Key points are not available for this paper at this time.
Activation of insulin-like growth factor I receptor (IGF-IR) kinase is an important site of control of IGF-I-linked intracellular signaling pathways. One potentially important regulatory variable is IGF-IR dephosphorylation. It has been shown that SHP-2, a tyrosine phosphatase, can bind to the activated IGF-IR in vitro; however, its role in IGF-IR dephosphorylation in whole cells is unknown. These studies were undertaken to determine whether SHP-2 was a candidate for mediating IGF-IR dephosphorylation. The IGF-IR in smooth muscle cells was dephosphorylated rapidly beginning 10 min after ligand addition, and this was temporally associated with SHP-2 binding to the receptor. IGF-I stimulated SHPS-1 phosphorylation and the subsequent recruitment of SHP-2. In cells expressing a SHPS-1 mutant that did not bind SHP-2 there was no recruitment of SHP-2 to the IGF-IR. Cells expressing a catalytically inactive form of SHP-2 showed SHP-2 recruitment to SHPS-1, but this did not result in SHPS-1 dephosphorylation, and there was a prolonged IGF-IR phosphorylation response after IGF-I stimulation. These studies indicate that IGF-IR stimulates phosphorylation of SHPS-1 which is critical for SHP-2 recruitment to the plasma membrane and for its recruitment to the IGF-IR. Recruitment of SHP-2 to the receptor then results in receptor dephosphorylation. The regulation of this process may be an important determinant of IGF-IR-mediated signaling. Activation of insulin-like growth factor I receptor (IGF-IR) kinase is an important site of control of IGF-I-linked intracellular signaling pathways. One potentially important regulatory variable is IGF-IR dephosphorylation. It has been shown that SHP-2, a tyrosine phosphatase, can bind to the activated IGF-IR in vitro; however, its role in IGF-IR dephosphorylation in whole cells is unknown. These studies were undertaken to determine whether SHP-2 was a candidate for mediating IGF-IR dephosphorylation. The IGF-IR in smooth muscle cells was dephosphorylated rapidly beginning 10 min after ligand addition, and this was temporally associated with SHP-2 binding to the receptor. IGF-I stimulated SHPS-1 phosphorylation and the subsequent recruitment of SHP-2. In cells expressing a SHPS-1 mutant that did not bind SHP-2 there was no recruitment of SHP-2 to the IGF-IR. Cells expressing a catalytically inactive form of SHP-2 showed SHP-2 recruitment to SHPS-1, but this did not result in SHPS-1 dephosphorylation, and there was a prolonged IGF-IR phosphorylation response after IGF-I stimulation. These studies indicate that IGF-IR stimulates phosphorylation of SHPS-1 which is critical for SHP-2 recruitment to the plasma membrane and for its recruitment to the IGF-IR. Recruitment of SHP-2 to the receptor then results in receptor dephosphorylation. The regulation of this process may be an important determinant of IGF-IR-mediated signaling. insulin-like growth factor I insulin-like growth factor I receptor insulin receptor substrate 1 growth hormone porcine smooth muscle cell(s) full-length and truncated SHPS-1, respectively serum free medium The insulin-like growth factor I (IGF-I)1 receptor (IGF-IR) is composed of two extracellular subunits and two transmembrane β subunits. Upon ligand binding, the kinase domain of the receptor autophosphorylates several tyrosine residues that are located in the intracellular domains of the β subunits (1Kato H. Faria T.N. Stannard B. Roberts Jr., C.T. LeRoith D. J. Biol. Chem. 1993; 268: 2655-2661Abstract Full Text PDF PubMed Google Scholar, 2Kato H. Faria T.N. Stannard B. Roberts Jr., C.T. LeRoith D. Mol. Endocrinol. 1994; 8: 40-50Crossref PubMed Scopus (109) Google Scholar, 3Gronberg M. Wulf B.S. Rasmussen J.S. Kjeldsen T. Gammelloft S. J. Biol. Chem. 1993; 268: 23435-23440Abstract Full Text PDF PubMed Google Scholar). This provides binding sites for other molecules, including insulin receptor substrate 1 (IRS-1) and SHC (4Caparo A. O'Neill T.J. Gustafson T.A. J. Biol. Chem. 1995; 270: 15639-15643Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 5Dey B.R. Frick K. Lopaczynski W. Nissley S.P. Furlanetto R.W. Mol. Endocrinol. 