RGS16 Attenuates Gαq-dependent p38 Mitogen-activated Protein Kinase Activation by Platelet-activating Factor

Abstract

The large gene family encoding the regulators of G protein signaling (RGS) proteins has been implicated in the fine tuning of a variety of cellular events in response to G protein-coupled receptor activation. Several studies have shown that the RGS proteins can attenuate G protein-activated extracellular signal-regulated kinase (ERK) group of mitogen-activated protein kinases. We demonstrate herein that the production of inositol trisphosphate and the activation of the p38 group of mitogen-activated protein kinases by the G protein-coupled platelet-activating factor (PAF) receptor was attenuated by RGS16 in both CHO cells transiently and stably expressing RGS16. The inhibition was not observed with RGS2, RGS5, and a functionally defective form of RGS16, RGS16R169S/F170C. The PAF-induced p38 and ERK pathways appeared to be preferentially regulated by RGS16 and RGS1, respectively. Overexpression of a constitutively active form of Gα11 (Gα11Q209L) prevented the RGS16-mediated attenuation of p38 activity, suggesting that Gαq/11 is involved in PAF activation of p38. The Gαq/11 involvement is further supported by the observation that p38 activation by PAF was pertussis toxin-insensitive. These results demonstrate for the first time that apart from ERK, p38 activation by a G protein-coupled receptor can be attenuated by an RGS protein and provide further evidence for the specificity of RGS function in G protein signaling pathways. The large gene family encoding the regulators of G protein signaling (RGS) proteins has been implicated in the fine tuning of a variety of cellular events in response to G protein-coupled receptor activation. Several studies have shown that the RGS proteins can attenuate G protein-activated extracellular signal-regulated kinase (ERK) group of mitogen-activated protein kinases. We demonstrate herein that the production of inositol trisphosphate and the activation of the p38 group of mitogen-activated protein kinases by the G protein-coupled platelet-activating factor (PAF) receptor was attenuated by RGS16 in both CHO cells transiently and stably expressing RGS16. The inhibition was not observed with RGS2, RGS5, and a functionally defective form of RGS16, RGS16R169S/F170C. The PAF-induced p38 and ERK pathways appeared to be preferentially regulated by RGS16 and RGS1, respectively. Overexpression of a constitutively active form of Gα11 (Gα11Q209L) prevented the RGS16-mediated attenuation of p38 activity, suggesting that Gαq/11 is involved in PAF activation of p38. The Gαq/11 involvement is further supported by the observation that p38 activation by PAF was pertussis toxin-insensitive. These results demonstrate for the first time that apart from ERK, p38 activation by a G protein-coupled receptor can be attenuated by an RGS protein and provide further evidence for the specificity of RGS function in G protein signaling pathways. A wide array of extracellular signals are transduced into cells by membrane-bound receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins) 1The abbreviations used are: G protein, guanine nucleotide-binding regulatory protein; ATF2, activating transcription factor-2; ERK, extracellular signal-regulated kinase; IP3, inositol 1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; PAF, platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine); PAFR, PAF receptor; PMA, phorbol 12-myristate 13-acetate; PTX, pertussis toxin; RGS, regulator of G protein signaling; CHO, Chinese hamster ovary. 1The abbreviations used are: G protein, guanine nucleotide-binding regulatory protein; ATF2, activating transcription factor-2; ERK, extracellular signal-regulated kinase; IP3, inositol 1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; PAF, platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine); PAFR, PAF receptor; PMA, phorbol 12-myristate 13-acetate; PTX, pertussis toxin; RGS, regulator of G protein signaling; CHO, Chinese hamster ovary.(1Hepler J.R. Gilman A.G. Trends Biochem. Sci. 1992; 17: 383-387Abstract Full Text PDF PubMed Scopus (919) Google Scholar, 2Neer E.J. Cell. 1995; 80: 249-257Abstract Full Text PDF PubMed Scopus (1283) Google Scholar, 3Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar, 4Fields T.A. Casey P.J. Biochem. J. 1997; 321: 561-571Crossref PubMed Scopus (247) Google Scholar, 5Schneider T. Igelmund P. Hescheler T. Trends Pharmacol. Sci. 1997; 18: 8-11Abstract Full Text PDF PubMed Scopus (52) Google Scholar). Various G protein effectors have been identified (6Miller B.A. Bell L. Hansen C.A. Robishaw J.D. Linder M.E. Cheung J.Y. J. Clin. Invest. 