Research and Clinical Interests
Molecular and regulatory properties of G protein-coupled receptors role of receptor dysregulation in cancer and neurological disorders.
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.