RGS3 is a GTPase-activating protein for g(ialpha) and g(qalpha) and a potent inhibitor of signaling by GTPase-deficient forms of g(qalpha) and g(11alpha).
Many Regulators of G protein Signaling (RGS) proteins accelerate the intrinsic GTPase activity of G(ialpha) and G(qalpha)-subunits [i.e., behave as GTPase-activating proteins (GAPs)] and several act as G(qalpha)-effector antagonists. RGS3, a structurally distinct RGS member with a unique N-terminal domain and a C-terminal RGS domain, and an N-terminally truncated version of RGS3 (RGS3CT) both stimulated the GTPase activity of G(ialpha) (except G(zalpha)) and G(qalpha) but not that of G(salpha) or G(12alpha). RGS3 and RGS3CT had G(qalpha) GAP activity similar to that of RGS4. RGS3 impaired signaling through G(q)-linked receptors, although RGS3CT invariably inhibited better than did full-length RGS3. RGS3 potently inhibited G(qalpha)Q209L- and G(11alpha)Q209L-mediated activation of a cAMP-response element-binding protein reporter gene and G(qalpha)Q209L induced inositol phosphate production, suggesting that RGS3 efficiently blocks G(qalpha) from activating its downstream effector phospholipase C-beta. Whereas RGS2 and to a lesser extent RGS10 also inhibited signaling by these GTPase-deficient G proteins, other RGS proteins including RGS4 did not. Mutation of residues in RGS3 similar to those required for RGS4 G(ialpha) GAP activity, as well as several residues N terminal to its RGS domain impaired RGS3 function. A greater percentage of RGS3CT localized at the cell membrane than the full-length version, potentially explaining why RGS3CT blocked signaling better than did full-length RGS3. Thus, RGS3 can impair Gi- (but not Gz-) and Gq-mediated signaling in hematopoietic and other cell types by acting as a GAP for G(ialpha) and G(qalpha) subfamily members and as a potent G(qalpha) subfamily effector antagonist.
Scheschonka
A
A
B Cell Molecular Biology Section, Laboratory Immunoregulation, National Institutes of Health, Bethesda, Maryland 20892, USA.
Dessauer
C W
CW
Sinnarajah
S
S
Chidiac
P
P
Shi
C S
CS
Kehrl
J H
JH
D002478:Cells, Cultured; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins; D020690:GTPase-Activating Proteins; D006367:HeLa Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D020710:RGS Proteins / Q000378:metabolism / Q000502:physiology*; D043643:Receptor, Muscarinic M1; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D015398:Signal Transduction
D020690:GTPase-Activating Proteins; D020710:RGS Proteins; C485898:RGS3 protein, human; D043643:Receptor, Muscarinic M1; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; C415085:Rgs3 protein, mouse; C098799:RGS4 protein; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins