Leukocyte Antigen-related Deficiency Enhances Insulin-like Growth Factor-1 Signaling in Vascular Smooth Muscle Cells and Promotes Neointima Formation in Response to Vascular Injury

Abstract

Increase in the expression of leukocyte antigen-related (LAR) protein causes insulin resistance, an important contributor to atherosclerosis. However, the function of LAR in atherosclerosis is not known. To address whether LAR is important in the response of vascular cells to atherogenic stimuli, we investigated cell proliferation, migration, and insulin-like growth factor-1 receptor (IGF-1R) signaling in wild-type and LAR-/- mouse vascular smooth muscle cells (VSMC) treated with IGF-1. Absence of LAR significantly enhanced proliferation and migration of VSMC compared with wild-type cells after IGF-1 treatment. U0126 and LY249002, specific inhibitors of MAPK/ERK kinase (MEK) and phosphoinositide 3-kinase, respectively, inhibited IGF-1-induced DNA synthesis and migration in both wild-type and LAR-/- VSMC. IGF-1 markedly enhanced IGF-1R phosphorylation in both wild-type and LAR-/- VSMC, but the phosphorylation was 90% higher in knock-out cells compared with wild-type cells. Absence of LAR enhanced phosphorylation of insulin receptor substrate-1 and insulin receptor substrate-1-associated phosphoinositide 3-kinase activity in VSMC treated with IGF-1. IGF-1-induced phosphorylation of ERK1/2 also increased significantly in LAR-/- VSMC compared with wild-type cells. Furthermore, LAR directly binds to IGF-1R in glutathione S-transferase-LAR pull-down and IGF-1R immunoprecipitation experiments and recombinant LAR dephosphorylates IGF-1R in vitro. Neointima formation in response to arterial injury and IGF-1R phosphorylation in neointima increased significantly in LAR-/- mice compared with wild-type mice. A significant decrease in body weight, fasting insulin, and IGF-1 levels were observed in LAR-/- mice compared with wild-type mice. Together, these data indicate that LAR regulates IGF-1R signaling in VSMC and dysregulation of this phosphatase may lead to VSMC hyperplasia. Increase in the expression of leukocyte antigen-related (LAR) protein causes insulin resistance, an important contributor to atherosclerosis. However, the function of LAR in atherosclerosis is not known. To address whether LAR is important in the response of vascular cells to atherogenic stimuli, we investigated cell proliferation, migration, and insulin-like growth factor-1 receptor (IGF-1R) signaling in wild-type and LAR-/- mouse vascular smooth muscle cells (VSMC) treated with IGF-1. Absence of LAR significantly enhanced proliferation and migration of VSMC compared with wild-type cells after IGF-1 treatment. U0126 and LY249002, specific inhibitors of MAPK/ERK kinase (MEK) and phosphoinositide 3-kinase, respectively, inhibited IGF-1-induced DNA synthesis and migration in both wild-type and LAR-/- VSMC. IGF-1 markedly enhanced IGF-1R phosphorylation in both wild-type and LAR-/- VSMC, but the phosphorylation was 90% higher in knock-out cells compared with wild-type cells. Absence of LAR enhanced phosphorylation of insulin receptor substrate-1 and insulin receptor substrate-1-associated phosphoinositide 3-kinase activity in VSMC treated with IGF-1. IGF-1-induced phosphorylation of ERK1/2 also increased significantly in LAR-/- VSMC compared with wild-type cells. Furthermore, LAR directly binds to IGF-1R in glutathione S-transferase-LAR pull-down and IGF-1R immunoprecipitation experiments and recombinant LAR dephosphorylates IGF-1R in vitro. Neointima formation in response to arterial injury and IGF-1R phosphorylation in neointima increased significantly in LAR-/- mice compared with wild-type mice. A significant decrease in body weight, fasting insulin, and IGF-1 levels were observed in LAR-/- mice compared with wild-type mice. Together, these data indicate that LAR regulates IGF-1R signaling in VSMC and dysregulation of this phosphatase may lead to VSMC hyperplasia. Vascular smooth muscle cell (VSMC) 2The abbreviations used are: VSMC, vascular smooth muscle cell; PTK, protein-tyrosine kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PTP, protein-tyrosine phosphatase; LAR, leukocyte antigen-related protein; IR, insulin receptor; PI3K, phosphatidylinositol 3-kinase; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; PDGF, platelet-derived growth factor; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; GST, glutathione S-transferase; PBS, phosphate-buffered saline. 