1996; 10: 631-641Crossref PubMed Scopus (102) Google Scholar), and the activated IGF-IR transmits downstream signals via tyrosine phosphorylation of these molecules. Activation of these tyrosines is not only critical for the downstream signaling, but also for sustained stimulation of IGF-I-stimulated biologic responses. Mutation of specific tyrosines in the receptor has been shown to result in attenuation of the ability of IGF-I to stimulate DNA synthesis, cell migration, and inhibition of apoptosis (6Baserga R. Cancer Res. 1995; 55: 249-252PubMed Google Scholar). Most important is the triple tyrosine motif that is phosphorylated rapidly in response to catalytic activation of the receptor, and mutation of any of these residues results in loss of signaling and IGF-I responsiveness (7Blakesley V.A. Scrimgeour A. Esposito D. LeRoith D. Cytokine Growth Factor Rev. 1996; 7: 153-159Crossref PubMed Scopus (156) Google Scholar). The tyrosine phosphorylation status of proteins in growth factor signaling pathways is maintained by a balance between the activity of tyrosine kinases and tyrosine phosphatases. Because phosphorylation of these tyrosines in the receptor β subunit is so important for IGF-I signaling it has been assumed that dephosphorylation of the receptor would result in appropriate regulatory control of this signaling stimulus. The time course of phosphorylation of tyrosine kinase-containing growth factor receptors has been shown to be biphasic with an early peak resulting in activation of the signaling intermediates within 0–10 min of ligand occupancy of the receptor followed by a slower phase of receptor dephosphorylation usually proceeding over the next 10–30 min. One candidate phosphatase for dephosphorylation of the IGF-IR is the tyrosine phosphatase SHP-2 (Syp, PTP-1D, SHPTP2). SHP-2 is a nontransmembrane phosphotyrosine phosphatase that contains two SH-2 domains (8Freeman Jr., R.M. Pltuzky J. Neel B.G. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11239-11243Crossref PubMed Scopus (327) Google Scholar, 9Ahmad S. Banville D. Zhao Z. Fischer E.H. Shen S.H. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 2197-2201Crossref PubMed Scopus (196) Google Scholar). It has been shown to bind to a number of growth factor receptors including the IGF-IR (10Rocchi S. Tartare-Deckert S. Sawka-Verhelte D. Gamha A. Van Obberghen E. Endocrinology. 1996; 137: 4944-4952Crossref PubMed Scopus (0) Google Scholar,11Seely B.L. Reichart D.R. Staubs P.A. Jhun B.H. Hsu D. Maegawa H. Milarski K.L. Saltiel A.R. Olefsky J.M. J. Biol. Chem. 1995; 270: 19151-19157Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), the insulin receptor (10Rocchi S. Tartare-Deckert S. Sawka-Verhelte D. Gamha A. Van Obberghen E. Endocrinology. 1996; 137: 4944-4952Crossref PubMed Scopus (0) Google Scholar), and also to IRS-1 (12Sun X.J. Crimmins D.L. Myers Jr., M.G. Miralpeix M. White M.F. Mol. Cell. Biol. 1993; 13: 7418-7428Crossref PubMed Google Scholar, 13Kuhne M.R. Pawson T. Lienhard G.E. Feng G.S. J. Biol. Chem. 1993; 268: 11479-11481Abstract Full Text PDF PubMed Google Scholar); however, whether it dephosphorylates the IGF-IR in whole cells has not been determined. Growth hormone (GH) activation of GH receptor has been shown to result in binding of SHP-2 to the GH receptor and tyrosine phosphorylation of SHP-2 (14Stofega M.R. Wang H. Ullrich A. Carter-Su C. J. Biol. Chem. 1998; 273: 7112-7117Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 15Kim S.O. Jiang J. Yi W. Feng G.S. Frank S.J. J. Biol. Chem. 1998; 273: 2344-2354Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 16Stofega M.R. Herrington J. Billestrup N. Carter-Su C. Mol. Endocrinol. 