Insulin and Insulin-like Growth Factor I Receptors Utilize Different G Protein Signaling Components

We examined the role of heterotrimeric G protein signaling components in insulin and insulin-like growth factor I (IGF-I) action. In HIRcB cells and in 3T3L1 adipocytes, treatment with the Gαi inhibitor (pertussis toxin) or microinjection of the Gβγ inhibitor (glutathioneS-transferase-βARK) inhibited IGF-I and lysophosphatidic acid-stimulated mitogenesis but had no effect on epidermal growth factor (EGF) or insulin action. In basal state, Gαi and Gβ were associated with the IGF-I receptor (IGF-IR), and after ligand stimulation the association of IGF-IR with Gαi increased concomitantly with a decrease in Gβ association. No association of Gαi was found with either the insulin or EGF receptor. Microinjection of anti-β-arrestin-1 antibody specifically inhibited IGF-I mitogenic action but had no effect on EGF or insulin action. β-Arrestin-1 was associated with the receptors for IGF-I, insulin, and EGF in a ligand-dependent manner. We demonstrated that Gαi, βγ subunits, and β-arrestin-1 all play a critical role in IGF-I mitogenic signaling. In contrast, neither metabolic, such as GLUT4 translocation, nor mitogenic signaling by insulin is dependent on these protein components. These results suggest that insulin receptors and IGF-IRs can function as G protein-coupled receptors and engage different G protein partners for downstream signaling. We examined the role of heterotrimeric G protein signaling components in insulin and insulin-like growth factor I (IGF-I) action. In HIRcB cells and in 3T3L1 adipocytes, treatment with the Gαi inhibitor (pertussis toxin) or microinjection of the Gβγ inhibitor (glutathioneS-transferase-βARK) inhibited IGF-I and lysophosphatidic acid-stimulated mitogenesis but had no effect on epidermal growth factor (EGF) or insulin action. In basal state, Gαi and Gβ were associated with the IGF-I receptor (IGF-IR), and after ligand stimulation the association of IGF-IR with Gαi increased concomitantly with a decrease in Gβ association. No association of Gαi was found with either the insulin or EGF receptor. Microinjection of anti-β-arrestin-1 antibody specifically inhibited IGF-I mitogenic action but had no effect on EGF or insulin action. β-Arrestin-1 was associated with the receptors for IGF-I, insulin, and EGF in a ligand-dependent manner. We demonstrated that Gαi, βγ subunits, and β-arrestin-1 all play a critical role in IGF-I mitogenic signaling. In contrast, neither metabolic, such as GLUT4 translocation, nor mitogenic signaling by insulin is dependent on these protein components. These results suggest that insulin receptors and IGF-IRs can function as G protein-coupled receptors and engage different G protein partners for downstream signaling. insulin-like growth factor I IGF-I receptor insulin-sensitive glucose transporter mitogen-activated protein insulin receptor glutathione S-transferase lysophosphatidic acid epidermal growth factor receptor tyrosine kinase G protein-coupled receptor tetramethyl rhodamine isothiocyanate Dulbecco's modified Eagle's medium fetal calf serum bromodeoxyuridine phosphate-buffered saline polyacrylamide gel electrophoresis pertussis toxin Although the insulin-like growth factor I receptor (IGF-IR)1 and the insulin receptor (IR) are structurally and functionally related heterotetrameric proteins and share many of the same signaling molecules, they modulate different responses within the cell. IGF-I has been implicated mostly in mitogenic functions and insulin in metabolic actions (1Cheatman B. Khan C.R. Endocr. Rev. 1995; 16: 117-142PubMed Google Scholar, 2Baserga R. Hongo A. Rubini M. Prisco M. Valentinis B. Biochim. Biophys. Acta. 1997; 1332: F105-F126Crossref PubMed Scopus (485) Google Scholar). The insulin and IGF-I receptors consist of two extracellular α-subunits and two transmembrane β-subunits and are members of the receptor tyrosine kinase (RTK) class of membrane localized receptors (2Baserga R. Hongo A. Rubini M. Prisco M. Valentinis B. Biochim. Biophys. Acta. 1997; 1332: F105-F126Crossref PubMed Scopus (485) Google Scholar, 3Ullrich A. Bell J.R. Chen E.Y. Herrera R. Petruzzeli L.M. Dull T.J. Gray A. Coussens L. Liao Y.C. Tsubokawa M. Mason A. Seeburg P.H. Grunfeld C. Rosen O.M. Ramachandran J. Nature. 