Insulin-like growth factor-I (IGF-I) plays a role in mutually exclusive processes such as proliferation and differentiation in a variety of cell types. IGF-I is a potent mitogen and motogen for dedifferentiated vascular smooth muscle cells (VSMCs) in vivo and in vitro. However, in differentiated VSMCs, IGF-I is only required for maintaining the differentiated phenotype. Here we investigated the VSMC phenotype-dependent signaling and biological processes triggered by IGF-I. In differentiated VSMCs, IGF-I activated a protein-tyrosine phosphatase, SHP-2, recruited by insulin receptor substrate-1 (IRS-1). The activated SHP-2 then dephosphorylated IRS-1 Tyr(P)-895, resulting in blockade of the pathways from IRS-1/Grb2/Sos to the ERK and p38 MAPK. Conversely, such negative regulation was silent in dedifferentiated VSMCs, where IGF-I activated both MAPKs via IRS-1/Grb2/Sos interaction-linked Ras activation, leading to proliferation and migration. Thus, our present results demonstrate that the IRS-1/SHP-2 interaction acts as a switch controlling VSMC phenotype-dependent IGF-I-induced signaling pathways and biological processes, and this mechanism is likely to be applicable to other cells. Insulin-like growth factor-I (IGF-I) plays a role in mutually exclusive processes such as proliferation and differentiation in a variety of cell types. IGF-I is a potent mitogen and motogen for dedifferentiated vascular smooth muscle cells (VSMCs) in vivo and in vitro. However, in differentiated VSMCs, IGF-I is only required for maintaining the differentiated phenotype. Here we investigated the VSMC phenotype-dependent signaling and biological processes triggered by IGF-I. In differentiated VSMCs, IGF-I activated a protein-tyrosine phosphatase, SHP-2, recruited by insulin receptor substrate-1 (IRS-1). The activated SHP-2 then dephosphorylated IRS-1 Tyr(P)-895, resulting in blockade of the pathways from IRS-1/Grb2/Sos to the ERK and p38 MAPK. Conversely, such negative regulation was silent in dedifferentiated VSMCs, where IGF-I activated both MAPKs via IRS-1/Grb2/Sos interaction-linked Ras activation, leading to proliferation and migration. Thus, our present results demonstrate that the IRS-1/SHP-2 interaction acts as a switch controlling VSMC phenotype-dependent IGF-I-induced signaling pathways and biological processes, and this mechanism is likely to be applicable to other cells. The insulin-like growth factors (IGFs) 1The abbreviations used are: IGF, insulin-like growth factor; IGF-IR, IGF-I receptor; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; ERK, extracellular signal-regulated kinase; IRS-1, insulin receptor substrate-1; PKB(Akt), protein kinase B; VSMCs, vascular smooth muscle cells; MHC, myosin heavy chain; CaD, caldesmon; CN, calponin; BSA, bovine serum albumin; RBD, Ras-binding-domain; PTPase, protein-tyrosine phosphatase; PDGF-BB, platelet-derived growth factor-BB; BrdUrd, 5-bromo-2-deoxyuridine; CCH, carbachol; wt, wild type; DN, dominant negative; HA, hemagglutinin. are involved in a variety of biological processes regulating cell proliferation, migration, survival, size control, and differentiation (1LeRoith D. Werner H. Beitner-Johnson D. Roberts Jr., C.T. Endocr. Rev. 1995; 16: 143-163Crossref PubMed Scopus (1251) Google Scholar, 2Yenush L. White M.F. BioEssays. 