Copyright © 1999, CRC Press LLC — Files may be downloaded for personal use only. Reproduction of this material without the consent of the publisher is prohibited. 215 Critical Reviews in Biochemistry and Molecular Biology, 34(4):215–251 (1999) Whither Goest the RGS Proteins? David P. Siderovski, Bentley Strockbine, and Cynthia I. Behe Department of Pharmacology, School of Medicine, The University of North Carolina at Chapel Hill, Campus Box #7365, Mary Ellen Jones Building, Room 906B, Chapel Hill, NC 27599-7365 Referee: Dr. Richard Neubig, Department of Pharmacology, University of Michigan at Ann Arbor, 1150 West Medical Center Drive, Ann Arbor, MI 48109–0632 ABSTRACT: Studies of the desensitization of G protein-coupled signal transduction have led to the discovery of a family of guanosine triphosphatase-activating proteins (GAPs) for heterotrimeric G protein alpha subunits — the “regulator of G protein signaling” or RGS proteins. In considering both documented and potential functions of several RGS protein family members with demonstrable multidomain compositions (p115RhoGEF, PDZRhoGEF, Axin, Axil/Conductin, D-AKAP2, the G protein-coupled receptor kinases [GRKs], the DEP/GGL/RGS subfamily [RGS6, RGS7, RGS9, RGS11], and RGS12), this review explores the shift in our appreciation of the RGS proteins from unidimensional desensitizing agents to multifocal signal transduction regulators. KEY WORDS: desensitization, effector proteins, GGL, GoLoco, PDZ, PTB, regulators of G protein signaling, RGS, scaffold proteins, signal transduction TABLE OF CONTENTS I. INTRODUCTION .................................................................................................... 216 II. DISCOVERY ............................................................................................................ 217 III. ORIGINAL VIEW ................................................................................................... 218 IV. HARBINGERS OF THE PARADIGM SHIFT .................................................... 220 A. p115RhoGEF and PDZRhoGEF: Effector Proteins for G a12/13 .......................... 221 B. Axin and Axil/Conductin: Scaffold Proteins for the Wnt Signaling Pathway .................................................................................................... 225 C. D-AKAP2: A Scaffold for Protein Kinase A Regulation? .................................. 227 D. GRKs: Scaffolds for Multifocal Desensitization and Signal Generation? ............................................................................................................... 228 E. The DEP/GGL/RGS Subfamily: Coup de Grâce Against a Central Tenet of Heterotrimeric G-Protein Assembly ........................................ 230 F. RGS12: A Scaffold for the Coordination of G Protein and Tyrosine Kinase Signaling? .................................................................................... 234 V. CONCLUSION ......................................................................................................... 240 Critical Reviews in Biochemistry and Molecular Biology Downloaded from informahealthcare.com by 175.100.75.91 on 05/20/14 For personal use only.