1985; 313: 756-761Crossref PubMed Scopus (1512) Google Scholar, 4Ullrich A. Gray A. Tam A. Yang-Feng T. Tsubokawa M. Collins C. Henzel W. LeBon T. Kathuria S. Chen E. Jacobs S. Francke U. Ramachandran J. Fujita-Yamaguchi Y. EMBO J. 1986; 5: 2503-2512Crossref PubMed Scopus (1501) Google Scholar). Ligand binding activates the tyrosine kinase activity of the β subunits (2Baserga R. Hongo A. Rubini M. Prisco M. Valentinis B. Biochim. Biophys. Acta. 1997; 1332: F105-F126Crossref PubMed Scopus (485) Google Scholar, 3Ullrich A. Bell J.R. Chen E.Y. Herrera R. Petruzzeli L.M. Dull T.J. Gray A. Coussens L. Liao Y.C. Tsubokawa M. Mason A. Seeburg P.H. Grunfeld C. Rosen O.M. Ramachandran J. Nature. 1985; 313: 756-761Crossref PubMed Scopus (1512) Google Scholar, 4Ullrich A. Gray A. Tam A. Yang-Feng T. Tsubokawa M. Collins C. Henzel W. LeBon T. Kathuria S. Chen E. Jacobs S. Francke U. Ramachandran J. Fujita-Yamaguchi Y. EMBO J. 1986; 5: 2503-2512Crossref PubMed Scopus (1501) Google Scholar) leading to autophosphorylation, as well as tyrosine phosphorylation of a variety of endogenous substrates, such as the IRS proteins (5Myers Jr., M.G. White M.F. Annu. Rev. Pharmacol. Toxicol. 1996; 36: 615-658Crossref PubMed Scopus (296) Google Scholar), Shc (6Pelicci G. Lanfrancone L. Grignani F. McGlade J. Cavallo F. Forni G. Nicoletti I. Pawson T. Pelicci P.G. Cell. 1992; 70: 93-104Abstract Full Text PDF PubMed Scopus (1136) Google Scholar, 7Sasaoka T. Rose D.W. Jhun B.H. Saltiel A.R. Draznin B. Olefsky J.M. J. Biol. Chem. 1994; 269: 13689-13694Abstract Full Text PDF PubMed Google Scholar), Gab1 (8Janez A. Worrall D.S. Imamura T. Sharma P.M. Olefsky J.M. J. Biol. Chem. 2000; 275: 26870-26876Abstract Full Text Full Text PDF PubMed Google Scholar), and Gαq/11 (9Imamura T. Vollenweider P. Egawa K. Clodi M. Ishibashi K. Nakashima N. Ugi S. Adams J.W. Brown J.H.B. Olefsky J.M. Mol. Cell. Biol. 1999; 19: 6765-6774Crossref PubMed Scopus (145) Google Scholar). It is thought that these endogenous substrates then go on to mediate the biologic effects of these two hormones through a variety of mechanisms (5Myers Jr., M.G. White M.F. Annu. Rev. Pharmacol. Toxicol. 1996; 36: 615-658Crossref PubMed Scopus (296) Google Scholar, 6Pelicci G. Lanfrancone L. Grignani F. McGlade J. Cavallo F. Forni G. Nicoletti I. Pawson T. Pelicci P.G. Cell. 1992; 70: 93-104Abstract Full Text PDF PubMed Scopus (1136) Google Scholar, 7Sasaoka T. Rose D.W. Jhun B.H. Saltiel A.R. Draznin B. Olefsky J.M. J. Biol. Chem. 1994; 269: 13689-13694Abstract Full Text PDF PubMed Google Scholar, 8Janez A. Worrall D.S. Imamura T. Sharma P.M. Olefsky J.M. J. Biol. Chem. 2000; 275: 26870-26876Abstract Full Text Full Text PDF PubMed Google Scholar, 9Imamura T. Vollenweider P. Egawa K. Clodi M. Ishibashi K. Nakashima N. Ugi S. Adams J.W. Brown J.H.B. Olefsky J.M. Mol. Cell. Biol. 1999; 19: 6765-6774Crossref PubMed Scopus (145) Google Scholar). Heptahelical receptors are another broad class of membrane receptors, and this receptor class is often referred to as G protein-coupled receptors (GPCRs), because they exert their biologic effects by interacting with a family of heterotrimeric G protein signaling molecules (10Watson S. Arkinstall A. The G-protein Linked Receptor Facts Book. Academic Press, San