1997; 19: 491-500Crossref PubMed Scopus (253) Google Scholar). IGFs activate the IGF-I receptor (IGF-IR) tyrosine kinase, resulting in the tyrosine phosphorylation of downstream signaling molecules and/or direct interaction with them (1LeRoith D. Werner H. Beitner-Johnson D. Roberts Jr., C.T. Endocr. Rev. 1995; 16: 143-163Crossref PubMed Scopus (1251) Google Scholar). The major targets of IGF-IR are three adaptor proteins: IRS-1, Shc, and Gab1. IRS-1, an important substrate for both the insulin receptor and IGF-IR, contains multiple tyrosine phosphorylation sites that recognize Src homology 2 domain-containing signaling molecules, such as Grb2, Nck, the p85 subunit of phosphoinositide 3-kinase (p85 PI3K), and SHP-2 (1LeRoith D. Werner H. Beitner-Johnson D. Roberts Jr., C.T. Endocr. Rev. 1995; 16: 143-163Crossref PubMed Scopus (1251) Google Scholar). Of these, the binding of Grb2 associated with Sos to tyrosine-phosphorylated IRS-1 activates Ras, which switches on the Raf-1/mitogen-activated protein kinase (MAPK) kinase (MEK)/extracellular signal-regulated kinase (ERK) cascade (3Rozakis-Adcock M. McGlade J. Mbamalu G. Pelicci G. Daly R. Li W. Batzer A. Thomas S. Brugge J. Pelicci P.G. Schlessinger J. Pawson T. Nature. 1992; 360: 689-692Crossref PubMed Scopus (827) Google Scholar). The ligand-engaged IGF-IR triggers another pathway involving PI3K. The interaction between tyrosine-phosphorylated IGF-IRβ or insulin receptor substrate-1 (IRS-1) and p85 PI3K activates PI3K and its downstream molecules, protein kinase B (PKB(Akt)) and p70S6K (4Oldham S. Hafen E. Trends Cell Biol. 2003; 13: 79-85Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar). Shc, an Src homology 2 domain-containing substrate for receptor tyrosine kinases, interacts directly with IGF-IR (5Giorgetti S. Pelicci P.G. Pelicci G. Van Obberghen E. Eur. J. Biochem. 1994; 223: 195-202Crossref PubMed Scopus (98) Google Scholar). After tyrosine phosphorylation of Shc, it recruits the Grb2-Sos complex and activates the Ras/Raf-1/MEK/ERK axis (3Rozakis-Adcock M. McGlade J. Mbamalu G. Pelicci G. Daly R. Li W. Batzer A. Thomas S. Brugge J. Pelicci P.G. Schlessinger J. Pawson T. Nature. 1992; 360: 689-692Crossref PubMed Scopus (827) Google Scholar). Gab1 functions as an adaptor protein downstream of receptor tyrosine kinases including IGF-IR (6Gu H. Neel B.G. Trends Cell Biol. 2003; 13: 122-130Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar). Tyrosine-phosphorylated Gab1 interacts with Grb2, p85 PI3K, and SHP-2 (7Rocchi S. Tartare-Deckert S. Murdaca J. Holgado-Madruga M. Wong A.J. Van Obberghen E. Mol. Endocrinol. 1998; 12: 914-923Crossref PubMed Scopus (65) Google Scholar). Thus, the cross-talk among IGF-induced signaling pathways is critical for regulating the variety of biological processes described above. Recent studies (8Coolican S.A. Samuel D.S. Ewton D.Z. McWade F.J. Florini J.R. J. Biol. Chem. 1997; 272: 6653-6662Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar) have demonstrated the involvement of IGF-induced signals in the mutually exclusive processes of cell proliferation and differentiation. For instance, pharmacological study showed that although the MAPK pathway induced by IGF-I is involved in the mitogenic response of myoblasts, the PI3K/p70S6K pathway is critical for myogenic differentiation. In hematopoietic cells, IGF-I signaling via IRS-1 plays a role in proliferation and via Shc in differentiation (9Valentinis B. Romano G. Peruzzi F. Morrione A. Prisco M. Soddu S. Cristofanelli B. Sacchi A. Baserga R. J. Biol. Chem. 1999; 274: 12423-23430Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). In 3T3-L1 preadipocytes, the IGF-I-induced tyrosine phosphorylation of Shc, Shc-Grb2 complex formation, and ERK activation is observed in proliferating, but not differentiating, cells (10Boney C.M Smith R.M. Gruppuso P.A. Endocrinology. 1998; 139: 1638-1644Crossref PubMed Scopus (60) Google Scholar). In osteoblasts, IGF-IR-mediated signals via the PI3K, ERK, and p38 MAPK pathways are all involved in differentiation (11Yeh L.C. Adamo M.L. Olson M.S. Lee J.C. Endocrinology. 1997; 138: 4181-4190Crossref PubMed Scopus (86) Google Scholar). Thus, the downstream pathways of IGF-I signaling seem to depend on the cellular context. IGF-I is also a potent mitogen and motogen for vascular smooth muscle cells (VSMCs) in vivo and in vitro (12Bornfeldt K.E. Rainco E.W. Nakano T. Groves L.M. Krebs E. Ross R. J. Clin. Investig. 1993; 93: 1266-1274Crossref Scopus (381) Google Scholar, 13Bayes-Genis A. Conover C.A. Schwartz R.S. Circ. Res. 2000; 86: 125-130Crossref PubMed Scopus (384) Google Scholar); disruption of the IGF-I/IGF-IR interaction by a neutralizing anti-IGF-IR antibody (14Avena R. Mitchell M.E. Carmody B. Arora S. Neville R.F. Sidaway A.N. Am. J. Surg. 1999; 178: 156-161Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar) and suppression of IGF-IR expression by antisense oligonucleotides (15Simons M. Ariyoshi H. Salzman E.W. Rosenberg R.D. Am. J. Physiol. 1995; 268: C856-C868Crossref PubMed Google Scholar) and transcripts (16Du J. Delafontaine P. Circ. Res. 1995; 76: 963-972Crossref PubMed Scopus (74) Google Scholar) inhibit IGF-I-induced VSMC proliferation and migration in culture. Targeted overexpression of IGF-I in arteries in vivo (17Zhu B. Zhao G. Witte D.P. Hui D.Y. Fagin J.A. Endocrinology. 2001; 142: 3598-3606Crossref PubMed Scopus (64) Google Scholar) and infusion of IGF-I into the circulatory system (18Chen Y. Capron L. Magnusson J.O. Wallby L.A. Arnqvist H.J. Growth Horm. IGF Res. 1998; 8: 299-303Crossref PubMed Scopus (27) Google Scholar) have been shown to accelerate neointimal formation after vascular injury. On the other hand, we recently reported a primary culture system of VSMCs that exhibit a differentiated in which VSMCs are on M. W. H. J. Cell Biol. 1999; PubMed Scopus Google Scholar, M. W. Y. A. J. H. Circ. Res. 2001; PubMed Scopus Google Scholar). this culture we demonstrated that IGF-I is involved in maintaining the differentiated via the pathway and that the activation of ERK and p38 MAPK triggered by other growth factors VSMC we that in the between the of the and the ERK and p38 MAPK pathways the VSMC phenotype. However, of including VSMCs, the cellular phenotype-dependent of the IGF-induced signaling Here we the VSMC phenotype-dependent of IGF-I by the IGF-I-induced signaling In differentiated VSMCs, SHP-2 associated with IRS-1 and the interaction between IRS-1 and resulting in a blockade of the pathways from Ras to ERK and p38 MAPK. in differentiated VSMCs, activates the which plays a role in maintaining the differentiated phenotype. Conversely, the proliferation and migration of dedifferentiated VSMCs in response to IGF-I of an IGF-I-induced interaction between IRS-1 and by the activation of Ras and its downstream kinases, ERK and p38 MAPK. is the that the cellular phenotype-dependent IRS-1/SHP-2 interaction functions as a switch for IGF-I and biological and and from as MAPK, and and antibody antibody and and PI3K, and Tyr(P)-895, and and heavy antibody antibody was by T. and M. Y. T. A. A. W. M. M. 2003; PubMed Scopus Google Scholar) also VSMC a of VSMCs, we our M. W. Y. A. J. H. Circ. Res. 2001; PubMed Scopus Google Scholar) as the from and for in the and bovine serum the of and The VSMC and in and for VSMCs a The cells on and in with 2 and other as VSMCs from the VSMC of as described L. J. Cell Res. 1998; PubMed Scopus Google Scholar). VSMCs used as dedifferentiated of expression of and CN, and was by to the expression of as described M. W. Y. A. J. H. Circ. Res. 2001; PubMed Scopus Google Scholar, M. Y. T. A. A. W. M. M. 2003; PubMed Scopus Google Scholar). of kinases or and MAPK after with MAPK, or The kinase in the as described M. W. H. J. Cell Biol. 1999; PubMed Scopus Google Scholar, H. Y. Y. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, W. Y. A. J. H. 2003; PubMed Scopus Google Scholar). for and MAPK as VSMCs with the expression for or MAPK and or the expression for or After with IGF-I for the expression of the cell by The IRS-1 was by T. of IRS-1 and The expression for and by T. of between of both culture with the of IGF-I and in 2 and for The interaction of signaling molecules of or SHP-2 or IRS-1 was as VSMCs with the expression for and or the expression for or or with the expression for or then with IGF-I for of of the cell with the for The by with protein or protein for 2 in the by by the with a and the Ras Ras was a Ras to the In the VSMC with of the Ras binding of for Ras to was by an antibody and then with IGF-I or platelet-derived growth for The SHP-2 protein in the cell was an The in the tyrosine-phosphorylated as a substrate W. S. M. M. M. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Cell and of both for and then with the of IGF-I. VSMC proliferation was by the of for was by with an by with with and The migration of differentiated VSMCs in was for by a on an The migration of dedifferentiated VSMCs was by of dedifferentiated VSMCs with a After with the of IGF-I for the of cells The proliferation of dedifferentiated VSMCs with or was as VSMCs with the expression and for After serum in the IGF-I and for The expression of was with and The migration of dedifferentiated VSMCs with the expression was as described above. After with IGF-I for the expression of was as described above. The of cells and cells of IRS-1 VSMC IGF-I demonstrated M. W. H. J. Cell Biol. 1999; PubMed Scopus Google Scholar, M. W. Y. A. J. H. Circ. Res. 2001; PubMed Scopus Google primary VSMCs on showed the differentiated as by a cell and expression of such as CN, and the and protein VSMCs, a of and of expression in to of from the the dedifferentiated phenotype. both of VSMCs, we the response to IGF-I with our study M. W. Y. A. J. H. Circ. Res. 2001; PubMed Scopus Google IGF-I activated in differentiated and dedifferentiated VSMCs, and its activation a IGF-I an IGF-I for showed a to IGF-I in in both of VSMCs, from 2 to not that the IGF-I-induced signaling is The activation by IGF-I in both VSMC was by or but not by or that IGF-I the activation via PI3K. not activate ERK or p38 MAPK in differentiated VSMCs, it activated them in dedifferentiated a and of ERK and p38 MAPK, IGF-I and In the activation of and ERK by IGF-I but p38 MAPK showed a IGF-I The IGF-I-induced ERK activation was by but not by or The p38 MAPK activation by IGF-I was only by or not results that IGF-I activates VSMC phenotype-dependent signaling IGF-I-induced between molecules, including IGF-IR, IRS-1, PI3K, Grb2, Ras, ERK, p38 MAPK, SHP-2, and Shc, have been shown to be involved in IGF-I signaling in a variety of cells, including VSMCs (1LeRoith D. Werner H. Beitner-Johnson D. Roberts Jr., C.T. Endocr. Rev. 1995; 16: 143-163Crossref PubMed Scopus (1251) Google Scholar, M. McGlade J. Mbamalu G. Pelicci G. Daly R. Li W. Batzer A. Thomas S. Brugge J. Pelicci P.G. Schlessinger J. Pawson T. Nature. 1992; 360: 689-692Crossref PubMed Scopus (827) Google Scholar, R. Mitchell M.E. Carmody B. Arora S. Neville R.F. Sidaway A.N. Am. J. Surg. 1999; 178: 156-161Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, J. Delafontaine P. Circ. Res. 1995; 76: 963-972Crossref PubMed Scopus (74) Google Scholar, B. Zhao G. Witte D.P. Hui D.Y. Fagin J.A. Endocrinology. 2001; 142: 3598-3606Crossref PubMed Scopus (64) Google Scholar). the expression of signaling molecules The IRS-1, Shc, and Ras in dedifferentiated VSMCs with differentiated VSMCs, ERK, p38 MAPK, p85 PI3K, PKB(Akt), SHP-2, and Grb2 in both VSMC Thus, signaling molecules expression in VSMC the mechanism involved in VSMC phenotype-dependent IGF-I we the tyrosine phosphorylation and of the signaling After IGF-I and an antibody tyrosine-phosphorylated with of and in both VSMC as IGF-IRβ and IRS-1 by and antibody also IGF-IRβ in an IGF-I not Tyrosine-phosphorylated IGF-IRβ and/or IRS-1 a complex with p85 PI3K but not with Shc in VSMC and and a complex of Grb2 and Sos in the and not of both VSMC with or IGF-I of the with and showed that a complex of tyrosine-phosphorylated