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

Abstract

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.

Insulin-like Growth Factor-I-stimulated Insulin Receptor Substrate-1 Negatively Regulates Src Homology 2 Domain-containing Protein-tyrosine Phosphatase Substrate-1 Function in Vascular Smooth Muscle Cells

“…Our prior studies have shown that when IRS-1 levels are substantially increased (e.g. VSMCs maintained in 5 mM glucose), SHPS-1 phosphorylation, SHP-2 transfer, and Shc/MAPK activation are suppressed (29,70). Consequently, although the protein synthesis response to IGF-I is maintained, the cell migration and proliferation responses are significantly decreased.…”

“…In normal mice, VSMCs are maintained in the quiescent state (71,72) and have a minimal proliferative response to IGF-I administration. In contrast, the presence of diabetes cell proliferation is increased substantially (70). Because differentiated VSMCs in blood vessels are maintained in a non-proliferative state, expression of IRS-1 may be one of the important determinants that allow normal protein synthesis and hypertrophic responses to IGF-I and insulin while functioning simultaneously to inhibit cell replication.…”

Attenuation of proliferation and migration of retinal pericytes in the absence of thrombospondin-1

“…TSP1 also interacts with ␣ v ␤ 3 -integrin through CD47 (integrin-associated protein) impacting VSMC adhesion and migration (21). Furthermore, expression of CD47 and its interaction with TSP1 have been shown to be important in the proliferative and migratory responses of VSMCs to IGF-I (30). However, the role of these interactions in the modulation of retinal PC adhesion and migration requires further investigation.…”

Recruitment of Nox4 to a Plasma Membrane Scaffold Is Required for Localized Reactive Oxygen Species Generation and Sustained Src Activation in Response to Insulin-like Growth Factor-I

“…Hyperglycemia was induced in C57/B6 mice (Taconic, Hudson, NY) using the low dose streptozotocin protocol previously described (20). Briefly, after withdrawal of food for 4 h, the mice were injected intraperitoneally with streptozotocin (50 mg/kg) (n ϭ 72) daily for 5 days.…”