2000; 14: 1338-1350Crossref PubMed Google Scholar). Mutation of tyrosine 595, which is required for SHP-2 binding, results in prolonged GH receptor phosphorylation, suggesting that SHP-2 activation contributes to dephosphorylation of the GH receptor and GH receptor-mediated signaling (16Stofega M.R. Herrington J. Billestrup N. Carter-Su C. Mol. Endocrinol. 2000; 14: 1338-1350Crossref PubMed Google Scholar). In addition to binding and interacting with SHP-2, activated GH, insulin, and growth factor receptors have also been shown to stimulate the phosphorylation of a transmembrane protein termed SHPS-1 (Sirp α, Bit) (14Stofega M.R. Wang H. Ullrich A. Carter-Su C. J. Biol. Chem. 1998; 273: 7112-7117Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 17Tsuda M. Matozaki T. Fukanaga K. Fujioka Y. Imamoto A. Noguchi T. Takada T. Yamao T. Takeda H. Ochi F. Yamamoto T. Kasuga M. J. Biol. Chem. 1998; 273: 13223-13229Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 18Fujioka Y. Matozaki T. Noguchi T. Iwamatsu A. Yamao T. Nobuaki T. Tsuda M. Takada T. Kasuga M. Mol. Cell. Biol. 1996; 16: 6887-6899Crossref PubMed Scopus (382) Google Scholar, 19Kharitonenkov A. Chen Z. Sures I. Wang H. Schilling J. Ullrich A. Nature. 1997; 386: 181-186Crossref PubMed Scopus (540) Google Scholar, 20Noguchi T. Matozaki T. Fujioka Y. Yamao T. Tsuda M. Takada T. Kasuga M. J. Biol. Chem. 1996; 271: 27652-27658Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). After phosphorylation of two tyrosines that are contained in the intracellular domain of SHPS-1, SHP-2 is recruited from the cytoplasm to the plasma membrane, and its binding to SHPS-1 activates its phosphatase activity (18Fujioka Y. Matozaki T. Noguchi T. Iwamatsu A. Yamao T. Nobuaki T. Tsuda M. Takada T. Kasuga M. Mol. Cell. Biol. 1996; 16: 6887-6899Crossref PubMed Scopus (382) Google Scholar, 19Kharitonenkov A. Chen Z. Sures I. Wang H. Schilling J. Ullrich A. Nature. 1997; 386: 181-186Crossref PubMed Scopus (540) Google Scholar, 20Noguchi T. Matozaki T. Fujioka Y. Yamao T. Tsuda M. Takada T. Kasuga M. J. Biol. Chem. 1996; 271: 27652-27658Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Mutation of these tyrosines in SHPS-1 results in the failure of SHP-2 to be recruited to the membrane (21Takada T. Matozaki T. Takeda H. Fukanaga K. Noguchi T. Fujioka Y. Okazaki I. Tsuda M. Yamao T. Ochi F. Kasuga M. J. Biol. Chem. 1998; 273: 9234-9242Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). The recruitment of SHP-2 to SHPS-1 has been shown to correlate with the negative effect of SHPS-1 on insulin signaling (19Kharitonenkov A. Chen Z. Sures I. Wang H. Schilling J. Ullrich A. Nature. 1997; 386: 181-186Crossref PubMed Scopus (540) Google Scholar), and in the case of the GH receptor, loss of SHP-2 recruitment to SHPS-1 has been shown to result in prolonged GH receptor phosphorylation (22Stofega M.R. Argetsinger L.S. Wang H. Ullrich A. Carter-Su C. J. Biol. Chem. 2000; 275: 28222-28229Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). Based on these prior observations, we attempted to determine whether SHP-2 dephosphorylates the IGF-IR after IGF-I-induced receptor to the role of SHPS-1 in recruitment of SHP-2 to the activated receptor, and to determine the of this recruitment IGF-I was a from were from was from and were from The IGF-IR β was from The SHP-2 and the phosphotyrosine were from SHPS-1 were The was from and was to the domain of SHPS-1 the was in a the of the SHPS-1 an other were from were A. T. D.R. Endocrinology. 1995; PubMed Google and maintained in medium with and serum in The cells were between and SHP-2 and SHPS-1 were by from a that been from SHP-2 the to of the SHP-2 but with the addition, the of the The was The the are The was to and was After DNA to that the been the was SHPS-1 the to of SHPS-1 and the was to After DNA to that the been the was the was to a of by in the catalytic site of SHP-2 This mutation was shown to result in a negative catalytically inactive form of SHP-2 A. T. D.R. Endocrinology. 