IRS-1 and in the but not in the VSMCs that the complex of IRS-1, Grb2, and Sos on the IGF-I-induced tyrosine phosphorylation of of the with and showed the in the dedifferentiated VSMCs not The complex was also in the the IGF-I-induced tyrosine-phosphorylated Shc an Shc and IGF-IRβ or interaction was in VSMC phenotype. a control, induced tyrosine phosphorylation of Shc and an interaction between Shc and The protein by antibody in the Shc from both of VSMC was an heavy antibody with heavy in or induced the tyrosine phosphorylation of Shc in both VSMC and not IGF-I signaling in VSMCs is Thus, our results that tyrosine-phosphorylated IRS-1 recruits the Grb2-Sos complex in dedifferentiated but not in differentiated VSMC of Tyrosine-phosphorylated IRS-1 and is on multiple tyrosine in response to of IRS-1 been as a binding for Grb2 M. G. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the phosphorylation of IRS-1 by an The IRS-1 was by IGF-I only in dedifferentiated VSMCs is with the IGF-I-induced complex formation between tyrosine-phosphorylated IRS-1 and in but not in VSMCs is that tyrosine-phosphorylated IRS-1 interacts with SHP-2, the the leading to the or negative regulation of receptor tyrosine T. T. Y. M. Mol. Biol. 1994; PubMed Scopus Google Scholar, S. T. H. Jr., J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, A. S.A. T. T. T. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Jr., R. P. R. White M.F. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). IRS-1 tyrosine for SHP-2 and R.D. E. G. Neel B.G. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). the tyrosine phosphorylation of sites and In a the antibody IRS-1 but the not recognize not the of IRS-1 in In response to IGF-I IRS-1 was in both VSMC then the involvement of SHP-2 in the VSMC phenotype-dependent interaction between IRS-1 and In both VSMC and all of the SHP-2 protein was by IGF-I the of SHP-2 in differentiated VSMCs, its was in dedifferentiated a control, the of SHP-2 in both the VSMC The be from the SHP-2 SHP-2 J.A. J. 1998; PubMed Scopus Google Scholar) in differentiated VSMCs showed the of the SHP-2 Thus, the IGF-I-induced activation is VSMC with an interaction between SHP-2 and tyrosine-phosphorylated IRS-1 was only in differentiated The interaction a after IGF-I and interaction with the in phosphorylation of Thus, the of this interaction in differentiated VSMCs depend on the phosphorylation of and in IRS-1/SHP-2 interaction was in dedifferentiated VSMCs, IRS-1 was by IGF-I that an mechanism of this interaction in dedifferentiated between SHP-2 and other tyrosine-phosphorylated adaptor such as and Shc, in VSMC the reported L.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, not our results that SHP-2 recruited to IRS-1 the IRS-1 in differentiated VSMCs of the IRS-1 and by the of and SHP-2 on the IGF-I-induced interaction between IRS-1 and The from and dedifferentiated VSMCs with expression for Grb2 and or with an by with an antibody in differentiated VSMCs a interaction between IRS-1 and Grb2, but results that with activated SHP-2, leading to of the IRS-1 and In dedifferentiated VSMCs, the formation of this but negative regulation in dedifferentiated VSMCs be to of the IRS-1 by the the IGF-I-induced interaction between Grb2 and or its and with or Grb2 with In differentiated VSMCs, with Grb2 in response to IGF-I and Conversely, and in dedifferentiated VSMCs a complex with Grb2 but Grb2 that was associated with or also a complex with Sos not a complex formation among signaling Thus, SHP-2 the IRS-1 and interaction in a VSMC phenotype-dependent and IRS-1 phosphorylation of ERK and p38 MAPK by the negative regulation of ERK and p38 MAPK by SHP-2, we both of VSMCs with expression for or or or and or MAPK, and we the ERK and p38 MAPK in the IGF-I activated ERK and p38 MAPK in differentiated