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W2032847998 abstract "The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase (Peterson, J. E., Jelinek, T., Kaleko, M., Siddle, K., and Weber, M. J. (1994) J. Biol. Chem. 269, 27315-27321). The goal of the present study was to analyze the mechanistic basis and functional significance of the Src-induced phosphorylation and activation of the IGF-I receptor. 1) We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. The juxtamembrane and kinase-domain peptides were phosphorylated both in vivo and in vitro. The carboxyl-terminal site, although phosphorylated in vitro and in src-transformed cells, was not a major site of ligand-induced phosphorylation in vivo. 2) We determined that the sites of Src-induced phosphorylation of the IGF-I receptor are the same as the ligand-induced autophosphorylation sites and that the Src kinase can catalyze these phosphorylations directly. 3) We showed that cells cultured from mice in which the IGF-I receptor has been knocked out by homologous recombination are defective for morphological transformation by src. Thus, the Src kinase can substitute for the receptor kinase in phosphorylating and activating the IGF-I receptor, and this receptor phosphorylation and activation are essential for transformation by src. The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase (Peterson, J. E., Jelinek, T., Kaleko, M., Siddle, K., and Weber, M. J. (1994) J. Biol. Chem. 269, 27315-27321). The goal of the present study was to analyze the mechanistic basis and functional significance of the Src-induced phosphorylation and activation of the IGF-I receptor. 1) We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. The juxtamembrane and kinase-domain peptides were phosphorylated both in vivo and in vitro. The carboxyl-terminal site, although phosphorylated in vitro and in src-transformed cells, was not a major site of ligand-induced phosphorylation in vivo. 2) We determined that the sites of Src-induced phosphorylation of the IGF-I receptor are the same as the ligand-induced autophosphorylation sites and that the Src kinase can catalyze these phosphorylations directly. 3) We showed that cells cultured from mice in which the IGF-I receptor has been knocked out by homologous recombination are defective for morphological transformation by src. Thus, the Src kinase can substitute for the receptor kinase in phosphorylating and activating the IGF-I receptor, and this receptor phosphorylation and activation are essential for transformation by src. INTRODUCTIONInsulin and the insulin-like growth factor type I (IGF-I) 1The abbreviations used are: IGF-Iinsulin-like growth factor type I. are peptide hormones that regulate distinct biological functions through interaction with their cognate receptors (Drop et al., 12Drop S.L. Brinkman A. Kortleve D.J. Groffen C.H. Schuller A. Zwarthoff E.C. Spencer E.M. Modern Concepts of Insulin-like Growth Factors. Elsevier Science Publishing Co., Inc., New York1991: 311-328Google Scholar; Jacobs and Moxham, 21Jacobs S. Moxham C.P. Spencer E.M. Modern Concepts of Insulin-like Growth Factors. Elsevier Science Publishing Co., Inc., New York1991: 431-438Google Scholar; Soos et al., 49Soos M.A. Taylor C.E. Lammers R. Ullrich A. Siddle K. Spencer E.M. Modern Concepts of Insulin-like Growth Factors. Elsevier Science Publishing Co., Inc., New York1991: 461-472Google Scholar; Treadway et al., 62Treadway J.L. Morrison B.D. Frattali A.L. Pessin J.E. Spencer E.M. Modern Concepts of Insulin-Like Growth Factors. Elsevier Science Publishing Co., Inc., New York1991: 449-460Google Scholar; Adamo et al., 1Adamo M. Roberts Jr., C.T. LeRoith D. Biofactors. 