1996; 98: 1728-1736Crossref PubMed Scopus (25) Google Scholar, 7Honda Z. Takano T. Hirose N. Suzuki T. Muto A. Kume S. Mikoshiba K. Itoh K. Shimizu T. J. Biol. Chem. 1995; 270: 4840-4844Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 8Buhl A.M. Johnson N.L. Dhanasekaran N. Johnson G.L. J. Biol. Chem. 1995; 270: 24631-24634Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar, 9Fromm C. Coso O.A. Montaner S. Xu N. Gutkind J.S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10098-10103Crossref PubMed Scopus (195) Google Scholar, 10Rhee S.G. Bae Y.S. J. Biol. Chem. 1997; 272: 15045-15048Crossref PubMed Scopus (809) Google Scholar, 11Pitcher J.A. Inglese J. Higgins J.B. Arriza J.L. Casey P.J. Kim C. Benovic J.L. Kwatra M.M. Caron M.G. Lefkowitz R.J. Science. 1992; 257: 1264-1267Crossref PubMed Scopus (563) Google Scholar, 12Vanhaesebroeck B. Leevers S.J. Panayotou G. Waterfield M.D. Trends Biochem. Sci. 1997; 22: 267-272Abstract Full Text PDF PubMed Scopus (827) Google Scholar), including the three classes of highly conserved mitogen-activated protein kinases: MAPK/ERK, c-Jun NH2-terminal kinase/stress-activated protein kinase, and p38 MAPK (3Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar, 13Robinson M.J. Cobb M.H. Curr. Opin. Cell Biol. 1997; 9: 180-186Crossref PubMed Scopus (2274) Google Scholar, 14Coso O.A. Teramoto H. Simonds W.F. Gutkind J.S. J. Biol. Chem. 1996; 271: 3963-3966Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 15Nahas N. Molski T.F.P. Fernandez G.A. Sha'afi R.I. Biochem. J. 1996; 318: 247-253Crossref PubMed Scopus (121) Google Scholar, 16Yamauchi J. Nagao M. Kaziro Y. Itoh H. J. Biol. Chem. 1997; 272: 27771-27777Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 17Reiser C.O.A. Lanz T. Hofmann F. Hofer G. Rupprecht H.D. Goppelt-Struebe M. Biochem. J. 1998; 330: 1107-1114Crossref PubMed Scopus (74) Google Scholar). Understanding the functional linkage in the receptor-G protein-effector cascade is a formidable task. The recently appreciated gene family encoding regulators of G protein signaling (RGS proteins) has provided new insights into the perplexing G protein-mediated signaling pathways.RGS proteins serve as GTPase-activating proteins of a variety of G protein α-subunits, terminating the signaling process by G protein-coupled receptors (18Dohlman H.G. Thorner J. J. Biol. Chem. 1997; 272: 3871-3874Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 19Koelle M.R. Curr. Opin. Cell Biol. 1997; 9: 143-147Crossref PubMed Scopus (172) Google Scholar, 20Berman D.M. Gilman A.G. J. Biol. Chem. 1998; 273: 1269-1272Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar, 21Kehrl J.H. Immunity. 1998; 8: 1-10Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). To date, about 20 mammalian RGS proteins have been identified, all of which are defined by a highly conserved domain of 120 amino acid residues in length. Underscoring the significance of their sequence similarity within the RGS domain, RGS proteins seem to have functional promiscuity as assayed by both their G protein binding and functional resemblance to that of the Sst2 protein in yeast. It is noteworthy that the RGS proteins vary in size, ranging from 21 to 150 kDa, and contain divergent sequences flanking the conserved RGS domain. The divergent sequences among their flanking regions may be the specificity determinants for RGS function. specificity is by the that the RGS protein to and and and T. M.J. Gilman A.G. G. Science. 1998; PubMed Scopus Google Scholar, M.J. T. Gilman A.G. G. Science. 1998; PubMed Scopus Google Scholar). studies have shown that and protein inhibition of C. J.R. Gilman A.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar), RGS1, RGS2, and attenuate activation of the ERK group of MAPK J.H. 1996; PubMed Scopus Google Scholar, Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1997; 272: PubMed Scopus Google Scholar). and protein of inositol trisphosphate C. J.R. Gilman A.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar, Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1997; 272: PubMed Scopus Google Scholar, J.D. A. J.H. 1997; PubMed Scopus Google have identified and RGS16 as T. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google and have shown that RGS16 and in the C. B. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google and that RGS16 has GTPase-activating G proteins C. 1998; PubMed Scopus Google Scholar). that RGS16 platelet-activating factor p38 MAPK activation. The RGS inhibition of p38 can be by the which an involvement of Gαq/11 in the PAF that RGS have the G protein-mediated activation of ERK and p38. that p38 activation by a G protein-coupled receptor can be attenuated by an RGS protein and provide further evidence that RGS as regulators for G protein signaling results demonstrate for the first time that activation of p38 MAPK by the G protein-coupled PAF receptor can be attenuated by an RGS family RGS16. an was not observed with RGS2, RGS5, the which is defective in G protein and RGS16 for ERK and p38 MAPK, in response to PAF The RGS16 attenuation of p38 can be by the not that Gαq/11 signaling the G protein-coupled PAF receptor and p38 and have shown that RGS proteins are with to G protein in their GTPase-activating for to and as a GTPase-activating protein and D.M. Gilman A.G. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. T. Gilman A.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, N. Linder M.E. J.H. 1996; PubMed Scopus Google Scholar, J.R. D.M. Gilman A.G. T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). RGS16 to T. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, C. B. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), and The promiscuity of RGS proteins is by the that not all of the RGS proteins can the function of Sst2 in signaling assayed a J.H. 1996; PubMed Scopus Google Scholar, C. B. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, H.G. J. Thorner J. Cell. Biol. 1996; PubMed Google Scholar, A. S. M. Curr. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of RGS function in mammalian cells that RGS family seem to be in the of G signaling pathways. RGS1, RGS2, and in their to receptor signaling of ERK, with the inhibition by RGS1, and J.H. 1996; PubMed Scopus Google Scholar). G by activation of receptors are by of RGS1, not C.A. N. P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). a not RGS1, RGS2, can the by the J.D. A. J.H. 1997; PubMed Scopus Google Scholar). The that p38 MAPK is attenuated by RGS16 and attenuated by not by RGS2, RGS5, and that is RGS16 in ERK provide further evidence of be that in may not in mammalian not contain the of have identified a mammalian protein that to the NH2-terminal of a of RGS and It is that protein may RGS functional specificity in G protein with signaling pathways. is that as and and in to the specificity of RGS of evidence that p38 activation by G protein-coupled receptor can be by Gαq/11 and J. Nagao M. Kaziro Y. Itoh H. J. Biol. Chem. 1997; 272: 27771-27777Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, K. T. 1997; PubMed Scopus Google Scholar, A. A. Biochem. J. 1998; PubMed Scopus Google Scholar). can the kinase which is for the activation of as in cells for K. T. 1997; PubMed Scopus Google Scholar). The receptor p38 MAPK in A. A. Biochem. J. 1998; PubMed Scopus Google Scholar). p38 MAPK activation by receptor both and receptors in cells J. Nagao M. Kaziro Y. Itoh H. J. Biol. Chem. 1997; 272: 27771-27777Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). It is that can C.A. N. P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar), RGS16 not to a in the of p38 MAPK activation. The may be by the that RGS proteins may be to be that RGS16 may with signaling pathways by functional significance of RGS16 inhibition of p38 MAPK is as PAF a wide variety of and in cells and as in and and and Biochem. J. PubMed Scopus Google Scholar). It is that p38 of the PAF p38 MAPK is to an in the of cellular J. L. R.J. Science. PubMed Scopus Google Scholar, S. M.J. J.R. M.M. J.R. J.L. PubMed Scopus Google Scholar, J. Y. Z. R.J. 1997; PubMed Scopus Google Scholar). RGS16 is to fine the response the of have observed in RGS16 are with S. Y. and and RGS16 of MAPK is that both and RGS16 are for fine tuning the events by that RGS proteins of G protein-mediated p38 and ERK to of RGS proteins in G A wide array of extracellular signals are transduced into cells by membrane-bound receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins) 1The abbreviations used are: G protein, guanine nucleotide-binding regulatory protein; ATF2, activating transcription factor-2; ERK, extracellular signal-regulated kinase; IP3, inositol 1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; PAF, platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine); PAFR, PAF receptor; PMA, phorbol 12-myristate 13-acetate; PTX, pertussis toxin; RGS, regulator of G protein signaling; CHO, Chinese hamster ovary. 