The Heparin Binding Domain of Vitronectin Is the Region that Is Required to Enhance Insulin-Like Growth Factor-I Signaling

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

doi:10.1210/me.2005-0382

Cited by 32 publications

(37 citation statements)

References 32 publications

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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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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

View full text Add to dashboard Cite

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“…We next tested whether there was any cross-talk between the effects of g-OxLDL and ␣V␤3 ligand occupancy on IGF-I signaling responses. We have determined that binding of the Vn HBD to a specific region of the ␤3 subunit, referred to as the cysteine loop, is sufficient to mediate the positive effects of Vn on the response of SMC to IGF-I (20,39). The addition of a peptide homologous to the Vn HBD was sufficient to permit a 1.8 Ϯ 0.08-fold increase in cell number in response to IGF-I.…”

Section: G-oxldl Enhances Igf-i Signaling In a Manner Distinct From Cmentioning

confidence: 99%

Glucose-Oxidized Low-Density Lipoproteins Enhance Insulin-Like Growth Factor I-Stimulated Smooth Muscle Cell Proliferation by Inhibiting Integrin-Associated Protein Cleavage

et al. 2008

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Prior published reports have demonstrated that glucose-oxidized low-density lipoproteins (g-Ox-LDL) enhance the proliferative response of vascular smooth muscle cells (SMC) to IGF-I. Our previous studies have determined that the regulation of cleavage of integrin-associated protein (IAP) by matrix-metalloprotease-2 (MMP-2) in diabetic mice in response to hyperglycemia is a key regulator of the response of SMC to IGF-I. Because chronic hyperglycemia enhances glucose-induced LDL oxidation, these studies were conducted to determine whether g-OxLDL modulates the response of SMC to IGF-I by regulating MMP-2-mediated cleavage of IAP. We determined that exposure of SMC to g-OxLDL, but not native LDL, was sufficient to facilitate an increase in cell proliferation in response to IGF-I. Exposure to an anti-CD36 antibody, which has been shown to inhibit g-OxLDLmediated signaling, inhibited the effects of g-OxLDL on IGF-I-stimulated SMC proliferation. The effect of g-OxLDL could be attributed, in part, to an associated decrease in proteolytic cleavage of IAP leading to increase in the basal association between IAP and Src homology 2 domain-containing protein tyrosine phosphatase substrate-1, which is required for IGF-I-stimulated proliferation. The inhibitory effect of g-OxLDL on IAP cleavage appeared to be due to its ability to decrease the amount of activated MMP-2, the protease responsible for IAP cleavage. In conclusion, these data provide a molecular mechanism to explain previous studies that have reported an enhancing effect of g-OxLDL on IGF-I-stimulated SMC proliferation. (Endocrinology 150: 1321-1329, 2009)

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“…More importantly, the antibody was found to inhibit IGF-Istimulated activation of Shc and MAP kinase, and blocked cell migration and proliferation. To confirm that hyperglycemia induced β3 ligands, vitronectin was added to SMC in low glucose, and the ability of IGF-I to stimulate signaling leading to enhanced cell migration and proliferation was assessed (40). Under these conditions vitronectin stimulated Shc and MAP kinase phosphorylation, and enhanced the ability of IGF-I to promote cell growth.…”

Section: Role Of Hyperglycemiamentioning

confidence: 99%

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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The Heparin Binding Domain of Vitronectin Is the Region that Is Required to Enhance Insulin-Like Growth Factor-I Signaling

Cited by 32 publications

References 32 publications

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

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

Glucose-Oxidized Low-Density Lipoproteins Enhance Insulin-Like Growth Factor I-Stimulated Smooth Muscle Cell Proliferation by Inhibiting Integrin-Associated Protein Cleavage

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

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