1995; PubMed Google Scholar, Y. C. D.R. J. 1997; PubMed Scopus (81) Google Scholar). the SHP-2 DNA were The was the that to full-length the was to but it also contained the of the DNA which an The was The are and the site of the is The was a to but it also contained a the to an and it to the The was The are and the is with The the are with The was the that to the full-length SHP-2. The two were then the After the two were and from the The was in the of the to the DNA and the The was the site in the to the DNA and the The DNA were then the by and and the DNA the full-length SHP-2 the was the After and the was the was to a truncated form of SHPS-1 that resulting in the loss of the two tyrosine residues that been shown to be required for SHP-2 binding A. T. D.R. Endocrinology. 1995; PubMed Google Scholar). The was the that to the full-length SHPS-1, and the that was was to that it contained to a the of the The was The site is The DNA was the After and it was the The and were with the In were the Y. C. D.R. J. 1997; PubMed Scopus (81) Google Scholar). were and maintained in serum and were in subsequent between and Cells were in and then to IGF-I for the appropriate of time in 1 1 1 1 1 1 and 1 The were by for 10 min. was then The were with the appropriate SHP-2, SHPS-1 a were then by protein and for a The were then for 10 min and the with The was in of for and the proteins by After the proteins were to a The were in serum in with for The were with of SHP-2, SHPS-1, a of and then in of the was the and to the U. K. were by and was to between The results that are shown are of After a stimulation of with IGF-I there was a in IGF-IR After a with IGF-I there was a in IGF-IR min there was a in receptor phosphorylation with the of phosphorylation which is 10 min. in shown in In it can be that there was SHP-2 associated with the IGF-IR in the and after min of IGF-I stimulation. after a stimulation there was SHP-2 and min there was a in SHP-2 with the IGF-IR. These results that there is a between the time which the phosphorylation of the IGF-IR is and the time which the SHP-2 tyrosine phosphatase Because SHP-2 is a it be recruited to the plasma membrane it can bind to the IGF-IR. The phosphorylation of SHPS-1 and its subsequent recruitment of SHP-2 from the have been shown to be stimulated by growth that with other growth IGF-I stimulated a in SHPS-1 IGF-I stimulated phosphorylation of SHPS-1 after a and this was followed by a in SHPS-1 phosphorylation by 10 min. next whether SHP-2 was recruited to SHPS-1 after IGF-I-stimulated SHPS-1 that there was no SHP-2 with SHPS-1 in the but SHP-2 was recruited to SHPS-1 after a to The of SHP-2 with SHPS-1 and is 10 min. The recruitment of SHP-2 to SHPS-1 and then its subsequent that this was a by which SHP-2 be recruited to the plasma membrane and then to bind to the IGF-IR. The SHP-2 binding site on SHPS-1 has been the two tyrosine residues A. T. D.R. Endocrinology. 1995; PubMed Google Scholar). whether SHP-2 recruitment to IGF-IR required that SHP-2 be recruited from the to SHPS-1 we a truncated form of SHPS-1 which the two tyrosine residues and SHP-2 recruitment to SHPS-1 and the IGF-IR after IGF-I stimulation. that after and with the SHPS-1 to the of SHPS-1 protein were in cells and in cells with the that no SHPS-1 protein can be in cells expressing the to the of SHPS-1 was to SHPS-1 protein can be in cells with the This that the truncated form of SHPS-1 is in a negative In it can be that of SHPS-1 protein in the cells expressing to in cells expressing the there was no recruitment of SHP-2 to SHPS-1 in cells expressing the truncated form of the cells with the showed SHP-2 to SHPS-1 after min of IGF-I stimulation. This was to for to that there was no SHP-2 in the cells expressing truncated that loss of SHPS-1 recruitment of SHP-2 would SHP-2 with IGF-IR we the cells expressing the truncated form of In it can be that after IGF-I stimulation there was no recruitment of SHP-2 to the IGF-IR in cells expressing the truncated form of This was to for to that there was no SHP-2 