Diego, CA1994Google Scholar, 11Bourne H.R. Curr. Opin. Cell Biol. 1997; 9: 134-142Crossref PubMed Scopus (526) Google Scholar, 12Lefkowitz R.J. J. Biol. Chem. 1998; 273: 18667-18680Abstract Full Text Full Text PDF Scopus (903) Google Scholar). Although it is often thought that the RTKs and heptahelical/GPCRs represent structurally and functionally different classes of receptor types, recent evidence indicates that this may not be strictly the case (13Dhanasekaran N. Heasley L.E. Johnson G.L. Endocrinol. Rev. 1995; 16: 259-270Crossref PubMed Scopus (178) Google Scholar, 14Luttrell L.M. Daaka Y. Lefkowitz R.J. Curr. Opin. Cell Biol. 1999; 11: 177-183Crossref PubMed Scopus (603) Google Scholar, 15Daub H. Wallach C. Lankenau A. Herrlich A. Ullrich A. EMBO J. 1997; 16: 7032-7044Crossref PubMed Scopus (586) Google Scholar, 16Maudsley S. Pierce K.L. Zamah A.M. Miller W.E. Ahn S. Daaka Y. Lefkowitz R.J. Luttrell L.M. J. Biol. Chem. 2000; 275: 9572-9580Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). For example, it has now been established that specific heptahelical receptor biologic responses, such as activation of MAP kinase (16Maudsley S. Pierce K.L. Zamah A.M. Miller W.E. Ahn S. Daaka Y. Lefkowitz R.J. Luttrell L.M. J. Biol. Chem. 2000; 275: 9572-9580Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar, 17van Biesen T. Luttrell L.M. Hawes B.E. Lefkowitz R.J. Endocrinol. Rev. 1996; 17: 698-714Crossref PubMed Scopus (390) Google Scholar, 18Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar, 19Pace A.M. Faure M. Bourne H.R. Mol. Biol. Cell. 1995; 6: 1685-1695Crossref PubMed Scopus (65) Google Scholar), can be mediated by tyrosine kinase events initiated through activation of Src kinase (20Chen Y.H. Pouyssegur J. Courtneidge S.A. Van obberghen-Schilling E. J. Biol. Chem. 1994; 269: 27377-27732Google Scholar, 21Dikic I. Tokiwa G. Lev S. Coutneidge S. Schlessinger J. Nature. 1996; 383: 547-550Crossref PubMed Scopus (877) Google Scholar, 22Luttrell L.M. Hawes B.E. van Biesen T. Luttrell D.K. Lansing T.J. Lefkowitz R.J. J. Biol. Chem. 1996; 271: 19443-19450Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar, 23Della Rocca G.J. van Biesen T. Daaka Y. Luttrell D.K. Luttrell L.M. Lefkowitz R.J. J. Biol. Chem. 1997; 272: 19125-19132Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar, 24Cao W. Luttrell L.M. Medvedev A.V. Pierce K.L. Daniel K.W. Dixon T.M. Lefkowitz R.J. Collins S. J. Biol. Chem. 2000; 275: 38131-38134Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). Further, several reports have appeared that show a strict dependence of insulin receptor and IGF-I signaling on heterotrimeric G proteins (9Imamura T. Vollenweider P. Egawa K. Clodi M. Ishibashi K. Nakashima N. Ugi S. Adams J.W. Brown J.H.B. Olefsky J.M. Mol. Cell. Biol. 1999; 19: 6765-6774Crossref PubMed Scopus (145) Google Scholar, 25Luttrell L.M. Van Biesen T. Hawes B.E. Koch W.J. Touhara K. Lefkowitz R.J. J. Biol. Chem. 1995; 270: 16495-16498Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). Evidence exists to indicate that the IGF-I receptor requires a heterotrimeric G protein containing Gαi for some of its biologic effects. Thus, treatment with pertussis toxin (an inhibitor of Gαi-mediated signaling) blocks IGF-I-induced activation of MAP kinase, and inhibition of Gβγ function also impairs MAP kinase signaling from the IGF-I receptor (25Luttrell L.M. Van Biesen T. Hawes B.E. Koch W.J. Touhara K. Lefkowitz R.J. J. Biol. Chem. 1995; 270: 16495-16498Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). Furthermore, recent work from our laboratory has shown that Gαq/11 plays a key role in insulin-induced GLUT4 translocation and stimulation of glucose transport in 3T3-L1 adipocytes. In these that the with and Gαq/11 and that this G protein is for insulin