1992; 3: 151-157PubMed Google Scholar; Pessin, 40Pessin J.E. Adv. Exp. Med. Biol. 1993; 343: 133-144Crossref PubMed Google Scholar; De Meyts, 1994; Faria et al., 14Faria T.N. Blakesley V.A. Kato H. Stannard B. LeRoith D. Roberts Jr., C.T. J. Biol. Chem. 1994; 269: 13922-13928Abstract Full Text PDF PubMed Google Scholar; LeRoith et al., 30LeRoith D. Sampson P.C. Roberts Jr., C.T. Horm. Res. 1994; 41 (Suppl 2): 74-79Crossref PubMed Scopus (32) Google Scholar; Soos et al., 50Soos M.A. Nave B.T. Siddle K. Adv. Exp. Med. Biol. 1993; 343: 145-157Crossref PubMed Google Scholar; Baserga et al., 1995). The normal function of insulin is primarily to regulate metabolism in liver, fat, and muscle, whereas IGF-I acts to regulate growth and differentiation. Recently, there has been considerable interest in the IGF-I receptor because of its ability to inhibit apoptosis (Harrington et al., 18Harrington E.A. Bennett M.R. Fanidi A. Evan G.I. EMBO J. 1994; 13: 3286-3295Crossref PubMed Scopus (732) Google Scholar, 19Harrington E.A. Fanidi A. Evan G.I. Curr. Opin. Genet. Dev. 1994; 4: 120-129Crossref PubMed Scopus (267) Google Scholar) and because of its central role in malignant transformation by various oncogenes (Baserga, 3Baserga R. Cancer Res. 1995; 55: 249-252PubMed Google Scholar).Normal activation of insulin family receptors occurs through ligand binding by the α-subunits, which results in activation of the receptor tyrosine kinase. Increased receptor phosphorylation on tyrosine occurs through intersubunit phosphorylation between the two β-subunits, and it is the phosphorylation of these tyrosines that regulates the activity of the receptor (Rosen et al., 45Rosen O.M. Herrera R. Olowe Y. Petruzzelli L.M. Cobb M.H. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 3237-3240Crossref PubMed Scopus (304) Google Scholar; Cobb et al., 5Cobb M.H. Sang B.-C. Gonzalez R. Goldsmith E. Ellis L. J. Biol. Chem. 1989; 264: 18701-18706Abstract Full Text PDF PubMed Google Scholar; Czech and Massague, 9Czech M.P. Massague J. Fed. Proc. 1982; 41: 2719-2723PubMed Google Scholar; Czech, 10Czech M.P. Cell. 1989; 59: 235-238Abstract Full Text PDF PubMed Scopus (348) Google Scholar; Mooney et al., 36Mooney R.A. Freund G.G. Way B.A. Bordwell K.L. J. Biol. Chem. 1992; 267: 23443-23446Abstract Full Text PDF PubMed Google Scholar; Begum et al., 4Begum N. Olefsky J.M. Draznin B. J. Biol. Chem. 1993; 268: 7917-7922Abstract Full Text PDF PubMed Google Scholar; Frattali and Pessin, 15Frattali A.L. Pessin J.E. J. Biol. Chem. 1993; 268: 7393-7400Abstract Full Text PDF PubMed Google Scholar; Lee et al., 29Lee J. O'Hare T. Pilch P.F. Shoelson S.E. J. Biol. Chem. 1993; 268: 4092-4098Abstract Full Text PDF PubMed Google Scholar; Pessin and Frattali, 41Pessin J.E. Frattali A.L. Mol. Reprod. Dev. 1993; 35: 339-345Crossref PubMed Scopus (19) Google Scholar; Hubbard et al., 20Hubbard S.R. Wei L. Ellis L. Hendrickson W.A. Nature. 1994; 372: 746-754Crossref PubMed Scopus (954) Google Scholar; Van Obberghen, 65Van Obberghen E. Diabetologia. 1994; 37 (Suppl 2): S125-S134Crossref PubMed Scopus (60) Google Scholar). Signaling via the insulin and IGF-I receptors requires both a functional tyrosine kinase and also the phosphorylation of conserved tyrosines within the β-subunit of the receptors.The sequence homology between the insulin and IGF-I receptor β-subunits is highest in the tyrosine kinase domain (85%), intermediate in the juxtamembrane region (61%), and lowest in their cytoplasmic tails (44%) (Ullrich et al., 64Ullrich A. Gray A. Tam A.W. Yang-Feng T. Tsubokawa M. Collins C. Henzel W. Le Bon T. Kathuria S. Chen E. Jacobs S. Francke U. Ramachandran J. Fujita-Yamaguchi Y. EMBO J. 1986; 5: 2503-2512Crossref PubMed Scopus (1495) Google Scholar). Ligand stimulation of the insulin receptor results in phosphorylation of tyrosines clustered in each of these three regions (Tornqvist et al., 59Tornqvist H.E. Pierce M.W. Frackelton A.R. Nemenoff R.A. Avruch