Direct interaction of effector proteins such as the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), SYP (SH2-domain-containing tyrosine phosphatase) and GAP (Ras-GTPase activating protein) with the insulin receptor (IR) and insulin-like growth factor-1 (IGF-1) type 1 receptor (IGF-1R) has been reported in some studies. Interaction of SYP and GAP with IR and IGF-1R was re-investigated here in the two-hybrid system by assessing his3/lacZ activation in S. cerevisiae. The experiments were performed with the cytoplasmic beta domain of IR and IGF-1R and various SH2-subdomains of SYP and GAP. None of the subdomains of SYP and GAP tested were able to activate his3/lacZ, whereas these reporter genes were strongly activated when p85 was used as we have recently shown. Thus, interaction of SYP and GAP with IR and IGF-1R, if any, would be weak and/or transient as compared to that of p85.