Insulin-like growth factor-I-stimulated Akt phosphorylation and oligodendrocyte progenitor cell survival require cholesterol-enriched membranes

✍ Scribed by Robert J. Romanelli; Kedar R. Mahajan; Clifton G. Fulmer; Teresa L. Wood

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 268 KB
• Volume: 87
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.22099

✦ Synopsis

Abstract

Previously we showed that insulin‐like growth factor‐I (IGF‐I) promotes sustained phosphorylation of Akt in oligodendrocyte progenitor cells (OPCs) and that Akt phosphorylation is required for survival of these cells. The direct mechanisms, however, by which IGF‐I promotes Akt phosphorylation are currently undefined. Recently, cholesterol‐enriched membranes (CEMs) have been implicated in regulation of growth factor‐mediated activation of the PI3K/Akt pathway and survival of mature oligodendrocytes; however, less is know about their role in OPC survival. In the present study, we investigate the role of CEMs in IGF‐I‐mediated Akt phosphorylation and OPC survival. We report that acute disruption of membrane cholesterol with methyl‐β‐cyclodextrin results in altered OPC morphology and inhibition of IGF‐I‐mediated Akt phosphorylation. We also report that long‐term inhibition of cholesterol biosynthesis with 25‐hydroxycholesterol blocks IGF‐I stimulated Akt phosphorylation and cell survival. Moreover, we show that the PI3K regulatory subunit, p85, Akt, and the IGF‐IR are sequestered within cholesterol‐enriched fractions in steady‐state stimulation of the IGF‐IR and that phosphorylated Akt and IGF‐IR are present in cholesterol‐enriched fractions with IGF‐I stimulation. Together, the results of these studies support a role for CEMs or “lipid rafts” in IGF‐I‐mediated Akt phosphorylation and provide a better understanding of the mechanisms by which IGF‐I promotes OPC survival. © 2009 Wiley‐Liss, Inc.