stimulation of GLUT4 translocation and glucose In a of Gαq/11 was to the effects of insulin by GLUT4 translocation and glucose transport on its (9Imamura T. Vollenweider P. Egawa K. Clodi M. Ishibashi K. Nakashima N. Ugi S. Adams J.W. Brown J.H.B. Olefsky J.M. Mol. Cell. Biol. 1999; 19: 6765-6774Crossref PubMed Scopus (145) Google Scholar). on these can suggest that the is a a to heptahelical receptors of the the and have now the of different G protein signaling components in these action β-Arrestin-1 and were from protein Gαi were from antibody was by MAP kinase antibody was from and MAP kinase antibody was from tetramethyl rhodamine and and were from Dulbecco's modified Eagle's medium and fetal calf serum were from were from were from HIRcB are the of the were as H. J. Dull T.J. Ullrich A. Olefsky J.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar) in medium with and in a established from were in with and calf serum in a were to 3T3-L1 were in with and in a 3T3-L1 were by the of the same containing and the medium was and with containing and after the of the the cells were in a of The medium was of the cells of adipocytes. to the of cells were containing glucose HIRcB cells were on well to and then in medium for were with either insulin, epidermal growth factor or lysophosphatidic acid was and cells were for were then for in and with antibody by with and were on cells in represent the of a of cells in a cells with cells to a were and as Rose D.W. M. Olefsky J.M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). HIRcB cells were on to were in medium for after the cells were with either insulin, IGF-I, or was as For GLUT4 translocation 3T3L1 were on and on in for microinjection on Microinjection of the was a microinjection for microinjection were in microinjection containing were the of the with to of the of GLUT4 was as P. T. M. Rose D.W. Olefsky J.M. 1997; PubMed Scopus Google Scholar). 3T3L1 were in in phosphate-buffered saline for the cells were and with and in for The cells were then with GLUT4 antibody in with GLUT4 and were by with antibody and by was to the cells were as for GLUT4 translocation they were to have a of the In all the was to the of were in in for and with in serum in for cells were to the MAP kinase antibody in serum MAP kinase was by with or antibody in serum and MAP kinase specifically with MAP kinase and not with MAP kinase by HIRcB cells or 3T3L1 in were as in cells were for in a containing and were for to For the of were by for in in or or and and by gel electrophoresis For the of were with antibody as in for were from the with protein with and for in containing and and by gel were to membrane by For were and with to the with proteins were by the 3T3L1 were in containing glucose for were then with and serum and either or as in transport was by the of containing as A. G. W.J. J. Google Scholar). was by the of containing The was after by and glucose was by with were in and was by were for protein by protein are as the were by of was the effects of treatment of HIRcB cells on mediated by insulin, IGF-I, or and was by insulin or EGF was not These results indicate that the for and Gαi and mitogenic signaling (25Luttrell L.M. Van Biesen T. Hawes B.E. Koch W.J. Touhara K. Lefkowitz R.J. J. Biol. Chem. 1995; 270: 16495-16498Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar) have shown that Gβγ subunits are for IGF-I-induced MAP kinase Thus, in our the role of Gβγ in growth We a protein containing the of the receptor kinase to and Gβγ subunits and as a inhibitor of Gβγ signaling I. Jr., F. J. 1994; PubMed Scopus Google Scholar). We HIRcB cells and insulin, IGF-I, and EGF shown in microinjection of blocks and but not that by insulin or in with the IGF-I receptor in the basal state, and the of Gαi increased