Faculty

G protein and GPCR Mechanisms and Drug Design. Our laboratory studies molecular, cellular, and physiological aspects of signaling by guanine nucleotide binding proteins (G proteins) and G protein coupled receptors (GPCRs). GPCRs are the target of nearly half of current drugs on the market yet they narrowly focus ligands targeting the receptor binding site. Recent developments make it clear that classical linear models of GPCR signaling are oversimplified and that signaling involves complex networks of interacting targeting and regulatory proteins.

Major Projects in the Neubig Lab include:
Drug design and high-throughput screening for novel GPCR-related drug targets. Dr. Neubig started (with the LSI) the UM Center for Chemical Genomics (CCG) for high throughput screening for bioactive small molecules. The CCG has robotics, detectors, chemical libraries (>30,000 compounds), and informatics resources. We are running screens for a number of GPCR-related signaling pathways (see below).

Physiological role of RGS proteins. RGS proteins (Regulators of G protein Signaling). RGS proteins play a critical role in controlling G protein signals and serve as scaffolds to recruit and integrate different signaling pathways (Neubig & Siderovski Nature Rev Drug Disc 1: 187-197, 2002). We use mice resistant to RGS action to examine the physiology function of RGS proteins and study RGS expression and function in cell culture models using RNAi. We developed a novel high throughput flow cytometry protein-interaction assay (FCPIA) to screen for small molecule inhibitors of RGS function and are currently evaluating lead compounds with specific RGS inhibitory activity.

Rho signaling pathways in cancer. Rho signaling plays an important role in cancer cell growth, motility, and metastasis. A number of GPCRs (lysophosphatidic acid, thrombin, bombesin, etc) activate rho via a family of RGS-domain-containing rho guanine nucleotide exchange factors (rhoGEFs). We are chemically targeting several domains of leukemia-associated rhoGEF (LARG).

Receptor interacting proteins and signaling complexes. G protein signaling depends on cell membrane organization and not just the random collisions of receptor and G protein (FASEB Journal 8:939-947, 1994). The structural basis and functional consequences of this is being explored. PDZ domains and other proteins interacting with GPCRs are being studied as potential drug targets.

Representative Publications

1. Clark, M.J., Harrison, C., Zhong, H., Neubig, R.R. and Traynor, J.R., "Endogenous RGS Protein Action Modulates µ-Opioid Signaling through Go. Effects on Adenyl Cyclase, Extracellular Signal-Regulated Kinases, and Intracellular Calcium Pathways", J. Biol. Chem., 2003, 278, 9418.

2. Zhong, H., Wade, S.M., Woolf, P.J., Linderman, J.J., Traynor, J.R. and Neubig, R.R., "A Spatial Focusing Model for G Protein Signals: RGS Protein-mediated Kinetic Scaffolding", JBC, 2003, 278, 7278.

3. Sarvazyan, N., Lim, W. and Neubig, R., "Fluorescence Analysis of Receptor-G Protein Interactions in Cell Membranes", Biochemistry, 2002, 41, 12858.

4. Wang, Q., Liu, M., Mullah, B., Siderovski, D.P. and Neubig, R.R., "Receptor-selective Effects of Endogenous RGS3 and RGS5 to Regulate MAP Kinase Activation in Rat Vascular Smooth Muscle Cells", J. Biol. Chem., 2002, 277, 24949.

5. Neubig, R. and Siderovski, D., "Regulators of G-Protein Signalling As New Central Nervous System Drug Targets", Nature Reviews Drug Discovery, 2002, 1, 187.