Recruitment of SHP-2 to the IGF-IR in cells expressing the is also The in SHPS-1 phosphorylation and loss of SHP-2 with SHPS-1 are with phosphorylated SHPS-1 a substrate for SHP-2 phosphatase (18Fujioka Y. Matozaki T. Noguchi T. Iwamatsu A. Yamao T. Nobuaki T. Tsuda M. Takada T. Kasuga M. Mol. Cell. Biol. 1996; 16: 6887-6899Crossref PubMed Scopus (382) Google Scholar, 20Noguchi T. Matozaki T. Fujioka Y. Yamao T. Tsuda M. Takada T. Kasuga M. J. Biol. Chem. 1996; 271: 27652-27658Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). that the recruitment of SHP-2 to SHPS-1 and its subsequent were required for SHP-2 with and dephosphorylation of the IGF-IR we a catalytically inactive form of SHP-2 which then the time course of IGF-IR dephosphorylation in these that the cells SHP-2 and that the cells with the In it can be that in cells expressing the catalytically inactive form of SHP-2, SHPS-1 was phosphorylated after min of stimulation with however, cells that SHP-2, cells expressing the SHP-2 mutant showed no in SHPS-1 phosphorylation 10 min. that in to the cells with the the cells expressing SHP-2 showed no of SHP-2 from SHPS-1 over the time course that was This was by that was followed by for SHP-2, no SHP-2 be not This that of SHP-2 binding to SHPS-1 was associated with a loss of binding to the IGF-IR. that after a to cells expressing the mutant cells with an showed a in IGF-IR After 10 min there is a in IGF-IR phosphorylation in the cells but no in cells expressing the and these cells a in receptor phosphorylation the time These that in the of SHP-2 from SHPS-1 there is no recruitment of SHP-2 to the IGF-IR and no receptor dephosphorylation. The in IGF-IR phosphorylation which after ligand binding is and is followed by a in the of IGF-IR Because there are no in IGF-IR protein over this time this that there are activation and recruitment of a tyrosine phosphatase to the studies have shown that a catalytically inactive form of SHP-2 can bind to of the insulin and IGF-IR (10Rocchi S. Tartare-Deckert S. Sawka-Verhelte D. Gamha A. Van Obberghen E. Endocrinology. 1996; 137: 4944-4952Crossref PubMed Scopus (0) Google Scholar). studies that SHP-2 receptors after it only a form of SHP-2 a and did not receptor (10Rocchi S. Tartare-Deckert S. Sawka-Verhelte D. Gamha A. Van Obberghen E. Endocrinology. 1996; 137: 4944-4952Crossref PubMed Scopus (0) Google Scholar). the studies we that the recruitment of SHP-2 to the IGF-IR via SHPS-1 is for the in IGF-IR phosphorylation after IGF-I-induced receptor activation and is an important of IGF-I signaling. This was by an between the time which the IGF-IR phosphorylation was and the time which the SHP-2 phosphatase associated with the receptor. This is by that in cells expressing a truncated form of SHPS-1, SHP-2 is not recruited to the IGF-IR and by the of sustained IGF-IR phosphorylation in cells expressing the catalytically inactive form of SHP-2 which is not from SHPS-1 has been a transmembrane with tyrosine phosphorylation and SH-2 binding in its domain M. Matozaki T. Fukanaga K. Fujioka Y. Imamoto A. Noguchi T. Takada T. Yamao T. Takeda H. Ochi F. Yamamoto T. Kasuga M. J. Biol. Chem. 1998; 273: 13223-13229Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 18Fujioka Y. Matozaki T. Noguchi T. Iwamatsu A. Yamao T. Nobuaki T. Tsuda M. Takada T. Kasuga M. Mol. Cell. Biol. 1996; 16: 6887-6899Crossref PubMed Scopus (382) Google Scholar, 19Kharitonenkov A. Chen Z. Sures I. Wang H. Schilling J. Ullrich A. Nature. 1997; 386: 181-186Crossref PubMed Scopus (540) Google Scholar, 20Noguchi T. Matozaki T. Fujioka Y. Yamao T. Tsuda M. Takada T. Kasuga M. J. Biol. Chem. 1996; 271: 27652-27658Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). It has been shown to be phosphorylated on tyrosines in response to ligand occupancy of several growth factor receptors and the insulin receptor two binding sites for SHP-2 M. Matozaki T. Fukanaga K. Fujioka Y. Imamoto A. Noguchi T. Takada T. Yamao T. Takeda H. Ochi F. Yamamoto T. Kasuga M. J. Biol. Chem. 1998; 273: 13223-13229Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 18Fujioka Y. Matozaki T. Noguchi T. Iwamatsu A. Yamao T. Nobuaki T. Tsuda M. Takada T. Kasuga M. Mol. Cell. Biol. 1996; 16: 6887-6899Crossref PubMed Scopus (382) Google Scholar, 19Kharitonenkov A. Chen Z. Sures I. Wang H. Schilling J. Ullrich A. Nature. 