-4607
(215) 503-4358 fax

Research and Clinical Interests

Regulation of receptor signaling, mechanisms of cell migration and chemosensation

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. G protein-coupled receptor kinase 5 modifies cancer cell resistance to paclitaxel
  2. Effects of oncogenic Gαq and Gα11 inhibition by FR900359 in uveal melanoma
  3. Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors
  4. Pepducins as a potential treatment strategy for asthma and COPD
  5. Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines
  6. G protein-coupled receptor kinases: Past, present and future
  7. Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling
  8. G protein-coupled receptor kinase 3 and protein kinase C phosphorylate the distal C-terminal tail of the chemokine receptor CXCR4 and mediate recruitment of β-arrestin
  9. Structural basis for ß-arrestins in gpcr trafficking
  10. Dysregulated GPCR signaling and therapeutic options in uveal melanoma
  11. Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5
  12. G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans
  13. c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes
  14. β-arrestin-biased signaling through the β 2 -adrenergic receptor promotes cardiomyocyte contraction
  15. The αarrestin ARRDC3 regulates the endosomal residence time and intracellular signaling of the β2-adrenergic receptor
  16. From biased signalling to polypharmacology: Unlocking unique intracellular signalling using pepducins
  17. Interdicting Gq activation in airway disease by receptor-dependent and receptor-independent mechanisms
  18. Atomic structure of GRK5 reveals distinct structural features novel for G protein-coupled receptor kinases
  19. Structural biology: Arresting developments in receptor signalling
  20. New frontiers in kinases