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

Abstract

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.

Insulin-like Growth Factor (IGF) Signaling Requires αvβ3-IGF1-IGF Type 1 Receptor (IGF1R) Ternary Complex Formation in Anchorage Independence, and the Complex Formation Does Not Require IGF1R and Src Activation

“…These findings suggest that ␣v␤3-IGF1 interaction is critical for IGF signaling (5). These findings are not consistent with a current paradigm in which IGF1 binds to IGF1R, ␣v␤3 binds to ECM ligands, and two separate signals merge inside the cells (1,(15)(16)(17)(18)(19). ␣v␤3 is a receptor for many ECM and non-ECM ligands.…”

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

“…These two receptors crossregulate each other in a number of cell types, including cancer, endothelial and vascular smooth muscle cells (Bahr and Groner, 2005;Clemmons, 2007;Delafontaine et al, 2004). 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).…”

Diabetes and Cancer: A Consensus Report

“…For example, hyperglycemia allows IGF-I to stimulate vascular smooth muscle cell proliferation and migration. 53 Although this process has been linked to the pathophysiology of atherosclerosis, abnormal vasculature growth is also a hallmark of cancer.…”