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Submitted on April 3, 2003
Accepted on August 12, 2003
1 Department of Endocrinology and Metabolism, University of Genova, Genova and Department of Biology, University of Padova, Padova, Italy
* To whom correspondence should be addressed. E-mail: record{at}unige.it.
Caveolae are lipid raft microdomains that regulate endocytosis and signal transduction. IGF-I Receptor (IGF-IR) localizes in caveolae and tyrosine phosphorylates caveolin 1, supporting a role of these subcellular regions in the compartmentalization of IGF-I signaling. Shc is the main mediator of IGF-I mitogenic action coupling IGF-IR phosphorylation to Ras-MAP Kinases activation. Here we show that IGF-I induces Shc tyrosine phosphorylation in the caveolae with a time-course significantly different from that observed in the non raft cellular fractions. In the same time, IGF-I recruits Grb2 to caveolae and activates p42/p44 MAP Kinases in these microdomains. Src family kinases regulate IGF-I action through a Shc dependent mechanism. In R-IGF-IRWT cells, IGF-I causes Fyn enrichment in the caveolae with a time-course consistent with Shc phosphorylation and Grb2 recruitment in these regions. Finally, we have observed that, after IGF-I stimulation, IGF-IR and Fyn colocalize in lipid raft caveolin 1 enriched microdomains. Since Insulin and IGF-I share common substrates, the effect of Insulin on these cellular processes was measured. Here we show that also Insulin induces Shc phosphorylation and Grb2 recruitment to caveolae but with a significantly different time-course compared with IGF-I. Our results suggest that: 1) IGF-I causes the colocalization of signaling proteins in caveolae through a phosphorylation regulated mechanism and 2) the time-course of phosphorylation and recruitment of substrates in caveolae by IR and IGF-IR could determine the specific actions of these receptors.
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