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.