2The abbreviations used are: VSMC, vascular smooth muscle cell; PTK, protein-tyrosine kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PTP, protein-tyrosine phosphatase; LAR, leukocyte antigen-related protein; IR, insulin receptor; PI3K, phosphatidylinositol 3-kinase; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; PDGF, platelet-derived growth factor; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; GST, glutathione S-transferase; PBS, phosphate-buffered saline. proliferation, dedifferentiation, and migration in response to atherogenic stimuli are all governed by activation of key intracellular signaling pathways that in turn are regulated by the phosphorylation status of requisite tyrosine and serine residues of the integral proteins. Many growth factor receptors are protein-tyrosine kinases (PTKs) and undergo tyrosine phosphorylation and dephosphorylation in a concerted manner in response to a stimulus to initiate a signaling cascade that results in a physiological response (1Meng T.C. Buckley D.A. Galic S. Tiganis T. Tonks N.K. J. Biol. Chem. 2004; 279: 37716-37725Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). The characterization of protein-tyrosine phosphatases (PTPs), which reverse the activity of PTKs is essential for understanding the pathophysiological function of these kinases that underlies many cardiovascular diseases such as cardiac hypertrophy, ischemia/reperfusion injury, and atherogenesis and for the identification of therapeutic targets (2Force T. Kuida K. Namchuk M. Parang K. Kyriakis J.M. Circulation. 2004; 109: 1196-1205Crossref PubMed Scopus (111) Google Scholar). A total of 48 PTPs have been identified and it is estimated that up to 100 PTPs are present in human genome (3Hooft van Huijsduijnen R. Gene (Amst). 1998; 225: 1-8Crossref PubMed Scopus (67) Google Scholar). Little is known, however, about which PTPs are expressed in vascular cells and blood vessels, the substrate specificity of those expressed and their role in vascular remodeling (4Wright M.B. Seifert R.A. Bowen-Pope D.F. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1189-1198Crossref PubMed Scopus (36) Google Scholar). Leukocyte antigen-related (LAR) protein-tyrosine phosphatase is a receptor-like tyrosine phosphatase with a broad tissue distribution including epithelial, neuronal, and cardiac cells (5Streuli M. Krueger N.X. Ariniello P.D. Tang M. Munro J.M. Blattler W.A. Adler D.A. Disteche C.M. Saito H. EMBO J. 1992; 11: 897-907Crossref PubMed Scopus (135) Google Scholar). LAR is expressed on the cell surface as a complex of two noncovalently associated subunits of 150 and 85 kDa, which are generated by the action of an endogenous protease on the pro-protein. The 150-kDa fragment, representing the amino terminus of the protein, is exclusively extracellular and is modified by N-linked glycosylation. The 85-kDa C-terminal subunit contains a short ectodomain, a transmembrane domain, and two tandem phosphatase domains. The membrane-proximal phosphatase domain exhibits enzyme activity in vitro. Many studies of LAR have focused on its role in regulating insulin signaling. Antisense suppression of LAR enhanced insulin-dependent insulin receptor (IR) phosphorylation and phosphatidylinositol 3-kinase (PI3K) activity in hepatoma cells (6Kulas D.T. Zhang W.R. Goldstein B.J. Furlanetto R.W. Mooney R.A. J. Biol. Chem. 1995; 270: 2435-2438Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Furthermore, LAR expression was not only increased in obese subjects but also correlated with enhanced IR dephosphorylation and insulin resistance (7Ahmad F. Considine R.V. Goldstein B.J. J. Clin. Investig. 1995; 95: 2806-2812Crossref PubMed Scopus (115) Google Scholar, 8Ahmad F. Azevedo J.L. Cortright R. Dohm G.L. Goldstein B.J. J. Clin. Investig. 1997; 100: 449-458Crossref PubMed Scopus (259) Google Scholar). LAR physically interacts with IR in vivo and activation of IR enhances its binding to LAR that suggest that LAR regulates insulin action at the receptor level (9Ahmad F. Goldstein B.J. J. Biol. Chem. 1997; 272: 448-457Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). LAR is likely important for other critical cellular functions. For instance, LAR plays a role in establishing and maintaining neuronal networks and deficiency of this PTP results in reduction in the size of basal forebrain cholinergic neurons and loss of cholinergic innervation of the dentate gyrus (10Yeo T.T. Yang T. Massa S.M. Zhang J.S. Honkaniemi