VSMCs or but not in or IGF-I to activate ERK and p38 MAPK in dedifferentiated VSMCs or but MAPK in dedifferentiated VSMCs or Thus, the VSMC phenotype-dependent interaction between IRS-1 and which is by SHP-2, is critical for the IGF-I-induced activation of both Ras as an for the IGF-I-induced of ERK and p38 the cascade is in cell R. PubMed Scopus Google the pathway from Ras to p38 MAPK, present results that Ras be involved in the IGF-I-induced activation of both ERK and p38 MAPK in dedifferentiated the IGF-I-induced Ras activation with a binding with the kinase and between signaling molecules IGF-I activated Ras in but not VSMCs activation was Ras in dedifferentiated VSMCs was activated after IGF-I and the activation IGF-I activated ERK and p38 MAPK for and after Thus, the activation of Ras induced by IGF-I to and of both but the the after the direct involvement of Ras in the IGF-I-induced MAPK activation in dedifferentiated VSMCs, we dedifferentiated VSMCs with M. D. M. Mol. Biol. 1995; PubMed Scopus (60) Google or H. S. H. T. H. T. Y. Mol. Biol. 1998; PubMed Scopus Google and or MAPK, and we for the ERK and p38 MAPK in the or the IGF-I-induced activation of both both MAPK to them to the In by IGF-I Thus, the cascade induced by IGF-I activates both ERK and p38 MAPK in dedifferentiated between IGF-I and of IGF-I on of the between VSMC phenotype-dependent IGF-I signaling and its biological we the IGF-I-induced cell proliferation and migration. differentiated VSMCs cell proliferation, as by or migration that IGF-I acts to the differentiated but not as a mitogen or Conversely, IGF-I the proliferation and migration of dedifferentiated VSMCs and with or the and migration, but with both them and that biological depend on the IGF-I-induced activation of ERK and p38 MAPK. the of the interaction between and on the and migration of dedifferentiated VSMCs by or VSMCs showed and migration with or results that the negative regulation of ERK and p38 MAPK by blockade of the IRS-1 and interaction results in of the proliferation and migration of dedifferentiated of the IRS-1 and SHP-2 or Grb2 interaction on the IGF-I-induced proliferation and migration of dedifferentiated The of IRS-1 on the proliferation as by and the migration of dedifferentiated VSMCs are IRS-1 are the of with an and of and IRS-1 and of both of are shown The the of cells of the IRS-1 to the of for In the cell migration of the and after IGF-I and of the IRS-1 in the are shown and the of the VSMC and after IGF-I The the of cells of the IRS-1 to cells. the of for studies have that IGF-I is a potent mitogen and motogen for VSMCs, IGF-I-induced activation of PI3K and/or MAPKs is involved in the proliferation and migration of VSMCs (12Bornfeldt K.E. Rainco E.W. Nakano T. Groves L.M. Krebs E. Ross R. J. Clin. Investig. 1993; 93: 1266-1274Crossref Scopus (381) Google Scholar, 13Bayes-Genis A. Conover C.A. Schwartz R.S. Circ. Res. 2000; 86: 125-130Crossref PubMed Scopus (384) Google Scholar). Conversely, we demonstrated by our VSMC culture system that IGF-I plays a critical role in maintaining the differentiated of VSMCs via the but not the ERK or p38 MAPK, pathway M. W. H. J. Cell Biol. 1999; PubMed Scopus Google Scholar, M. W. Y. A. J. H. Circ. Res. 2001; PubMed Scopus Google Scholar). Here we demonstrate the signaling from IGF-IR to and in VSMC and that the the biological of IGF-I on VSMCs is of the VSMC IGF-I activated ERK and p38 MAPK, via and Ras only in dedifferentiated VSMCs and resulting in of the VSMC proliferation and migration and in vivo studies demonstrated that overexpression of IGF-I in VSMCs (17Zhu B. Zhao G. Witte D.P. Hui D.Y. Fagin J.A. Endocrinology. 