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Molecular and Cellular Biology, July 2001, p. 4553-4567, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4553-4567.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Redistribution of Glycolipid Raft Domain Components Induces Insulin-Mimetic Signaling in Rat Adipocytes

Günter Müller,* Christian Jung, Susanne Wied, Stefan Welte, Holger Jordan, and Wendelin Frick

Aventis Pharma Germany, 65926 Frankfurt am Main, Germany

Received 8 November 2000/Returned for modification 8 February 2001/Accepted 15 April 2001

Caveolae and caveolin-containing detergent-insoluble glycolipid-enriched rafts (DIG) have been implicated to function as plasma membrane microcompartments or domains for the preassembly of signaling complexes, keeping them in the basal inactive state. So far, only limited in vivo evidence is available for the regulation of the interaction between caveolae-DIG and signaling components in response to extracellular stimuli. Here, we demonstrate that in isolated rat adipocytes, synthetic intracellular caveolin binding domain (CBD) peptide derived from caveolin-associated pp59Lyn (10 to 100 µM) or exogenous phosphoinositolglycan derived from glycosyl-phosphatidylinositol (GPI) membrane protein anchor (PIG; 1 to 10 µM) triggers the concentration-dependent release of caveolar components and the GPI-anchored protein Gce1, as well as the nonreceptor tyrosine kinases pp59Lyn and pp125Fak, from interaction with caveolin (up to 45 to 85%). This dissociation, which parallels redistribution of the components from DIG to non-DIG areas of the adipocyte plasma membrane (up to 30 to 75%), is accompanied by tyrosine phosphorylation and activation of pp59Lyn and pp125Fak (up to 8- and 11-fold) but not of the insulin receptor. This correlates well to increased tyrosine phosphorylation of caveolin and the insulin receptor substrate protein 1 (up to 6- and 15-fold), as well as elevated phosphatidylinositol-3' kinase activity and glucose transport (to up to 7- and 13-fold). Insulin-mimetic signaling by both CBD peptide and PIG as well as redistribution induced by CBD peptide, but not by PIG, was blocked by synthetic intracellular caveolin scaffolding domain (CSD) peptide. These data suggest that in adipocytes a subset of signaling components is concentrated at caveolae-DIG via the interaction between their CBD and the CSD of caveolin. These inhibitory interactions are relieved by PIG. Thus, caveolae-DIG may operate as signalosomes for insulin-independent positive cross talk to metabolic insulin signaling downstream of the insulin receptor based on redistribution and accompanying activation of nonreceptor tyrosine kinases.

* Corresponding author. Mailing address: Aventis Pharma Germany GmbH, Disease Group Metabolic Diseases, Bldg. H825, 65926 Frankfurt am Main, Germany. Phone: 4969-305-4271. Fax: 4969-305-81901. E-mail: Guenter.Mueller{at}aventis.com.

Molecular and Cellular Biology, July 2001, p. 4553-4567, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4553-4567.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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