J. Butcher L.L. Longo F.M. J. Neurosc. Res. 1997; 47: 348-360Crossref PubMed Scopus (110) Google Scholar). Insulin-like growth factor-1 (IGF-1) is secreted by VSMC and other vascular cells and plays an important role in multiple vascular pathologies Arterioscler. Thromb. Vasc. Biol. 2004; PubMed Scopus Google Scholar). IGF-1 is a VSMC and factor and a for of these decrease in IGF-1 levels in of formation by VSMC and T.C. T. D.A. Res. PubMed Scopus Google but in to by the loss of VSMC Zhang K. M. Res. PubMed Scopus Google Scholar). with this enhanced IGF-1 binding was observed in J.M. J. Vasc. Full Text Full Text PDF PubMed Scopus Google Scholar). IGF-1 of its physiological by binding and its IGF-1R H. 1995; PubMed Scopus Google Scholar). IGF-1R is to IR H. 1995; PubMed Scopus Google and the of insulin is IGF-1R in VSMC R. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). IGF-1R is a critical of VSMC growth and of its expression activation an important role in the of such as growth and J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. Clin. Investig. PubMed Scopus Google Scholar). IGF-1R and other receptors also the function of IGF-1. For to of tyrosine phosphatase to IGF-1R and IGF-1R signaling J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). also that PTPs are important of IGF-1 signaling. However, is for the role of LAR with IGF-1 signaling in vascular cells. the present we investigated the of LAR on cellular and IGF-1-induced signaling pathways VSMC LAR knock-out mice. results that LAR interacts with IGF-1R and regulates IGF-1-induced signaling. Absence of LAR results in increased VSMC proliferation and migration in response to IGF-1 and enhanced neointima formation in response to arterial injury in mice. human was a of and U0126 were was The used were and 3-kinase ERK1/2 and and The IGF-1R used were the in IGF-1R is the in IGF-1R is the residues in IGF-1R are and and and were used in this The was an to amino of human LAR and the 150-kDa extracellular of mouse The was an in the domain of LAR and the 85-kDa C-terminal subunit of human LAR, but not that of mouse mice by of were generated by the (10Yeo T.T. Yang T. Massa S.M. Zhang J.S. Honkaniemi J. Butcher L.L. Longo F.M. J. Neurosc. Res. 1997; 47: 348-360Crossref PubMed Scopus (110) Google Scholar). VSMC were mice that were at the VSMC were wild-type and LAR-/- mice as by S. J. J. PubMed Google Scholar). were in Dulbecco's modified Eagle's fetal bovine as S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). experiments were VSMC and that were growth by in for of and LAR was by in expression and were expressed in and by on as by and PubMed Scopus Google Scholar). of were on and the were with The were with of VSMC at for and with and the were by in were of was by human LAR by of by of LAR the were were generated by of human cells with the recombinant the was on a by and Res. PubMed Scopus Google Scholar). A of the with was by of of VSMC was at a of of 100 in the cells were in for IGF-1R LAR-/- VSMC were treated with 100 IGF-1 for were and IGF-1R was and on protein The were and in the of recombinant LAR at The was by and for were by and with of specific activity of LAR IGF-1R was the LAR tyrosine phosphatase to VSMC as a substrate to the activity of LAR were the of IGF-1R by LAR phosphatase was the of the we used and to IR and as the activity of LAR was by of LAR with 150 at for The of was to the was in by the for The were in a for and were for and were in 150 and protease protease of and were as S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of protein were in VSMC were treated with 100 IGF-1 for and the cell of protein were with of activity was as M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). VSMC were treated with 100 IGF-1 in the of U0126 for were with for and its DNA was as S. J. J. PubMed Google Scholar). cell migration were modified with The of the were with extracellular protein bovine were for in tissue The were with PBS, and with bovine in VSMC were and in VSMC were treated with IGF-1 for and cells in 100 of were the of the with U0126 in the were at in a for The were with PBS, the cells the of the were with a and cells on the of the were for with a The of cells was for was a and levels were at the in the of IGF-1 and were to the and injury was as M. Zhang M.B. Arterioscler. Thromb. Vasc. Biol. 2000; 20: PubMed Scopus Google Scholar). a was and up to the to the were after arterial were at the level of were both were at for the