after IGF-I No association of Gαi with either the insulin receptor or EGF receptors was found in HIRcB cells that the IGF-I-induced association Gαi and IGF-IR with a from to and Gαi in was the same all and tyrosine phosphorylation has been shown for Gαi, or not phosphorylation was by IGF-I HIRcB cells were with IGF-I for by antibody or and with Gαi or IGF-I not to tyrosine phosphorylation of Gαi not Gβγ in the mitogenic effect of IGF-I, endogenous Gβ subunits with the IGF-I receptor. show association the IGF-IR and in to IGF-I decrease Gβ in was the same all The of receptor plays role in mitogenic signaling A.V. C. 1996; PubMed Scopus Google L.M. Daaka Y. Miller W.E. S. Rocca G.J. H. K. Luttrell D.K. M.G. Lefkowitz R.J. 1999; PubMed Scopus Google Scholar). it has been shown that β-arrestin-1 is for and IGF-IR J. M.G. Lefkowitz R.J. PubMed Scopus Google Scholar, S. S. Daniel K. M. M.G. Lefkowitz R.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, W.E. A.M. M.G. 1996; 271: PubMed Scopus Google Scholar, Daaka Y. Lefkowitz R.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), the that this protein was in the mitogenic effects by the receptors to We inhibited endogenous β-arrestin-1 function by microinjection of anti-β-arrestin-1 by of shown in microinjection of the β-arrestin-1 antibody cells inhibited in to IGF-I and but not to insulin or β-arrestin-1 can with IGF-I receptors in cells Daaka Y. Lefkowitz R.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar), endogenous of β-arrestin-1 with endogenous IGF-IRs in our shown in and in the basal state, β-arrestin-1 is associated with the and this association of IGF-I β-Arrestin-1 was also in and the of this association was to that for the IGF-IR and β-arrestin-1 also with the but the of association was and and that endogenous of and IGF-I the of Gαi, or β-arrestin-1 in the metabolic and mitogenic actions of insulin and glucose and GLUT4 shown in and not the effects of insulin on glucose or GLUT4 We also β-arrestin-1 was in this action of insulin anti-β-arrestin-1 antibody microinjection by insulin stimulation and for GLUT4 shown in inhibition of β-arrestin-1 function had no effect on GLUT4 T. Ishibashi S. Ugi S. Olefsky J.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), also show in this that microinjection not insulin-induced GLUT4 translocation our results show in 3T3L1 adipocytes, is no of a or β-arrestin-1 in insulin signaling leading to glucose and GLUT4 We also and MAP kinase activity in these same and these were in two kinase of a for cells by of with the same antibody to the of cells for MAP shown in and MAP kinase phosphorylation by IGF-I was by insulin MAP kinase phosphorylation was Gβγ subunits and β-arrestin-1 were in insulin or IGF-I signaling leading to MAP kinase and anti-β-arrestin-1 antibody and MAP kinase phosphorylation by of Microinjection of and anti-β-arrestin-1 antibody inhibited IGF-I-induced MAP kinase phosphorylation but not that by insulin These results indicate that in 3T3L1 adipocytes, IGF-I signaling leading to MAP kinase phosphorylation requires Gαi, and insulin-induced MAP kinase signaling These results also show that these and anti-β-arrestin-1 were IGF-I MAP kinase activation in these that the of effect on insulin metabolic actions was of the endogenous IGF-I receptors with the insulin receptors in HIRcB cells Y. C. Olefsky J.M. 1995; PubMed Scopus Google Scholar, T. M. T. H. Y. Imamura T. I. Olefsky J.M. M. 1996; PubMed Scopus Google Scholar), this may have our β-arrestin-1 or Gαi this in that endogenous of all these with the HIRcB Gαi and Gβ with the IGF-I receptor in the basal the of Gαi increased after of IGF-I the of Gβ No of with β-Arrestin-1 associated with receptors, and this was increased of ligand stimulation In have shown that