RGS proteins: Swiss army knives in seven-transmembrane domain receptor signaling networks.
Coordinated regulation of heterotrimeric guanine nucleotide-binding protein (G protein) activity is critical for the integration of information from multiple intracellular signaling networks. The human regulator of G protein signaling (RGS) protein family contains more than 35 members that are well suited for this purpose. Although all RGS proteins contain a core ~120-amino acid Galpha-interacting domain (called the RGS domain), they differ widely in size and organization of other functional domains. Architecturally complex RGS proteins contain multiple modular protein-protein interaction domains that mediate their interaction with diverse signaling effectors. Architecturally simple RGS proteins contain small amino-terminal domains; however, they show surprising versatility in the number of intracellular partners with which they interact. This Perspective focuses on RGS2, a simple RGS protein with the potential to integrate multiple signaling networks. In three recent studies, the amino-terminal domain of RGS2 was shown to interact with and regulate three different effector proteins: adenylyl cyclase, tubulin, and the cation channel TRPV6. To explain this growing list of RGS2-interacting partners, we propose two models: (i) The amino-terminal domain of RGS2 comprises several short effector protein interaction motifs; (ii) the amino-terminal domain of RGS2 adopts distinct structures to bind various targets. Whatever the precise mechanism controlling its target interactions, these studies suggest that RGS2 is a key point of integration for multiple intracellular signaling pathways, and they highlight the role of RGS proteins as dynamic, multifunctional signaling centers that coordinate a diverse range of cellular functions.
Heximer
Scott P
SP
Department of Physiology and Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. scott.heximer@utoronto.ca
Blumer
Kendall J
KJ
D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000378:metabolism* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
D020710:RGS Proteins; C087182:RGS2 protein, human; D043562:Receptors, G-Protein-Coupled; C450520:seven-transmembrane G-protein-coupled receptor; D019204:GTP-Binding Proteins