of the and with were by in a and the and were mice all vascular and the of the were in with the of and of were smooth muscle were and with was substrate for substrate for and the of the The were with and with were with and of and in the of of was was used to the of signaling in wild-type and LAR-/- VSMC treated with IGF-1. was at LAR and IGF-1 in J.M. Zhang W.R. Goldstein B.J. 1998; 47: PubMed Scopus Google increased insulin in the basal and insulin resistance by studies in LAR knock-out mice generated by However, in this LAR-/- mice of and were compared with an of it to whether the in insulin body weight, and LAR deficiency To the role of LAR in regulating we the of LAR-/- mice LAR-/- mice were in However, a but significant decrease in their body was observed compared with the wild-type mice. LAR-/- mice also fasting insulin levels and fasting IGF-1 levels compared with the wild-type mice. However, significant was observed in levels of LAR-/- and wild-type mice. Absence of LAR also significant on blood of mice. data indicate that LAR deficiency enhances in and levels and blood in wild-type and mice at of wild-type by wild-type by wild-type by blood blood wild-type by wild-type by in a and IGF-1-induced and IGF-1-induced in VSMC the used to mice may in a level expression of the M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google we LAR expression in VSMC wild-type and mice. LAR was expressed in wild-type VSMC as by to and tissue 1992; PubMed Scopus Google VSMC mice expression of this on these we VSMC these mice to in To the of LAR deficiency on VSMC we compared the of wild-type and LAR-/- VSMC. of cell growth a significant in cell proliferation with in both the However, cell proliferation was significantly in LAR-/- VSMC compared with wild-type VSMC. The expression of insulin receptor is in VSMC, and the of both insulin and IGF-1 are IGF-1 receptor T. 1995; Full Text PDF PubMed Scopus Google Scholar). IGF-1 VSMC proliferation and migration, two critical of the and of neointima formation arterial injury Res. 2000; PubMed Scopus Google Scholar). to the of IGF-1 on the of VSMC, we DNA synthesis and cell migration in wild-type and LAR-/- VSMC. in physiological of IGF-1 J. S. S. J. Clin. Investig. 1997; 100: PubMed Scopus Google Scholar, W.R. Biol. 1998; PubMed Scopus Google a and a in DNA synthesis as by in wild-type and LAR-/- VSMC compared with their was also significantly higher in LAR-/- VSMC compared with wild-type VSMC IGF-1 treatment. was not significantly wild-type and LAR-/- VSMC with IGF-1-induced in both wild-type and LAR-/- VSMC was significantly inhibited by and U0126 for compared with the inhibitors of and inhibitors significant on DNA the and function of VSMC are by their with extracellular R. J. PubMed Scopus Google we the migration of these cells on extracellular proteins. wild-type and LAR-/- VSMC migration and extracellular compared with and compared with bovine the of IGF-1 on migration of VSMC IGF-1 significantly enhanced migration of both wild-type and LAR-/- VSMC but the migration was in LAR-/- VSMC compared with the wild-type cells to their on and U0126 significantly IGF-1-induced migration in both wild-type and LAR-/- VSMC for with the results that of LAR PTP to increased VSMC proliferation in response to and IGF-1 and IGF-1-induced migration of VSMC. results also suggest that the signaling pathways are in IGF-1-induced VSMC proliferation and IGF-1R in LAR-/- VSMC with the that enhanced proliferation and migration in LAR-/- VSMC, we IGF-1R by of Little basal tyrosine phosphorylation of the IGF-1R was present in wild-type LAR-/- VSMC. phosphorylation of the IGF-1R increased IGF-1 in both the cell However, the and of IGF-1R tyrosine phosphorylation was in the of IGF-1-induced IGF-1R phosphorylation was and higher in LAR-/- VSMC in wild-type VSMC at and IGF-1-induced IGF-1R phosphorylation was observed at in LAR-/- VSMC, but not in wild-type VSMC. the tyrosine phosphorylation of IGF-1R in the of LAR may to the enhanced and of LAR-/- VSMC. LAR to and on the that phosphorylation of IR, an IGF-1R in the of LAR and LAR binds directly to IR (9Ahmad F. Goldstein B.J. J. Biol. Chem. 1997; 272: 448-457Abstract Full Text Full Text PDF PubMed Scopus (96) Google we that LAR also binds directly to However, it was not to experiments to this an a domain of LAR of not mouse LAR we were in two to mouse an we whether IGF-1R in VSMC treated with IGF-1 binds to in vitro. in A and and IGF-1R in wild-type and