the can with Gαq/11 protein and this G protein to glucose transport (9Imamura T. Vollenweider P. Egawa K. Clodi M. Ishibashi K. Nakashima N. Ugi S. Adams J.W. Brown J.H.B. Olefsky J.M. Mol. Cell. Biol. 1999; 19: 6765-6774Crossref PubMed Scopus (145) Google Scholar). In the no association of the IGF-IR with Gαq/11 not that and IGF-IRs specific G protein partners to mediate their biologic effects. The insulin and IGF-I receptors are heterotetrameric RTKs signaling share many of the same receptors can mitogenesis and metabolic insulin is metabolic and IGF-I is a (1Cheatman B. Khan C.R. Endocr. Rev. 1995; 16: 117-142PubMed Google R. Hongo A. Rubini M. Prisco M. Valentinis B. Biochim. Biophys. Acta. 1997; 1332: F105-F126Crossref PubMed Scopus (485) Google Scholar). the for these in mitogenic metabolic evidence has that some RTKs may also heterotrimeric G to the signaling events by heptahelical (9Imamura T. Vollenweider P. Egawa K. Clodi M. Ishibashi K. Nakashima N. Ugi S. Adams J.W. Brown J.H.B. Olefsky J.M. Mol. Cell. Biol. 1999; 19: 6765-6774Crossref PubMed Scopus (145) Google Scholar, 25Luttrell L.M. Van Biesen T. Hawes B.E. Koch W.J. Touhara K. Lefkowitz R.J. J. Biol. Chem. 1995; 270: 16495-16498Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). In the that insulin and IGF-I receptors in their to engage specific heterotrimeric G and that this in the these two receptors with to metabolic mitogenic signaling. show that the IGF-I receptor the of to heptahelical Thus, the mitogenic signaling effects of IGF-I are by treatment of cells with pertussis toxin and are also by microinjection of the Gβγ In inhibition of β-arrestin-1 also blocks IGF-I receptor signaling. that the IGF-I receptor with Gβγ subunits in a ligand-dependent manner. In contrast, no role for Gαi in insulin signaling was results with the IGF-I receptor are with the work of Luttrell (25Luttrell L.M. Van Biesen T. Hawes B.E. Koch W.J. Touhara K. Lefkowitz R.J. J. Biol. Chem. 1995; 270: 16495-16498Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar) and Daaka Y. Lefkowitz R.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, these have shown that MAP kinase activation is and and that IGF-I receptors with it is that the IGF-I receptor can Gαi and that this is for mitogenic signaling. Thus, from a of the IGF-I receptor as a Heptahelical receptors as the in the these two have been to to this of the IGF-I receptor is G it that receptors from two classes receptors and can be as For the role of β-arrestin-1 in signaling is well G protein-coupled receptor kinase phosphorylation of the β-arrestin-1 to the receptor. The receptor β-arrestin-1 a Src family tyrosine kinase to the receptor and this to activation of Src with downstream phosphorylation of Shc and MAP kinase activation R.J. J. Biol. Chem. 1998; 273: 18667-18680Abstract Full Text Full Text PDF Scopus (903) Google Scholar, 14Luttrell L.M. Daaka Y. Lefkowitz R.J. Curr. Opin. Cell Biol. 1999; 11: 177-183Crossref PubMed Scopus (603) Google L.M. Daaka Y. Miller W.E. S. Rocca G.J. H. K. Luttrell D.K. M.G. Lefkowitz R.J. 1999; PubMed Scopus Google Scholar, W.E. S. Ahn S. Khan Luttrell L.M. Lefkowitz R.J. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus (172) Google Scholar). In to Src kinase β-arrestin-1 heptahelical J. M.G. Lefkowitz R.J. PubMed Scopus Google Scholar, S. S. Daniel K. M. M.G. Lefkowitz R.J. J. Biol. Chem. Full Text PDF PubMed Google Scholar, W.E. A.M. M.G. 1996; 271: PubMed Scopus Google Scholar, J. P.H. S.A. M.G. J. Biol. Chem. 1999; Scholar), and Y. Luttrell L.M. Ahn S. Rocca G.J. M.G. Lefkowitz R.