IAP association with SHPS-1 regulates IGF-I signaling in vivo

Abstract

Objective: SMC maintained in medium containing normal levels of glucose do not proliferate in response to IGF-I whereas cells maintained in medium containing 25 mM glucose can respond. The aim of this study was to determine whether signaling events that have been shown to be required for stimulation of smooth muscle cell growth were regulated by glucose concentrations in vivo.

Methods: We compared IGF-I stimulated 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)/SHP-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 MAP 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 which occurred during exposure to normal glucose. In addition we demonstrated that the protease responsible for IAP cleavage was MMP-2. An anti-IAP antibody that disrupted IAP-SHPS-1 association resulted in complete inhibition of IGF-I stimulated proliferation.

Conclusion: 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 which is required for IGF-I stimulated proliferation of SMC.