1997; 386: 181-186Crossref PubMed Scopus (540) Google Scholar, 20Noguchi T. Matozaki T. Fujioka Y. Yamao T. Tsuda M. Takada T. Kasuga M. J. Biol. Chem. 1996; 271: 27652-27658Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). of the two SH-2 domains within SHP-2 to these binding sites on SHPS-1 SHP-2 and activates the phosphatase by the SH-2 domain from the phosphatase site S. T.J. C.T. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Nature. 1996; PubMed Scopus Google Scholar, S. S. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). SHPS-1 phosphorylation not only provides a binding site for SHP-2, but it is also a substrate for the phosphatase, resulting in dephosphorylation of SHPS-1 and loss of the SHP-2 binding sites (18Fujioka Y. Matozaki T. Noguchi T. Iwamatsu A. Yamao T. Nobuaki T. Tsuda M. Takada T. Kasuga M. Mol. Cell. Biol. 1996; 16: 6887-6899Crossref PubMed Scopus (382) Google Scholar, 20Noguchi T. Matozaki T. Fujioka Y. Yamao T. Tsuda M. Takada T. Kasuga M. J. Biol. Chem. 1996; 271: 27652-27658Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). It has been that SHP-2 has been recruited to SHPS-1, after its activation and the subsequent dephosphorylation of SHPS-1, it is to with other plasma proteins (21Takada T. Matozaki T. Takeda H. Fukanaga K. Noguchi T. Fujioka Y. Okazaki I. Tsuda M. Yamao T. Ochi F. Kasuga M. J. Biol. Chem. 1998; 273: 9234-9242Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, M.R. Argetsinger L.S. Wang H. Ullrich A. Carter-Su C. J. Biol. Chem. 2000; 275: 28222-28229Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). has been shown for the insulin, growth and the growth factor receptors (16Stofega M.R. Herrington J. Billestrup N. Carter-Su C. Mol. Endocrinol. 2000; 14: 1338-1350Crossref PubMed Google Scholar), we that IGF-I can stimulate an in SHPS-1 phosphorylation, and this results in an in the of SHP-2. The time course of SHPS-1 phosphorylation and SHP-2 recruitment after IGF-I stimulation IGF-IR phosphorylation and SHP-2 recruitment by the receptor. This the that recruitment of SHP-2 to the IGF-IR via SHPS-1 is the by which SHP-2 is recruited to the receptor. This is by that in cells expressing a truncated form of SHPS-1, in which the two tyrosines and that are to be the binding site for SHP-2 have been (21Takada T. Matozaki T. Takeda H. Fukanaga K. Noguchi T. Fujioka Y. Okazaki I. Tsuda M. Yamao T. Ochi F. Kasuga M. J. Biol. Chem. 1998; 273: 9234-9242Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar), SHP-2 is not recruited to SHPS-1 to the IGF-IR. The of the of SHP-2 from SHPS-1 is by the a of SHP-2 recruitment to the IGF-IR in cells expressing the catalytically inactive form of SHP-2. In these cells SHPS-1 is not SHP-2 is not and IGF-IR phosphorylation is stimulation of SHPS-1 phosphorylation after ligand occupancy of IGF-IR and the subsequent dephosphorylation of SHPS-1 by SHP-2 are critical that are required for the IGF-IR dephosphorylation response to be SHP-2 has been shown to bind signaling and the and the it has been shown to have and negative on signaling by intracellular that have been activated by tyrosine kinase of a form of IRS-1 which not bind SHP-2 results in tyrosine phosphorylation of which in the of kinase with IRS-1 and protein Jr., M.G. R. R. White M.F. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus (136) Google Scholar). mutation of the SHP-2 binding site in the GH receptor tyrosine phosphorylation of the GH receptor and the signaling proteins and K.L. Saltiel A.R. J. Biol. 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Maile et al. (Fri,) studied this question.