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) and Pierce K.L. S. Daaka Y. Luttrell L.M. Lefkowitz R.J. U. S. A. 2000; PubMed Scopus Google Scholar) have evidence that of these receptors is to the kinase signaling downstream of Thus, β-arrestin-1 mitogenic signaling in two the tyrosine kinase mediated signaling events that to activation and mediated signaling events that activation downstream of the IGF-I receptor is a tyrosine kinase, the role of β-arrestin-1 in IGF-I signaling is results of Gαi with β-arrestin-1 the that β-arrestin-1 may function as a protein Gαi to the IGF-I receptor It is that β-arrestin-1 may a to molecules to the IGF-I receptor may be in signaling it has been shown that β-arrestin-1 of and recent indicate that β-arrestin-1 IGF-I receptor Daaka Y. Lefkowitz R.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar) and that of the receptor is for MAP kinase activation and mitogenic signaling G. R.J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In this the inhibition of β-arrestin-1 by microinjection of anti-β-arrestin-1 mitogenic signaling by receptor results also show that of Gβγ subunits IGF-I signaling. For Gβγ subunits to G protein-coupled receptor in the of the the that to of Src and tyrosine kinase activation R.J. J. Biol. Chem. 1998; 273: 18667-18680Abstract Full Text Full Text PDF Scopus (903) Google Scholar, Biesen T. Hawes B.E. Luttrell D.K. Touhara K. E. M. Luttrell L.M. Lefkowitz R.J. Nature. 1995; PubMed Scopus Google Scholar). For IGF-I receptor the role of Gβγ subunits is It has been that Gβγ subunits can to of signaling molecules B.E. Luttrell L.M. van Biesen T. Lefkowitz R.J. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, H. Daaka Y. E. R. G. R. Miller R.J. Lefkowitz R.J. 1998; PubMed Scopus Google Scholar). Thus, is that in IGF-I signaling the Gβγ subunits with containing signaling molecules that from the IGF-I receptor to and to MAP We have also found evidence that the can as a Thus, the is associated with β-arrestin-1 in the basal after insulin a in association In to the IGF-I not evidence for Gαi in signaling. Thus, the actions of insulin were by treatment or microinjection of or β-arrestin-1 Furthermore, no Gαi was in that be some Gαi dependence of signaling because Luttrell (25Luttrell L.M. Van Biesen T. Hawes B.E. Koch W.J. Touhara K. Lefkowitz R.J. J. Biol. Chem. 1995; 270: 16495-16498Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar) of MAP kinase activity in this in results is because these of insulin, can the IGF-I receptor. Thus, it is that the was to inhibition of insulin MAP kinase through the IGF-I receptor. Although the not to be to Gαi in our have that GLUT4 translocation is dependent on Thus, found that Gαq/11 with the and tyrosine phosphorylation after insulin of Gαq/11 function blocks insulin glucose and Gαq/11 glucose transport and GLUT4 translocation in the of insulin (9Imamura T. Vollenweider P. Egawa K. Clodi M. Ishibashi K. Nakashima N. Ugi S. Adams J.W. Brown J.H.B. Olefsky J.M. Mol. Cell. Biol. 1999; 19: 6765-6774Crossref PubMed Scopus (145) Google Scholar). with the in the that the can as a but the IGF-I the G protein is In contrast, the IGF-I receptor not with Gαq/11 or this G protein in its signaling In our results suggest that the IGF-IR and can to G proteins to mediate biologic The IGF-IR the In contrast, the through the IGF-IR Gαi mitogenic Gαq/11 metabolic a for the that insulin is a metabolic IGF-I, IGF-I is a The insulin and IGF-I receptors are heterotetrameric RTKs that share a of of these receptors can specific G proteins and with Thus, the class of heptahelical receptors, these two RTKs can as the that a of RTKs may be G protein-coupled and that this is a as it is for the heptahelical In this these two classes of receptors engage a of downstream signaling components. We suggest that this be the case and that to the heptahelical receptors, the G proteins be receptor specific and We R. J. Lefkowitz for and for the of β-arrestin-1 We also for