LAR-/- VSMC IGF-1 enhanced the of LAR to IGF-1R and this was in LAR-/- VSMC in wild-type VSMC. To the specificity of we also LAR and the receptor of VSMC treated with were with and was of an LAR and the by not the binding of LAR to IGF-1R by human LAR in mouse VSMC by with by with of LAR with IGF-1R in basal and enhanced binding in response to IGF-1 treatment. Furthermore, enhanced binding of LAR with IGF-1R was observed in human VSMC treated with IGF-1 Together, these results indicate that LAR and directly with IGF-1R and IGF-1R is a substrate of LAR in we whether LAR dephosphorylates IGF-1R in vitro. LAR-/- VSMC were treated with IGF-1 for and IGF-1R in the was with and with recombinant LAR in of with that LAR IGF-1R in a IGF-1R tyrosine dephosphorylation was inhibited in the of a of tyrosine we the specific activity of LAR IGF-1R by the dephosphorylation of an IGF-1R LAR a specific activity of of of also whether IGF-1R tyrosine residues are to those in IR for H. 1992; PubMed Scopus Google and tyrosine residues Zhang W.R. Goldstein B.J. J. Biol. Chem. 1992; Full Text PDF PubMed Google in IR, LAR a specificity in tyrosine residues at and in LAR tyrosine at in to IGF-1R, recombinant LAR not LAR-/- VSMC results the that IGF-1R is a of LAR in LAR IGF-1-induced to tyrosine kinase activity of the IGF-1R and phosphorylation of intracellular including is by its binding of IGF-1 H. 1995; PubMed Scopus Google Scholar, T.C. J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). To whether enhanced IGF-1-induced IGF-1R activation in the of LAR results in increased we activation of and its with and the that IGF-1 results in tyrosine phosphorylation of in both wild-type and LAR-/- VSMC. the in phosphorylation was significantly higher in LAR-/- in wild-type VSMC A and increased tyrosine phosphorylation of results in enhanced with its subunit J.M. M. J. EMBO J. 1992; 11: PubMed Scopus Google we the of in and was increased by in LAR-/- VSMC compared with wild-type cells in response to IGF-1 The increased tyrosine phosphorylation of IGF-1 also to a 90% in with in LAR-/- VSMC compared with the wild-type cells and of protein in by with To whether the increased of with IGF-1 in increased we the activity of this kinase in activity was higher in LAR-/- VSMC compared with wild-type cells A and tyrosine kinase receptors to mitogen-activated protein kinases the activation of T.C. J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). To the role of enhanced binding with in we ERK1/2 ERK1/2 phosphorylation increased significantly in both wild-type and LAR-/- VSMC in response to IGF-1 treatment. phosphorylation of these was significantly higher in LAR-/- VSMC in wild-type cells and ERK1/2 activation in LAR-/- VSMC in response to IGF-1 specific as significant in the phosphorylation of these kinases was observed wild-type and LAR-/- VSMC treated with and Together, these results indicate that of LAR to activation of at two signaling pathways in VSMC treated with IGF-1. LAR in to the role of LAR in vivo in the of hyperplasia. The of mice and LAR-/- mice on in were a to LAR deficiency on these mice are to mice Arterioscler. Thromb. Vasc. Biol. PubMed Scopus Google Scholar). of arterial after injury markedly enhanced in LAR-/- mice compared with wild-type mice were significantly higher in LAR-/- in wild-type and cells were for muscle in and that the was of results suggest that LAR deficiency VSMC proliferation in vivo pathophysiological IGF-1R in the Neointima of LAR-/- the of enhanced IGF-1 signaling observed in LAR-/- VSMC in cell we phosphorylation in arterial of enhanced phosphorylation of was observed in the neointima of LAR-/- mice compared with wild-type mice. results the that LAR plays an important role in of cell proliferation and migration of VSMC. been on the therapeutic of protein phosphorylation for a of all of these studies have focused on the function of PTKs PubMed Scopus Google Scholar). The role of the endogenous inhibitors of to for vascular the present we the in and in vivo of VSMC mice that are in LAR data indicate that this receptor PTP plays an important role in VSMC proliferation and migration in response to IGF-1 and vascular other studies have the of PTKs in these R. PubMed Scopus Google the present data the of PTPs in of VSMC LAR is to have a on insulin signaling. is expressed in (7Ahmad F. Considine R.V. Goldstein B.J. J. Clin. Investig. 