SHIP2 is a phosphatidylinositol 3.4.5-trisphosphate (Ptdlns(3,4,5)P,) 5-phosphatase which contains motif's susceptible to mediate protein-protein interaction. Using yeast two-hybrid. GST-pulldown. and coimmunoprecipitation studies, we isolated the CAP cDNA as a specific partner of SHIP2 proline-rich domain and showed by GST-pulldown experiments that the interaction took place with the SH3C of CAP. The interaction was not modulated in COS-7 cells stimulated by EGF neither in CHO cells overexpressing the insulin receptor in the presence or absence of insulin stimulation. We also showed that SHIP2 was able to coimmunoprecipitate with endogenous c-Cbl protein in the absence of CAP and with the insulin receptor in CHO-IR cell extracts. The presence of SHIP2 in a complex around the insulin receptor could account for the very specific increase in insulin sensitivity of SHIP2 knock-out mice. (C) 2002 Elsevier Science (USA). All rights reserved.