J. J. Biol. Chem. 1987; 262: 10212-10219Abstract Full Text PDF PubMed Google Scholar; Tavaré and Denton, 57Tavaré J.M. Denton R.M. Biochem. J. 1988; 252: 607-615Crossref PubMed Scopus (63) Google Scholar; Tavaré et al., 56Tavaré J.M. O'Brien R.M. Siddle K. Denton R.M. Biochem. J. 1988; 253: 783-788Crossref PubMed Scopus (62) Google Scholar; Tornqvist and Avruch, 61Tornqvist H.E. Avruch J. J. Biol. Chem. 1988; 263: 4593-4601Abstract Full Text PDF PubMed Google Scholar; Tornqvist et al., 60Tornqvist H.E. Gunsalus J.R. Nemenoff R.A. Frackelton A.R. Pierce M.W. Avruch J. J. Biol. Chem. 1988; 263: 350-359Abstract Full Text PDF PubMed Google Scholar; White et al., 70White M.F. Livingston J.N. Backer J.M. Lauris V. Dull T.J. Ullrich A. Kahn C.R. Cell. 1988; 54: 641-649Abstract Full Text PDF PubMed Scopus (275) Google Scholar, 71White M.F. Shoelson S.E. Keutmann H. Kahn C.R. J. Biol. Chem. 1988; 263: 2969-2980Abstract Full Text PDF PubMed Google Scholar). Table I presents a comparison of the tyrosine-containing tryptic peptides derived from the β-subunits of the IGF-I and insulin receptors. The major sites of insulin receptor autophosphorylation are tyrosines 953 and 960 in the juxtamembrane region (Peptide I, Table I), tyrosines 1158, 1162, 1163 within the kinase domain (Peptide V, Table I), with additional phosphorylation on tyrosines 1316 and 1322 in the carboxyl terminus (Peptide X, Table I) (Tornqvist et al., 59Tornqvist H.E. Pierce M.W. Frackelton A.R. Nemenoff R.A. Avruch J. J. Biol. Chem. 1987; 262: 10212-10219Abstract Full Text PDF PubMed Google Scholar; Tavaré and Denton, 57Tavaré J.M. Denton R.M. Biochem. J. 1988; 252: 607-615Crossref PubMed Scopus (63) Google Scholar; Tavaré et al., 56Tavaré J.M. O'Brien R.M. Siddle K. Denton R.M. Biochem. J. 1988; 253: 783-788Crossref PubMed Scopus (62) Google Scholar; Tornqvist and Avruch, 61Tornqvist H.E. Avruch J. J. Biol. Chem. 1988; 263: 4593-4601Abstract Full Text PDF PubMed Google Scholar; Tornqvist et al., 60Tornqvist H.E. Gunsalus J.R. Nemenoff R.A. Frackelton A.R. Pierce M.W. Avruch J. J. Biol. Chem. 1988; 263: 350-359Abstract Full Text PDF PubMed Google Scholar; White et al., 70White M.F. Livingston J.N. Backer J.M. Lauris V. Dull T.J. Ullrich A. Kahn C.R. Cell. 1988; 54: 641-649Abstract Full Text PDF PubMed Scopus (275) Google Scholar, 71White M.F. Shoelson S.E. Keutmann H. Kahn C.R. J. Biol. Chem. 1988; 263: 2969-2980Abstract Full Text PDF PubMed Google Scholar). Interestingly, nearly all of the insulin receptor tyrosine phosphorylation sites important for signaling are conserved within the IGF-I receptor. This includes both tyrosines located in the juxtamembrane domain, the triplet of tyrosines in the kinase domain, and (although with less conservation of contextual sequence) one of the two tyrosines in the cytoplasmic domain. However, in spite of the central importance of the IGF-I receptor in growth and malignant transformation, no work prior to what is reported here has directly determined whether these conserved tyrosines in fact represent the major sites of IGF-I receptor phosphorylation on tyrosine.Table IComparison of the tyrosine-containing tryptic peptides from the β-subunits of the IGF-I receptor (top) and the insulin receptor, (bottom)Peptide no.Pro-receptor residue no.Amino acid sequence of tryptic peptides from the intracellular β-subunit of the IGF-I (top) and insulin (bottom) receptorsTyrosine at residue no. from peptide amino terminusI937–966LGNGVLYASVNPEYFSAAD—–VYVPDEWEVAR7, 14, 21944–981QPDGPL.P….S….L..S.vfpcs………S.10, 17, 29II974–989ELGQGSFGMVYEGVAK11989–1004………….N.R11III1059–1062SYLR21074–1077….2IV1082–1100MIQMAGEIADGMAYLNANK141090–1114P..T.QE…..A………..K21V1129–1137DIYETDYYR3, 7, 81144–1152………3, 7, 8VI1156–1193DGVFTTYSDVWSFGVVLWEIATLAEQPYQGLSNEQVLR7, 