Dynamic association of human insulin receptor with lipid rafts in cells lacking caveolae

Department of Molecular Medicine, National Public Health Institute, Biomedicum Helsinki, PO Box 104, Haartmaninkatu 8, 00251 Helsinki, Finland.
EMBO Reports (Impact Factor: 9.06). 02/2002; 3(1):95-100. DOI: 10.1093/embo-reports/kvf010
Source: PubMed


Cholesterol-sphingolipid rich plasma membrane domains, known as rafts, have emerged as important regulators of signal transduction. The adipocyte insulin receptor (IR) is localized to and signals via caveolae that are formed by polymerization of caveolins. Caveolin binds to IR and stimulates signalling. We report that, in liver-derived cells lacking caveolae, autophosphorylation of the endogenous IR is dependent on raft lipids, being compromised by acute cyclodextrin-mediated cholesterol depletion or by antibody clustering of glycosphingolipids. Moreover, we provide evidence that IR becomes recruited to detergent-resistant domains upon ligand binding and that clustering of GM2 ganglioside inhibits IR signalling apparently by excluding the ligand-bound IR from these domains. Our results indicate that, in cells derived from liver, an important insulin target tissue, caveolae are not required for insulin signalling. Rather, the dynamic recruitment of the ligand-bound IR into rafts may serve to regulate interactions in the initiation of the IR signalling cascade.

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    • "The IR has also been observed in caveolin-enriched hepatic plasma membrane microdomains that rapidly associate with the actin cytoskeleton in response to insulin [58]. IR autophosphorylation is thought to release a constraint that maintains the IR on the microvilli and allows free, mobile insulin-bound IR to reach competent membrane environments [59] [60]. The link with the actin network appears to be a key component of IR traffic because ANXA2 is also linked with the CEACAM1/b-catenin complexes (Fig. 5) that were shown to be involved in glucose metabolism and IR regulation [61] [62]. "
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    • "downstream signaling pathways [31] [32] [33] [34] [35]. Thus, the obtained results indicate that marked reduction in MPP1 in HEL cells results in significant inhibition of MAP kinase signaling, pointing to the role of this protein in proper lateral membrane organization crucial for signal transduction. "
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    • "Specific proteins, including many signaling proteins, move into lipid rafts, and this process is an important step for certain signal transduction events in a variety of cell types (Simons and Ikonen, 1997). Previously, many reports suggest that lipid rafts serve a functional role in the signal transduction machinery of insulin action (Cohen et al., 2003; Parpal et al., 2001; Vainio et al., 2002; Watson et al., 2001). In this study, we showed that MES accumulated the IR in lipid rafts and increased IR downstream molecule, Akt phosphorylation, but this effect of MES was disrupted by cholesterol ablation (Figs. 2 and 3). "
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