1The abbreviations used are: G protein, guanine nucleotide-binding regulatory protein; ATF2, activating transcription factor-2; ERK, extracellular signal-regulated kinase; IP3, inositol 1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; PAF, platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine); PAFR, PAF receptor; PMA, phorbol 12-myristate 13-acetate; PTX, pertussis toxin; RGS, regulator of G protein signaling; CHO, Chinese hamster ovary.(1Hepler J.R. Gilman A.G. Trends Biochem. Sci. 1992; 17: 383-387Abstract Full Text PDF PubMed Scopus (919) Google Scholar, 2Neer E.J. Cell. 1995; 80: 249-257Abstract Full Text PDF PubMed Scopus (1283) Google Scholar, 3Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar, 4Fields T.A. Casey P.J. Biochem. J. 1997; 321: 561-571Crossref PubMed Scopus (247) Google Scholar, 5Schneider T. Igelmund P. Hescheler T. Trends Pharmacol. Sci. 1997; 18: 8-11Abstract Full Text PDF PubMed Scopus (52) Google Scholar). Various G protein effectors have been identified (6Miller B.A. Bell L. Hansen C.A. Robishaw J.D. Linder M.E. Cheung J.Y. J. Clin. Invest. 1996; 98: 1728-1736Crossref PubMed Scopus (25) Google Scholar, 7Honda Z. Takano T. Hirose N. Suzuki T. Muto A. Kume S. Mikoshiba K. Itoh K. Shimizu T. J. Biol. Chem. 1995; 270: 4840-4844Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 8Buhl A.M. Johnson N.L. Dhanasekaran N. Johnson G.L. J. Biol. Chem. 1995; 270: 24631-24634Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar, 9Fromm C. Coso O.A. Montaner S. Xu N. Gutkind J.S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10098-10103Crossref PubMed Scopus (195) Google Scholar, 10Rhee S.G. Bae Y.S. J. Biol. Chem. 1997; 272: 15045-15048Crossref PubMed Scopus (809) Google Scholar, 11Pitcher J.A. Inglese J. Higgins J.B. Arriza J.L. Casey P.J. Kim C. Benovic J.L. Kwatra M.M. Caron M.G. Lefkowitz R.J. Science. 1992; 257: 1264-1267Crossref PubMed Scopus (563) Google Scholar, 12Vanhaesebroeck B. Leevers S.J. Panayotou G. Waterfield M.D. Trends Biochem. Sci. 1997; 22: 267-272Abstract Full Text PDF PubMed Scopus (827) Google Scholar), including the three classes of highly conserved mitogen-activated protein kinases: MAPK/ERK, c-Jun NH2-terminal kinase/stress-activated protein kinase, and p38 MAPK (3Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar, 13Robinson M.J. Cobb M.H. Curr. Opin. Cell Biol. 1997; 9: 180-186Crossref PubMed Scopus (2274) Google Scholar, 14Coso O.A. Teramoto H. Simonds W.F. Gutkind J.S. J. Biol. Chem. 1996; 271: 3963-3966Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 15Nahas N. Molski T.F.P. Fernandez G.A. Sha'afi R.I. Biochem. J. 1996; 318: 247-253Crossref PubMed Scopus (121) Google Scholar, 16Yamauchi J. Nagao M. Kaziro Y. Itoh H. J. Biol. Chem. 1997; 272: 27771-27777Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 17Reiser C.O.A. Lanz T. Hofmann F. Hofer G. Rupprecht H.D. Goppelt-Struebe M. Biochem. J. 1998; 330: 1107-1114Crossref PubMed Scopus (74) Google Scholar). Understanding the functional linkage in the receptor-G protein-effector cascade is a formidable task. The recently appreciated gene family encoding regulators of G protein signaling (RGS proteins) has provided new insights into the perplexing G protein-mediated signaling pathways. RGS proteins serve as GTPase-activating proteins of a variety of G protein α-subunits, terminating the signaling process by G protein-coupled receptors (18Dohlman H.G. Thorner J. J. Biol. Chem. 1997; 272: 3871-3874Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 19Koelle M.R. Curr. Opin. Cell Biol. 1997; 9: 143-147Crossref PubMed Scopus (172) Google Scholar, 20Berman D.M. Gilman A.G. J. Biol. Chem. 1998; 273: 1269-1272Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar, 21Kehrl J.H. Immunity. 