281171–1208……S..M……….TS……………K28VII1193–1209FVMEGGLLDKPDNCPDM01209–1225…D..Y..Q…..ER7VIII1217–1224MCWQYNPK51232–1239….F..N0IX1246–1256EVSFYYSEENK5, 61261–1271….FH…..0X1314–1323QPYAHMNGGR31315–1329.YE.HI..T…..K2, 8 Open table in a new tab It is well documented that phosphorylation on tyrosine is important for insulin and IGF-I receptor activation. Therefore, it is conceivable that a heterologous kinase capable of phosphorylating these tyrosines would also be capable of activating the receptor. Although IGF-I receptor activation normally requires the presence of IGF-I, there is some precedent for IGF-I receptor activation without its cognate ligand. For example, the insulin receptor can induce signaling by the IGF-I receptor through the formation of heterotetramers made up of one insulin receptor αβ dimer and one IGF-I receptor αβ dimer. Insulin binding to the insulin receptor leads to activation of the β-subunit of the IGF-I receptor through intersubunit phosphorylation within the hybrid receptor heterotetramer (McClain et al., 34McClain D.A. Maegawa H. Thies R.S. Olefsky J.M. J. Biol. Chem. 1990; 265: 1678-1682Abstract Full Text PDF PubMed Google Scholar; Janicot et al., 22Janicot M. Flores-Riveros J.R. Lane M.D. J. Biol. Chem. 1991; 266: 9382-9391Abstract Full Text PDF PubMed Google Scholar; Treadway et al., 63Treadway J.L. Morrison B.D. Soos M.A. Siddle K. Olefsky J. Ullrich A. McClain D.A. Pessin J.E. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 214-218Crossref PubMed Scopus (79) Google Scholar; Frattali and Pessin, 15Frattali A.L. Pessin J.E. J. Biol. Chem. 1993; 268: 7393-7400Abstract Full Text PDF PubMed Google Scholar; Takata and Kobayashi, 53Takata Y. Kobayashi M. Diabete Metab. 1994; 20: 31-36PubMed Google Scholar). Thrombin, perhaps via activation of pp60c−src, causes rapid tyrosine phosphorylation of the IGF-I receptor (Rao et al., 44Rao G.N. Delafontaine P. Runge M.S. J. Biol. Chem. 1995; 270: 27871-27875Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Previous reports from this laboratory have shown that the transforming non-receptor tyrosine kinase Src induces the phosphorylation of the IGF-I receptor in vivo (Kozma and Weber, 28Kozma L.M. Weber M.J. Mol. Cell. Biol. 1990; 10: 3626-3634Crossref PubMed Scopus (44) Google Scholar; Kozma et al., 27Kozma L.M. Reynolds A.B. Weber M.J. Mol. Cell. Biol. 1990; 10: 837-841Crossref PubMed Scopus (12) Google Scholar, Peterson et al., 42Peterson J.E. Jelinek T. Kaleko M. Siddle K. Weber M.J. J. Biol. Chem. 1994; 269: 27315-27321Abstract Full Text PDF PubMed Google Scholar). Src-induced phosphorylation of the receptor was correlated with an increase in the in vitro tyrosine kinase activity of the receptor, both toward itself and exogenous substrates (Peterson et al., 42Peterson J.E. Jelinek T. Kaleko M. Siddle K. Weber M.J. J. Biol. Chem. 1994; 269: 27315-27321Abstract Full Text PDF PubMed Google Scholar). The Src-induced increase in receptor activity was shown to be dependent on tyrosine phosphorylation, as treatment with a tyrosine-specific phosphatase lowered receptor activity (Peterson et al., 42Peterson J.E. Jelinek T. Kaleko M. Siddle K. Weber M.J. J. Biol. Chem. 1994; 269: 27315-27321Abstract Full Text PDF PubMed Google Scholar).We hypothesized that the Src-induced phosphorylation of the IGF-I receptor might be functionally important for transformation, because phosphorylation of the IGF-I receptor was one of only a few phosphorylations out of 30 analyzed that correlated with phenotypic transformation in cells infected with a panel of partially transforming src mutants (Kozma and Weber, 28Kozma L.M. Weber M.J. Mol. Cell. Biol. 1990; 10: 3626-3634Crossref PubMed Scopus (44) Google Scholar; Kozma et al., 27Kozma L.M. Reynolds A.B. Weber M.J. Mol. Cell. Biol. 1990; 10: 837-841Crossref PubMed Scopus (12) Google Scholar).In the present study, we