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Effect of Cholesterol Depletion on Mitogenesis and Survival: The Role of Caveolar and Noncaveolar Domains in Insulin-Like Growth Factor-Mediated Cellular Function

Endocrine Sciences (L.C.M., M.W.), Maternal and Fetal Health Research Centre (M.J.T.), and Smooth Muscle Physiology Group (M.J.T.), Cardiovascular Research, University of Manchester, Manchester M13 9PT, United Kingdom

Address all correspondence and requests for reprints to: Melissa Westwood, Endocrine Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom. E-mail: melissa.westwood{at}manchester.ac.uk.

The type 1 IGF receptor (IGF-IR) is thought to localize to a subset of lipid rafts, known as caveolae, but the impact on IGF signaling remains controversial. We investigated this potential regulatory mechanism by assessing IGF function in caveolae-positive (3T3L1 and NWTb3) and -negative (HepG2) cells. Coimmunoprecipitation studies demonstrated that IGF-IR and insulin receptor substrate 1 associated with caveolin, a caveolar marker, in 3T3L1 and NWTb3 cells. Subcellular fractionation showed that methyl-cyclodextrin, which disrupts lipid rafts by sequestration of cholesterol, disrupted the colocalization of caveolin and the IGF-IR at the plasma membrane. Methyl-cyclodextrin did not alter IGF-I-induced 3T3L1 or NWTb3 proliferation but significantly impaired the ability of IGF-I to protect these cells from apoptosis. Immunoblotting revealed that methyl-cyclodextrin had no effect on IGF-I-induced activation of the IGF-IR or insulin receptor substrate 1 but increased and decreased the phosphorylation of MAPK and protein kinase B, respectively. In caveolae-negative HepG2 cells, the effect of methyl-cyclodextrin on IGF signaling and cellular function was similar to that observed in caveolae-positive 3T3L1 and NWTb3 cells. Furthermore, transfecting caveolin into HepG2 cells to give morphologically identifiable caveolae made no difference to IGF action, despite a demonstrable interaction between caveolin and the IGF-IR. This suggests that although IGF-IR localizes to caveolin-rich subcellular fractions and coimmunoprecipitates with caveolin, caveolae may not be obligatory for IGF signaling.

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