1995; 95: 2806-2812Crossref PubMed Scopus (115) Google and increased of LAR with IR after insulin (9Ahmad F. Goldstein B.J. J. Biol. Chem. 1997; 272: 448-457Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Antisense of LAR enhanced insulin signaling in hepatoma cells (6Kulas D.T. Zhang W.R. Goldstein B.J. Furlanetto R.W. Mooney R.A. J. Biol. Chem. 1995; 270: 2435-2438Abstract Full Text Full Text PDF PubMed Scopus (146) Google of this PTP in muscle insulin receptor signaling and insulin resistance in mice J.M. S. S. PubMed Scopus Google Scholar). of LAR by insulin resistance in cells PubMed Scopus Google Scholar). However, for the role of LAR in the of insulin resistance, increased LAR expression and activity were observed in the tissue (7Ahmad F. Considine R.V. Goldstein B.J. J. Clin. Investig. 1995; 95: 2806-2812Crossref PubMed Scopus (115) Google and muscle F. Azevedo J.L. Cortright R. Dohm G.L. Goldstein B.J. J. Clin. Investig. 1997; 100: 449-458Crossref PubMed Scopus (259) Google of obese and to insulin loss in obese subjects is by expression and activity of LAR F. Considine R.V. Goldstein B.J. 1997; Full Text PDF PubMed Scopus (111) Google Scholar). with LAR-/- mice in the present a significant decrease in body weight, fasting insulin, and IGF-1 levels compared with wild-type mice. results that of LAR with IGF-1R is enhanced in response to IGF-1 and IGF-1R is a substrate for LAR in vitro. Furthermore, LAR dephosphorylates IGF-1R tyrosine residues to those by LAR in IR H. 1992; PubMed Scopus Google Scholar, Zhang W.R. Goldstein B.J. J. Biol. Chem. 1992; Full Text PDF PubMed Google and of LAR enhances IGF-1R tyrosine which suggest that LAR is a of IGF-1 signaling in VSMC. data also indicate that LAR is an important of VSMC proliferation and with H. 1997; PubMed Scopus Google enhanced IGF-1R phosphorylation in response to IGF-1 in LAR-/- VSMC to increased phosphorylation of protein, and its with protein, is that binding of to the domain of J.M. M. J. EMBO J. 1992; 11: PubMed Scopus Google and formation of complex to the of kinases T.C. J. J. Biol. Chem. Full Text PDF PubMed Google Scholar). data are in with these as we have observed increased activation of and ERK1/2 in both wild-type and LAR-/- VSMC treated with IGF-1. inhibitors of and kinase of inhibited IGF-1-induced and significantly IGF-1-induced migration of VSMC in both wild-type and LAR-/- VSMC and results indicate that both and ERK1/2 are in on growth and migration in VSMC. Furthermore, IGF-1-induced and ERK1/2 activation are significantly higher in LAR-/- VSMC in wild-type VSMC and these are correlated with higher and migration of LAR-/- VSMC compared with wild-type cells IGF-1 treatment. results indicate that protein tyrosine dephosphorylation by LAR, which activation by IGF-1, regulates signaling pathways that have pathophysiological IGF-1-induced in the of LAR, may lead to activation of such as the and phosphorylation of S. J. 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The that tyrosine phosphorylation of may increased growth and is by the that IGF-1 causes of M. S. T. T. PubMed Scopus Google its is enhanced in LAR-/- VSMC compared with wild-type cells in response to IGF-1 S. M. S. and R. and is in growth VSMC proliferation S. C.M. Res. PubMed Scopus Google Scholar). on data with to IGF-1-induced proliferation and migration of VSMC LAR-/- we that of LAR VSMC proliferation after arterial Vascular injury causes the of many growth and including IGF-1, which vascular growth J.S. J. Clin. Investig. 1992; PubMed Scopus Google Scholar). of IGF-1 in mouse VSMC was to neointima formation in response to arterial injury PubMed Scopus Google Scholar). was that of a phosphatase that but not with PTPs and is an endogenous of in VSMC, also inhibited J. Arterioscler. Thromb. Vasc. Biol. PubMed Scopus Google Scholar). data that of LAR, a of IGF-1 results in enhanced neointima formation in the in response to injury is with these to increased signaling in LAR-/- VSMC compared with wild-type increased IGF-1R phosphorylation was observed in neointima of LAR-/- mice compared with that in wild-type mice that LAR is in human with not that LAR is a critical of VSMC this is the that LAR regulates migration and proliferation of VSMC and that deficiency in LAR expression markedly the of expression of LAR in VSMC enhanced expression of this PTP in and muscle tissue to the of insulin PTP is an of by many for of and data the complex and PTPs in regulating multiple signaling pathways in vivo and the PTP inhibitors have on insulin resistance and are to of at for