identify the sites of IGF-I receptor tyrosine phosphorylation in response to ligand stimulation in vivo and in vitro and show that they are homologous to regulatory sites in the insulin receptor. We also show that in vivo and in vitro, Src is capable of phosphorylating the same sites observed upon ligand-induced autophosphorylation and that this is likely due to direct phosphorylation by the Src kinase. Finally, we show that cells cultured from mice in which the IGF-I receptor has been knocked out by homologous recombination (Liu et al., 33Liu D. Zong C.S. Wang L.H. J. Virol. 1993; 67: 6835-6840Crossref PubMed Google Scholar; Sell et al., 47Sell C. Baserga R. Rubin R. Cancer Res. 1995; 55: 303-306PubMed Google Scholar) are defective for transformation by src. Taken together, these data indicate that intracellular, ligand-independent phosphorylation and activation of the IGF-I receptor by the Src kinase occurs by a mechanism similar to ligand-induced autophosphorylation and that this interaction between Src and the IGF-I receptor is essential for transformation by this oncogene. INTRODUCTIONInsulin and the insulin-like growth factor type I (IGF-I) 1The abbreviations used are: IGF-Iinsulin-like growth factor type I. are peptide hormones that regulate distinct biological functions through interaction with their cognate receptors (Drop et al., 12Drop S.L. Brinkman A. Kortleve D.J. Groffen C.H. Schuller A. Zwarthoff E.C. Spencer E.M. Modern Concepts of Insulin-like Growth Factors. Elsevier Science Publishing Co., Inc., New York1991: 311-328Google Scholar; Jacobs and Moxham, 21Jacobs S. Moxham C.P. Spencer E.M. Modern Concepts of Insulin-like Growth Factors. Elsevier Science Publishing Co., Inc., New York1991: 431-438Google Scholar; Soos et al., 49Soos M.A. Taylor C.E. Lammers R. Ullrich A. Siddle K. Spencer E.M. Modern Concepts of Insulin-like Growth Factors. Elsevier Science Publishing Co., Inc., New York1991: 461-472Google Scholar; Treadway et al., 62Treadway J.L. Morrison B.D. Frattali A.L. Pessin J.E. Spencer E.M. Modern Concepts of Insulin-Like Growth Factors. Elsevier Science Publishing Co., Inc., New York1991: 449-460Google Scholar; Adamo et al., 1Adamo M. Roberts Jr., C.T. LeRoith D. Biofactors. 1992; 3: 151-157PubMed Google Scholar; Pessin, 40Pessin J.E. Adv. Exp. Med. Biol. 1993; 343: 133-144Crossref PubMed Google Scholar; De Meyts, 1994; Faria et al., 14Faria T.N. Blakesley V.A. Kato H. Stannard B. LeRoith D. Roberts Jr., C.T. J. Biol. Chem. 1994; 269: 13922-13928Abstract Full Text PDF PubMed Google Scholar; LeRoith et al., 30LeRoith D. Sampson P.C. Roberts Jr., C.T. Horm. Res. 1994; 41 (Suppl 2): 74-79Crossref PubMed Scopus (32) Google Scholar; Soos et al., 50Soos M.A. Nave B.T. Siddle K. Adv. Exp. Med. Biol. 1993; 343: 145-157Crossref PubMed Google Scholar; Baserga et al., 1995). The normal function of insulin is primarily to regulate metabolism in liver, fat, and muscle, whereas IGF-I acts to regulate growth and differentiation. Recently, there has been considerable interest in the IGF-I receptor because of its ability to inhibit apoptosis (Harrington et al., 18Harrington E.A. Bennett M.R. Fanidi A. Evan G.I. EMBO J. 1994; 13: 3286-3295Crossref PubMed Scopus (732) Google Scholar, 19Harrington E.A. Fanidi A. Evan G.I. Curr. Opin. Genet. Dev. 1994; 4: 120-129Crossref PubMed Scopus (267) Google Scholar) and because of its central role in malignant transformation by various oncogenes (Baserga, 3Baserga R. Cancer Res. 1995; 55: 249-252PubMed Google Scholar).Normal activation of insulin family receptors occurs through ligand binding by the α-subunits, which results in activation of the receptor tyrosine kinase. Increased receptor phosphorylation on tyrosine occurs through intersubunit phosphorylation between the two β-subunits, and it is the phosphorylation of these tyrosines that regulates the activity of the receptor (Rosen et al., 45Rosen O.M. Herrera R. Olowe Y. Petruzzelli L.M. Cobb M.H. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 3237-3240Crossref PubMed Scopus (304) Google Scholar; Cobb et al., 5Cobb M.H. Sang B.-C. Gonzalez R. Goldsmith E. Ellis L. J. Biol. Chem. 1989; 264: 18701-18706Abstract Full Text PDF PubMed Google Scholar; Czech and Massague, 9Czech M.P. Massague J. Fed. Proc. 1982; 41: 2719-2723PubMed Google Scholar; Czech, 10Czech M.P. Cell. 1989; 59: 235-238Abstract Full Text PDF PubMed Scopus (348) Google Scholar; Mooney et al., 36Mooney R.A. Freund G.G. Way B.A. Bordwell K.L. J. Biol. Chem. 1992; 267: 23443-23446Abstract Full Text PDF PubMed Google Scholar; Begum et al., 4Begum N. Olefsky J.M. Draznin B. J. Biol. Chem. 1993; 268: 7917-7922Abstract Full Text PDF PubMed Google Scholar; Frattali and Pessin, 15Frattali A.L. Pessin J.E. J. Biol. Chem. 1993; 268: 7393-7400Abstract Full Text PDF PubMed Google Scholar; Lee et al., 29Lee J. O'Hare T. Pilch P.F. Shoelson S.E. J. Biol. Chem. 1993; 268: 4092-4098Abstract Full Text PDF PubMed Google Scholar; Pessin and Frattali, 41Pessin J.E. Frattali A.L. Mol. Reprod. Dev. 1993; 35: 339-345Crossref PubMed Scopus (19) Google Scholar; Hubbard et al., 20Hubbard S.R. Wei L. Ellis L. Hendrickson W.A. Nature. 1994; 372: 746-754Crossref PubMed Scopus (954) Google Scholar; Van Obberghen, 65Van Obberghen E. Diabetologia. 1994; 37 (Suppl 2): S125-S134Crossref PubMed Scopus (60) Google Scholar). Signaling via the insulin and IGF-I receptors requires both a functional tyrosine kinase and also the phosphorylation of conserved tyrosines within the β-subunit of the receptors.The sequence homology between the insulin and IGF-I receptor β-subunits is highest in the tyrosine kinase domain (85%), intermediate in the juxtamembrane region (61%), and lowest in their cytoplasmic tails (44%) (Ullrich et al., 64Ullrich A. Gray A. Tam A.W. Yang-Feng T. Tsubokawa M. Collins C. Henzel W. Le Bon T. Kathuria S. Chen E. Jacobs S. Francke U. Ramachandran J. Fujita-Yamaguchi Y. EMBO J. 1986; 5: 2503-2512Crossref PubMed Scopus (1495) Google Scholar). Ligand stimulation of the insulin receptor results in phosphorylation of tyrosines clustered in each of these three regions (Tornqvist et al., 59Tornqvist H.E. Pierce M.W. Frackelton A.R. Nemenoff R.A. Avruch J. J. Biol. Chem. 1987; 262: 10212-10219Abstract Full Text PDF PubMed Google Scholar; Tavaré and Denton, 57Tavaré J.M. Denton R.M. Biochem. J. 1988; 252: 607-615Crossref PubMed Scopus (63) Google Scholar; Tavaré et al., 56Tavaré J.M. O'Brien R.M. Siddle K. Denton R.M. Biochem. J. 1988; 253: 783-788Crossref PubMed Scopus (62) Google Scholar; Tornqvist and Avruch, 61Tornqvist H.E. Avruch J. J. Biol. Chem. 1988; 263: 4593-4601Abstract Full Text PDF PubMed Google Scholar; Tornqvist et al., 60Tornqvist H.E. Gunsalus J.R. Nemenoff R.A. Frackelton A.R. Pierce M.W. Avruch J. J. Biol. Chem. 1988; 263: 350-359Abstract Full Text PDF PubMed Google Scholar; White et al., 70White M.F. Livingston J.N. Backer J.M. Lauris V. Dull T.J. Ullrich A. Kahn C.R. Cell. 1988; 54: 641-649Abstract Full Text PDF PubMed Scopus (275) Google Scholar, 71White M.F. Shoelson S.E. Keutmann H. Kahn C.R. J. Biol. Chem. 1988; 263: 2969-2980Abstract Full Text PDF PubMed Google Scholar). Table I presents a comparison of the tyrosine-containing tryptic peptides derived from the β-subunits of the IGF-I and insulin receptors. The major sites of insulin receptor autophosphorylation are tyrosines 953 and 960 in the juxtamembrane region (Peptide I, Table I), tyrosines 1158, 1162, 1163 within the kinase domain (Peptide V, Table I), with additional phosphorylation on tyrosines 1316 and 1322 in the carboxyl terminus (Peptide X, Table I) (Tornqvist et al., 59Tornqvist H.E. Pierce