1998; 8: 1-10Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). To date, about 20 mammalian RGS proteins have been identified, all of which are defined by a highly conserved domain of 120 amino acid residues in length. Underscoring the significance of their sequence similarity within the RGS domain, RGS proteins seem to have functional promiscuity as assayed by both their G protein binding and functional resemblance to that of the Sst2 protein in yeast. It is noteworthy that the RGS proteins vary in size, ranging from 21 to 150 kDa, and contain divergent sequences flanking the conserved RGS domain. The divergent sequences among their flanking regions may be the specificity determinants for RGS function. specificity is by the that the RGS protein to and and and T. M.J. Gilman A.G. G. Science. 1998; PubMed Scopus Google Scholar, M.J. T. Gilman A.G. G. Science. 1998; PubMed Scopus Google Scholar). studies have shown that and protein inhibition of C. J.R. Gilman A.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar), RGS1, RGS2, and attenuate activation of the ERK group of MAPK J.H. 1996; PubMed Scopus Google Scholar, Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1997; 272: PubMed Scopus Google Scholar). and protein of inositol trisphosphate C. J.R. Gilman A.G. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar, Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1997; 272: PubMed Scopus Google Scholar, J.D. A. J.H. 1997; PubMed Scopus Google Scholar). We have identified and RGS16 as T. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google and have shown that RGS16 and in the C. B. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google and that RGS16 has GTPase-activating G proteins C. 1998; PubMed Scopus Google Scholar). that RGS16 platelet-activating factor p38 MAPK activation. The RGS inhibition of p38 can be by the which an involvement of Gαq/11 in the PAF that RGS have the G protein-mediated activation of ERK and p38. that p38 activation by a G protein-coupled receptor can be attenuated by an RGS protein and provide further evidence that RGS as regulators for G protein signaling pathways. results demonstrate for the first time that activation of p38 MAPK by the G protein-coupled PAF receptor can be attenuated by an RGS family RGS16. an was not observed with RGS2, RGS5, the which is defective in G protein and RGS16 for ERK and p38 MAPK, in response to PAF The RGS16 attenuation of p38 can be by the not that Gαq/11 signaling the G protein-coupled PAF receptor and p38 and have shown that RGS proteins are with to G protein in their GTPase-activating for to and as a GTPase-activating protein and D.M. Gilman A.G. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. T. Gilman A.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, N. Linder M.E. J.H. 1996; PubMed Scopus Google Scholar, J.R. D.M. Gilman A.G. T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). RGS16 to T. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, C. B. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), and The promiscuity of RGS proteins is by the that not all of the RGS proteins can the function of Sst2 in signaling assayed a J.H. 1996; PubMed Scopus Google Scholar, C. B. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, H.G. J. Thorner J. Cell. Biol. 1996; PubMed Google Scholar, A. S. M. Curr. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of RGS function in mammalian cells that RGS family seem to be in the of G signaling pathways. RGS1, RGS2, and in their to receptor signaling of ERK, with the inhibition by RGS1, and J.H. 1996; PubMed Scopus Google Scholar). G by activation of receptors are by of RGS1, not C.A. N. P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). a not RGS1, RGS2, can the by the J.D. A. J.H. 1997; PubMed Scopus Google Scholar). The that p38 MAPK is attenuated by RGS16 and attenuated by not by RGS2, RGS5, and that is RGS16 in ERK provide further evidence of be that in may not in mammalian not contain the of have identified a mammalian protein that to the NH2-terminal of a of RGS and It is that protein may RGS functional specificity in G protein with signaling pathways. is that as and and in to the specificity of RGS of evidence that p38 activation by G protein-coupled receptor can be by Gαq/11 and J. Nagao M. Kaziro Y. Itoh H. J. Biol. Chem. 1997; 272: 27771-27777Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, K. T. 1997; PubMed Scopus Google Scholar, A. A. Biochem. J. 1998; PubMed Scopus Google Scholar). can the kinase which is for the activation of as in cells for K. T. 1997; PubMed Scopus Google Scholar). The