Regulation of tyrosine phosphorylation on insulin receptor substrate-1 (IRS-1) is essential for insulin signaling. The protein tyrosine phosphatase (PTP) C1-Ten/Tensin2 has been implicated in the regulation of IRS-1, but the molecular basis of this dephosphorylation is not fully understood. Here, we demonstrate that the cellular phosphatase activity of C1-Ten/Tensin2 on IRS-1 is mediated by the binding of the C1-Ten/Tensin2 Src-homology 2 (SH2) domain to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P₃). We show that the role of C1-Ten/Tensin2 is dependent on insulin-induced phosphoinositide 3-kinase activity. The C1-Ten/Tensin2 SH2 domain showed strong preference and high affinity for PtdIns(3,4,5)P₃. Using site-directed mutagenesis, we identified three basic residues in the C1-Ten/Tensin2 SH2 domain that were critical for PtdIns(3,4,5)P₃ binding but were not involved in phosphotyrosine binding and PTP activity. Using a PtdIns(3,4,5)P₃ binding-deficient mutant, we showed that the specific binding of the C1-Ten/Tensin2 SH2 domain to PtdIns(3,4,5)P₃ allowed C1-Ten/Tensin2 to function as a PTP in cells. Collectively, our findings suggest that the interaction between the C1-Ten/Tensin2 SH2 domain and PtdIns(3,4,5)P₃ produces a negative feedback loop of insulin signaling through IRS-1.

胰岛素受体底物1（IRS-1）上酪氨酸磷酸化的调节对于胰岛素信号传导至关重要。蛋白酪氨酸磷酸酶（PTP）C1-Ten / Tensin2已参与IRS-1的调控，但这种去磷酸化的分子基础尚不完全清楚。在这里，我们证明了C1-Ten / Tensin2在IRS-1上的细胞磷酸酶活性是由C1-Ten / Tensin2 Src-homology 2（SH2）域与磷脂酰肌醇3,4,5-三磷酸（ PtdIns（3,4,5）P ₃）。我们表明，C1-Ten / Tensin2的作用取决于胰岛素诱导的磷酸肌醇3-激酶活性。C1-Ten / Tensin2 SH2域显示出对PtdIns（3,4,5）P _3的强烈偏好和高亲和力。使用定点诱变，我们确定了C1-Ten / Tensin2 SH2域中的三个基本残基，这些残基对于PtdIns（3,4,5）P ₃结合至关重要，但不参与磷酸酪氨酸结合和PTP活性。使用PtdIns（3,4,5）P ₃结合缺陷型突变体，我们表明C1-Ten / Tensin2 SH2域与PtdIns（3,4,5）P ₃的特异性结合使C1-Ten / Tensin2能够在细胞中充当PTP。总的来说，我们的发现表明C1-Ten / Tensin2 SH2结构域与PtdIns（3,4,5）P ₃之间的相互作用产生了一个通过IRS-1产生的胰岛素信号负反馈回路。