Insulin-Like Growth Factor-I Signaling in Smooth Muscle Cells Is Regulated by Ligand Binding to the 177CYDMKTTC184 Sequence of the β3-Subunit of αVβ3

Maile, Laura A.; Busby, Walker H.; Sitko, Kevin; Capps, Byron E.; Sergent, Tiffany; Badley-Clarke, Jane; Clemmons, David R.

doi:10.1210/me.2005-0241

Cited by 45 publications

(50 citation statements)

References 22 publications

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“…We found that a 6 amino acid loop (positions 203-209) contained this site (39). An antibody to this region inhibited vitronectin binding, and prevented phosphorylation of β3 stimulated by vitronectin.…”

Section: Role Of Hyperglycemiamentioning

confidence: 80%

Role of the integrin αVβ3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress

Clemmons

Maile

Ling

et al. 2007

Growth Hormone & IGF Research

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Under usual conditions, the role of IGF-I in vascular cell types is to maintain cellular protein synthesis and cell size, and even excess IGF-I does not stimulate proliferation. In pathophysiologic states, such as hyperglycemia, smooth muscle cells (SMC) de-differentiate and change their responsiveness to IGF-I. During hyperglycemia IGF-I stimulates both SMC migration and proliferation. Our laboratory has investigated the molecular mechanism by which this change is mediated. Following hyperglycemia SMC secrete increased concentrations of thrombospondin, vitronectin and osteopontin, ligands for the integrin αVβ3. Activation of αVβ3 stimulates recruitment of a tyrosine phosphatase, SHP-2. Exposure of SMC to IGF-I results in phosphorylation of the transmembrane protein, SHPS-1, which provides a docking site for αVβ3-associated SHP-2. After IGF-I stimulation SHP-2 associates with Src kinase, which associates with the signaling protein Shc. Src phosphorylates Shc, resulting in activation of MAP kinases, which are necessary both for stimulation of cell proliferation and migration. Blocking activation of αVβ3 results in an inability of IGF-I to stimulate Shc phosphorylation. Under conditions of normoglycemia, there are insufficient αVβ3 ligands to recruit SHP-2, and no increase in Shc phosphorylation can be demonstrated in SMC. In contrast, if αVβ3 ligands are added to cells in normal glucose, the signaling events that are necessary for Shc phosphorylation can be reconstituted. Therefore when SMC are exposed to normal glucose they are protected from excessive stimulation of mitogenesis by IGF-I. With hyperglycemia there is a marked increased in αVβ3 ligands and Shc phosphorylation in response to IGF-I is sustained. These findings indicate that in SMC hyperglycemic stress may leads to altered IGF-I signaling, which allows the cells to undergo a mitogenic response, and which may contribute to the development of atherosclerosis.

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Section: Role Of Hyperglycemiamentioning

confidence: 80%

Role of the integrin αVβ3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress

Clemmons

Maile

Ling

et al. 2007

Growth Hormone & IGF Research

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“…This crossregulation involves not only association of the integrin with IGF1R (Brooks et al, 1997;Clemmons and Maile, 2005;De et al, 2003;Mira et al, 1999;Schneller et al, 1997), but also integrin-mediated control over the localization and/or activation of IGF1R signaling components or regulators, including IRS-1, SHC and SH2-domain-containing proteins, tyrosine phosphatase-2 (SHP-2) and substrate-1 (SHPS-1) (Clemmons, 2007;Clemmons and Maile, 2005;Clemmons et al, 2007;Lee and Streuli, 1999;Vuori and Ruoslahti, 1994). Indeed, IGF1R stimulation enhances the ligand-binding affinity of the avb3 integrin, with no change in receptor expression levels Maile et al, 2002), and avb3 stimulation enhances IGF1-mediated migration and proliferation (Maile et al, 2006a;Maile et al, 2006b;Xi et al, 2008). Moreover, integrin inhibition blocks IGF-stimulated migration (Clemmons et al, 1999;Doerr and Jones, 1996;KabirSalmani et al, 2003) and expression of a dominant-negative IGF1R construct inhibits MDA-MB-231 and MDA-MB-435 breast cancer cell invasion and metastasis in vitro and in vivo (Dunn et al, 1998;Sachdev et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation

Beauvais

Rapraeger

2010

Journal of Cell Science

104

144

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SummarySyndecan-1 (Sdc1) engages and activates the avb3 (and/or avb5) integrin when clustered in human carcinoma and endothelial cells. Although the engagement is extracellular, the activation mechanism is cytoplasmic. This talin-dependent, inside-out signaling pathway is activated downstream of the insulin-like growth factor-1 receptor (IGF1R), whose kinase activity is triggered by Sdc1 clustering. In vitro binding assays using purified receptors suggest that association of the Sdc1 ectodomain with the integrin provides a 'docking face' for IGF1R. IGF1R docking and activation of the associated integrin is blocked by synstatin (SSTN 92-119 ), a peptide derived from the integrin engagement site in Sdc1. IGF1R colocalizes with avb3 integrin and Sdc1 in focal contacts, but fails to associate with or activate the integrin in cells either lacking Sdc1 or expressing Sdc1 D67-121 , a mutant that is unable to form the Sdc1-integrin-IGF1R ternary complex. Integrin activation is also blocked by IGF1R inhibitors or by silencing IGF1R or talin expression with smallinterfering RNAs (siRNAs). In both cases, expression of the constitutively active talin F23 head domain rescues integrin activation.We recently reported that SSTN 92-119 blocks angiogenesis and impairs tumor growth in mice, therefore this Sdc1-mediated integrin regulatory mechanism might be a crucial regulator of disease processes known to rely on these integrins, including tumor cell metastasis and tumor-induced angiogenesis.

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“…When SMCs are grown in 25 mmol/l glucose and then exposed to IGF-I, Shc and MAPK phosphorylation are significantly increased. In contrast, when SMCs are grown in 5 mmol/l glucose, there is no increase in Shc or MAPK phosphorylation (10).…”

mentioning

confidence: 84%

“…When SMCs grown in 5 mmol/l glucose are exposed to IGF-I, there is no increase in migration or proliferation (9). However, when glucose is increased to 25 mmol/l, IGF-I stimulates significant increases in migration and proliferation (10). Phosphorylation of Shc and subsequent activation of the mitogenactivated protein kinase (MAPK) pathway is absolutely required for the migration and proliferation of SMCs in response to IGF-I (11).…”

mentioning

confidence: 99%

Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo

et al. 2008

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OBJECTIVE-Smooth muscle cell (SMC) maintained in medium containing normal levels of glucose do not proliferate in response to IGF-I, whereas cells maintained in medium containing 25 mmol/l glucose can respond. The aim of this study was to determine whether signaling events that have been shown to be required for stimulation of SMC growth were regulated by glucose concentrations in vivo. RESEARCH DESIGN AND METHODS-We compared IGF-Istimulated signaling events and growth in the aortic smooth muscle cells from normal and hyperglycemic mice.RESULTS-We determined that, in mice, hyperglycemia was associated with an increase in formation of the integrin-associated protein (IAP)/Src homology 2 domaine containing tyrosine phosphatase substrate 1 (SHPS-1) complex. There was a corresponding increase in Shc recruitment to SHPS-1 and Shc phosphorylation in response to IGF-I. There was also an increase in mitogen-activated protein kinase activation and SMC proliferation. The increase in IAP association with SHPS-1 in hyperglycemia appeared to be due to the protection of IAP from cleavage that occurred during exposure to normal glucose. In addition, we demonstrated that the protease responsible for IAP cleavage was matrix metalloprotease-2. An anti-IAP antibody that disrupted the IAP-SHPS-1 association resulted in complete inhibition of IGF-I-stimulated proliferation.CONCLUSIONS-Taken together, our results support a model in which hyperglycemia is associated with a reduction in IAP cleavage, thus allowing the formation of the IAP-SHPS-1 signaling complex that is required for IGF-I-stimulated proliferation of SMC.

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Insulin-Like Growth Factor-I Signaling in Smooth Muscle Cells Is Regulated by Ligand Binding to the 177CYDMKTTC184 Sequence of the β3-Subunit of αVβ3

Cited by 45 publications

References 22 publications

Role of the integrin αVβ3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress

Role of the integrin αVβ3 in mediating increased smooth muscle cell responsiveness to IGF-I in response to hyperglycemic stress

Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation

Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo

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