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

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.

mTOR: A Link from the Extracellular Milieu to Transcriptional Regulation of Oligodendrocyte Development

“…However, selective IGF-I stimulation of the IGF-1R in vitro under conditions where insulin levels are sufficient only to stimulate the insulin receptor but not the IGF-IR revealed roles for IGF signalling per se in OPC proliferation and protein synthesis as well as survival (Jiang et al, 2001; Ness et al, 2002; Ness and Wood, 2002; Frederick and Wood, 2004; Cui and Almazan, 2007; Frederick et al, 2007; Romanelli et al, 2007, 2009; Bibollet-Bahena and Almazan, 2009; Min et al, 2012). The effect of IGF-I in multiple processes during development of this lineage has made it difficult to determine whether IGF-I also directly regulates oligodendrocyte differentiation.…”

Effects of IGF-1 onIKandIK1Channels via PI3K/Akt Signaling in Neonatal Cardiac Myocytes

“…IGF-1 is known to activate PI3K and its downstream target Akt, a serine threonine kinase, also known as protein kinase [10–12]. IGF-1 binding to its receptor with downstream activation of PI3K and Akt has been demonstrated [13, 14].…”

Small molecule induction of neural‐like cells from bone marrow‐mesenchymal stem cells

“…LY294002, as a synthetic compound [Walker et al, 2000], has been used widely as pharmaceutical tools for the involvement of the PI3K pathway in various biological systems [Romanelli et al, 2009; Tang et al, 2009]. For example, LY294002 has been shown to inhibit rat NPC proliferation [Hsu et al, 2005; Hu et al, 2010], which suggested that PI3K/AKT signal has been implicated in cell cycle control.…”