M.W. Frackelton A.R. Nemenoff R.A. Avruch J. J. Biol. Chem. 1987; 262: 10212-10219Abstract Full Text PDF PubMed Google Scholar; Tavaré and Denton, 57Tavaré J.M. Denton R.M. Biochem. J. 1988; 252: 607-615Crossref PubMed Scopus (63) Google Scholar; Tavaré et al., 56Tavaré J.M. O'Brien R.M. Siddle K. Denton R.M. Biochem. J. 1988; 253: 783-788Crossref PubMed Scopus (62) Google Scholar; Tornqvist and Avruch, 61Tornqvist H.E. Avruch J. J. Biol. Chem. 1988; 263: 4593-4601Abstract Full Text PDF PubMed Google Scholar; Tornqvist et al., 60Tornqvist H.E. Gunsalus J.R. Nemenoff R.A. Frackelton A.R. Pierce M.W. Avruch J. J. Biol. Chem. 1988; 263: 350-359Abstract Full Text PDF PubMed Google Scholar; White et al., 70White M.F. Livingston J.N. Backer J.M. Lauris V. Dull T.J. Ullrich A. Kahn C.R. Cell. 1988; 54: 641-649Abstract Full Text PDF PubMed Scopus (275) Google Scholar, 71White M.F. Shoelson S.E. Keutmann H. Kahn C.R. J. Biol. Chem. 1988; 263: 2969-2980Abstract Full Text PDF PubMed Google Scholar). Interestingly, nearly all of the insulin receptor tyrosine phosphorylation sites important for signaling are conserved within the IGF-I receptor. This includes both tyrosines located in the juxtamembrane domain, the triplet of tyrosines in the kinase domain, and (although with less conservation of contextual sequence) one of the two tyrosines in the cytoplasmic domain. However, in spite of the central importance of the IGF-I receptor in growth and malignant transformation, no work prior to what is reported here has directly determined whether these conserved tyrosines in fact represent the major sites of IGF-I receptor phosphorylation on tyrosine.Table IComparison of the tyrosine-containing tryptic peptides from the β-subunits of the IGF-I receptor (top) and the insulin receptor, (bottom)Peptide no.Pro-receptor residue no.Amino acid sequence of tryptic peptides from the intracellular β-subunit of the IGF-I (top) and insulin (bottom) receptorsTyrosine at residue no. from peptide amino terminusI937–966LGNGVLYASVNPEYFSAAD—–VYVPDEWEVAR7, 14, 21944–981QPDGPL.P….S….L..S.vfpcs………S.10, 17, 29II974–989ELGQGSFGMVYEGVAK11989–1004………….N.R11III1059–1062SYLR21074–1077….2IV1082–1100MIQMAGEIADGMAYLNANK141090–1114P..T.QE…..A………..K21V1129–1137DIYETDYYR3, 7, 81144–1152………3, 7, 8VI1156–1193DGVFTTYSDVWSFGVVLWEIATLAEQPYQGLSNEQVLR7, 281171–1208……S..M……….TS……………K28VII1193–1209FVMEGGLLDKPDNCPDM01209–1225…D..Y..Q…..ER7VIII1217–1224MCWQYNPK51232–1239….F..N0IX1246–1256EVSFYYSEENK5, 61261–1271….FH…..0X1314–1323QPYAHMNGGR31315–1329.YE.HI..T…..K2, 8 Open table in a new tab It is well documented that phosphorylation on tyrosine is important for insulin and IGF-I receptor activation. Therefore, it is conceivable that a heterologous kinase capable of phosphorylating these tyrosines would also be capable of activating the receptor. Although IGF-I receptor activation normally requires the presence of IGF-I, there is some precedent for IGF-I receptor activation without its cognate ligand. For example, the insulin receptor can induce signaling by the IGF-I receptor through the formation of heterotetramers made up of one insulin receptor αβ dimer and one IGF-I receptor αβ dimer. Insulin binding to the insulin receptor leads to activation of the β-subunit of the IGF-I receptor through intersubunit phosphorylation within the hybrid receptor heterotetramer (McClain et al., 34McClain D.A. Maegawa H. Thies R.S. Olefsky J.M. J. Biol. Chem. 1990; 265: 1678-1682Abstract Full Text PDF PubMed Google Scholar; Janicot et al., 22Janicot M. Flores-Riveros J.R. Lane M.D. J. Biol. Chem. 1991; 266: 9382-9391Abstract Full Text PDF PubMed Google Scholar; Treadway et al., 63Treadway J.L. Morrison B.D. Soos M.A. Siddle K. Olefsky J. Ullrich A. McClain D.A. Pessin J.E. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 214-218Crossref PubMed Scopus (79) Google Scholar; Frattali and Pessin, 15Frattali A.L. Pessin J.E. J. Biol. Chem. 1993; 268: 7393-7400Abstract Full Text PDF PubMed Google Scholar; Takata and Kobayashi, 53Takata Y. Kobayashi M. Diabete Metab. 1994; 20: 31-36PubMed Google Scholar). Thrombin, perhaps via activation of pp60c−src, causes rapid tyrosine phosphorylation of the IGF-I receptor (Rao et al., 44Rao G.N. Delafontaine P. Runge M.S. J. Biol. Chem. 1995; 270: 27871-27875Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Previous reports from this laboratory have shown that the transforming non-receptor tyrosine kinase Src induces the phosphorylation of the IGF-I receptor in vivo (Kozma and Weber, 28Kozma L.M. Weber M.J. Mol. Cell. Biol. 1990; 10: 3626-3634Crossref PubMed Scopus (44) Google Scholar; Kozma et al., 27Kozma L.M. Reynolds A.B. Weber M.J. Mol. Cell. Biol. 1990; 10: 837-841Crossref PubMed Scopus (12) Google Scholar, Peterson et al., 42Peterson J.E. Jelinek T. Kaleko M. Siddle K. Weber M.J. J. Biol. Chem. 1994; 269: 27315-27321Abstract Full Text PDF PubMed Google Scholar). Src-induced phosphorylation of the receptor was correlated with an increase in the in vitro tyrosine kinase activity of the receptor, both toward itself and exogenous substrates (Peterson et al., 42Peterson J.E. Jelinek T. Kaleko M. Siddle K. Weber M.J. J. Biol. Chem. 1994; 269: 27315-27321Abstract Full Text PDF PubMed Google Scholar). The Src-induced increase in receptor activity was shown to be dependent on tyrosine phosphorylation, as treatment with a tyrosine-specific phosphatase lowered receptor activity (Peterson et al., 42Peterson J.E. Jelinek T. Kaleko M. Siddle K. Weber M.J. J. Biol. Chem. 1994; 269: 27315-27321Abstract Full Text PDF PubMed Google Scholar).We hypothesized that the Src-induced phosphorylation of the IGF-I receptor might be functionally important for transformation, because phosphorylation of the IGF-I receptor was one of only a few phosphorylations out of 30 analyzed that correlated with phenotypic transformation in cells infected with a panel of partially transforming src mutants (Kozma and Weber, 28Kozma L.M. Weber M.J. Mol. Cell. Biol. 1990; 10: 3626-3634Crossref PubMed Scopus (44) Google Scholar; Kozma et al., 27Kozma L.M. Reynolds A.B. Weber M.J. Mol. Cell. Biol. 1990; 10: 837-841Crossref PubMed Scopus (12) Google Scholar).In the present study, we identify the sites of IGF-I receptor tyrosine phosphorylation in response to ligand stimulation in vivo and in vitro and show that they are homologous to regulatory sites in the insulin receptor. We also show that in vivo and in vitro, Src is capable of phosphorylating the same sites observed upon ligand-induced autophosphorylation and that this is likely due to direct phosphorylation by the Src kinase. Finally, we show that cells cultured from mice in which the IGF-I receptor has been knocked out by homologous recombination (Liu et al., 33Liu D. Zong C.S. Wang L.H. J. Virol. 1993; 67: 6835-6840Crossref PubMed Google Scholar; Sell et al., 47Sell C. Baserga R. Rubin R. Cancer Res. 1995; 55: 303-306PubMed Google Scholar) are defective for transformation by src. Taken together, these data indicate that intracellular, ligand-independent phosphorylation and activation of the IGF-I receptor by the Src kinase occurs by a mechanism similar to ligand-induced autophosphorylation and that this interaction between Src and the IGF-I receptor is essential for transformation by this oncogene." @default.
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W2032847998 title "Src Phosphorylates the Insulin-like Growth Factor Type I Receptor on the Autophosphorylation Sites" @default.
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W2032847998 doi "https://doi.org/10.1074/jbc.271.49.31562" @default.
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