receptor p38 MAPK in A. A. Biochem. J. 1998; PubMed Scopus Google Scholar). p38 MAPK activation by receptor both and receptors in cells J. Nagao M. Kaziro Y. Itoh H. J. Biol. Chem. 1997; 272: 27771-27777Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). It is that can C.A. N. P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar), RGS16 not to a in the of p38 MAPK activation. The may be by the that RGS proteins may be to be that RGS16 may with signaling pathways by functional significance of RGS16 inhibition of p38 MAPK is as PAF a wide variety of and in cells and as in and and and Biochem. J. PubMed Scopus Google Scholar). It is that p38 of the PAF p38 MAPK is to an in the of cellular J. L. R.J. Science. PubMed Scopus Google Scholar, S. M.J. J.R. M.M. J.R. J.L. PubMed Scopus Google Scholar, J. Y. Z. R.J. 1997; PubMed Scopus Google Scholar). RGS16 is to fine the response the of have observed in RGS16 are with S. Y. and and RGS16 of MAPK is that both and RGS16 are for fine tuning the events by that RGS proteins of G protein-mediated p38 and ERK to of RGS proteins in G results demonstrate for the first time that activation of p38 MAPK by the G protein-coupled PAF receptor can be attenuated by an RGS family RGS16. an was not observed with RGS2, RGS5, the which is defective in G protein and RGS16 for ERK and p38 MAPK, in response to PAF The RGS16 attenuation of p38 can be by the not that Gαq/11 signaling the G protein-coupled PAF receptor and p38 We and have shown that RGS proteins are with to G protein in their GTPase-activating for to and as a GTPase-activating protein and D.M. Gilman A.G. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. T. Gilman A.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, N. Linder M.E. J.H. 1996; PubMed Scopus Google Scholar, J.R. D.M. Gilman A.G. T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). RGS16 to T. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, C. B. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), and The promiscuity of RGS proteins is by the that not all of the RGS proteins can the function of Sst2 in signaling assayed a J.H. 1996; PubMed Scopus Google Scholar, C. B. J. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, H.G. J. Thorner J. Cell. Biol. 1996; PubMed Google Scholar, A. S. M. Curr. Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of RGS function in mammalian cells that RGS family seem to be in the of G signaling pathways. RGS1, RGS2, and in their to receptor signaling of ERK, with the inhibition by RGS1, and J.H. 1996; PubMed Scopus Google Scholar). G by activation of receptors are by of RGS1, not C.A. N. P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). a not RGS1, RGS2, can the by the J.D. A. J.H. 1997; PubMed Scopus Google Scholar). The that p38 MAPK is attenuated by RGS16 and attenuated by not by RGS2, RGS5, and that is RGS16 in ERK provide further evidence of be that in may not in mammalian not contain the of have identified a mammalian protein that to the NH2-terminal of a of RGS and It is that protein may RGS functional specificity in G protein with signaling pathways. is that as and and in to the specificity of RGS function. Several of evidence that p38 activation by G protein-coupled receptor can be by Gαq/11 and J. Nagao M. Kaziro Y. Itoh H. J. Biol. Chem. 1997; 272: 27771-27777Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, K. T. 1997; PubMed Scopus Google Scholar, A. A. Biochem. J. 1998; PubMed Scopus Google Scholar). can the kinase which is for the activation of as in cells for K. T. 1997; PubMed Scopus Google Scholar). The receptor p38 MAPK in A. A. Biochem. J. 1998; PubMed Scopus Google Scholar). p38 MAPK activation by receptor both and receptors in cells J. Nagao M. Kaziro Y. Itoh H. J. Biol. Chem. 1997; 272: 27771-27777Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). It is that can C.A. N. P. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar), RGS16 not to a in the of p38 MAPK activation. The may be by the that RGS proteins may be to be that RGS16 may with signaling pathways by The functional significance of RGS16 inhibition of p38 MAPK is as PAF a wide variety of and in cells and as in and and and Biochem. J. PubMed Scopus Google Scholar). It is that p38 of the PAF p38 MAPK is to an in the of cellular J. L. R.J. Science. PubMed Scopus Google Scholar, S. M.J. 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