Caveolae are hot spots in IGF-I signalling as suggested by the facts that IGF-I receptors localize in caveolae, directly interact with and tyrosine phosphorylate caveolin 1, the major caveolar protein. Also a number of IGF-IR substrates reside in caveolae, supporting a role of these organelles in the regulation of IGF-I action. Recently, we have demonstrated that IGF-I could specifically regulate Shc phosphorylation in caveolae. Here we show that also IRS1 localizes in this region where it is tyrosine phosphorylated in the presence of IGF-I. Moreover, IRS1 co-immunoprecipitates with caveolin I and the specific phosphocaveolin 1-IRS1 interaction is increased by IGF-I. (C) 2004 Elsevier Inc. All rights reserved.