2001; 142: 3598-3606Crossref PubMed Scopus (64) Google Scholar) or IGF-I infusion into the circulatory system (18Chen Y. Capron L. Magnusson J.O. Wallby L.A. Arnqvist H.J. Growth Horm. IGF Res. 1998; 8: 299-303Crossref PubMed Scopus (27) Google Scholar) neointimal formation after vascular injury. on our present in vivo be by the that VSMCs are by such as vascular IGF-I accelerate the proliferation and migration of dedifferentiated VSMCs via the signaling pathway shown in In differentiated VSMCs, SHP-2 the activation of both ERK and p38 MAPK been reported that a variety of are involved in the and negative regulation of via receptor tyrosine kinases A. Trends Cell Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). For instance, the receptor signaling in M.L. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In hematopoietic cell mitogenic signals the and S. T. Neel B.G. Mol. Biol. 16: PubMed Scopus Google Scholar). SHP-2 receptor tyrosine signaling in a or negative regulation by SHP-2 been reported in mitogenic signaling the insulin receptor T. T. Y. M. Mol. Biol. 1994; PubMed Scopus Google Scholar, J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). However, SHP-2 also insulin mitogenic signaling Jr., R. P. R. White M.F. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) and activation A. S.A. T. T. T. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). present study that SHP-2 is critical for the VSMC phenotype-dependent regulation of IGF-I in differentiated VSMCs, an IRS-1/SHP-2 interaction the of SHP-2 and the of to IRS-1 by the of IRS-1 resulting in of the activation of both MAPKs and In SHP-2 in dedifferentiated VSMCs The of SHP-2 in dedifferentiated VSMCs is a of the IGF-I that the SHP-2 in dedifferentiated VSMCs and SHP-2 with signaling molecules such as IRS-1 or Shc not in the dedifferentiated and L.A. Circ. Res. 2003; 93: PubMed Scopus Google Scholar) have reported that SHP-2 in VSMCs with and IRS-1 in response to IGF-I and depend on is to that the pathway via not in differentiated VSMCs, that protein expression is in differentiated VSMCs in vivo M. H. Li H. J. Investig. 2001; PubMed Scopus (25) Google Scholar). results dedifferentiated VSMCs also showed this pathway to be the for this The IRS-1 was in dedifferentiated However, the IRS-1/SHP-2 interaction is not in dedifferentiated VSMCs such a tyrosine phosphorylation of IRS-1 The IGF-I-induced interaction between IRS-1 and and the activation of ERK and p38 MAPK are in dedifferentiated VSMCs and results that in dedifferentiated VSMCs, the of SHP-2 be by with other tyrosine-phosphorylated such of SHP-2 or IRS-1 resulting in blockade of the interaction between IRS-1 and Ras is a of mitogenic signaling in cell including VSMCs, in vitro and in is that Ras activates ERK in a variety of cells, protein kinases, including p38 MAPK, are activated by the cascade R. PubMed Scopus Google Scholar). demonstrate that the activation of Ras functions as an for both ERK and p38 MAPK in dedifferentiated VSMCs However, the ERK pathway the p38 MAPK pathway be by Ras, IGF-I activation of both MAPKs and been reported that in cell including PKB(Akt), leading to suppression of the axis S. 1999; PubMed Scopus Google Scholar). In our present study by both of VSMCs, with PI3K the ERK activation by IGF-I that the negative regulation of the ERK pathway not be present study a into the in VSMCs and into the pharmacological that be applicable for vascular such as and described in the IGF-I the mutually exclusive biological such as proliferation and differentiation of hematopoietic cells, myoblasts, and In cells, the signaling pathways to of VSMCs be involved in the biological of IGF-I. In our we have the pathways regulating the IGF-I-induced proliferation and differentiation of myogenic cells. T. M. and in Thus, the IGF-I-induced pathways demonstrated to a mechanism regulating the signals involved in cell proliferation and not in VSMCs, but in other cells as
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