Here we Calceolarioside-B demonstrate that Cav-1 and PTRF/Cavin, a new backbone Gelsemine protein in caveolar structure, regulate IGF-IR internalization and plasma membrane replacement. Cav-1 is a target of IGF-IR and plays a role in IGF-IR signalling pathway. IGF1causes Cav-1 tyrosine phosphorylation and IGF-IR co-localization with Cav-1 in the lipid rafts enriched fractions on plasma membrane. Our previous results showed that Cav-1 silencing impairs the activation of IGF-IR signalling pathway. IGF-IR and Cav-1 co-localize in basal condition and internalize following IGF1stimulation. Co-immunoprecipitation results demonstrate a direct interaction between these proteins with a time course consistent with protein redistribution as shown by immunofluorescence data. These data suggest a role of Cav-1 in the early steps of IGF-IR endocytosis as already shown for IGF1signalling in caveolae. As shown by FACS and biotinylation assay, Cav-1 silencing decreases significantly IGFIR internalization. Silencing of Cav-1 does not abolish completely IGF-IR endocytosis suggesting the presence of alternative pathway. It has been shown that Clathrin coated-pits could participate to IGFIR internalization. Here the down regulation of Clathrin Heavy Chain did not impair IGF-IR internalization. This conclusion was further supported by the finding that IGF-IR and Clathrin Heavy Chain did not co-localize in Hacat cells in the presence of IGF1. PTRF/Cavin, a recently identified caveolar protein, could act to maintain caveolae integrity, or as transcription terminator, as suggested also by the finding that PTRF/Cavin could be recruited to the nucleus by insulin stimulation. Our experiments confirmed that Cav-1 and PTRF/Cavin co-localize in the plasma membrane and show that IGF1increases their association with IGF-IR. These findings suggest that Cav-1 and PTRF/Cavin could cooperate to determine IGF-IR internalization but with two different roles. In fact we observed two different time courses of association between Cav-1 and PTRF/Cavin with IGF-IR. IGF1binding to IGF-IR also internalizes Cav-1 and PTRF/Cavin with quite different pattern of redistribution of these two proteins as shown by figure 1.