Institute of Biological Chemistry, Academia Sinica, Taipei, 115 Taiwan.
Biochem J. 2011 Oct 1;439(1):151-9. doi: 10.1042/BJ20110799.
PTP1B (protein tyrosine phosphatase 1B) is a negative regulator of IR (insulin receptor) activation and glucose homoeostasis, but the precise molecular mechanisms governing PTP1B substrate selectivity and the regulation of insulin signalling remain unclear. In the present study we have taken advantage of Drosophila as a model organism to establish the role of the SH3 (Src homology 3)/SH2 adaptor protein Dock (Dreadlocks) and its mammalian counterpart Nck in IR regulation by PTPs. We demonstrate that the PTP1B orthologue PTP61F dephosphorylates the Drosophila IR in S2 cells in vitro and attenuates IR-induced eye overgrowth in vivo. Our studies indicate that Dock forms a stable complex with PTP61F and that Dock/PTP61F associate with the IR in response to insulin. We report that Dock is required for effective IR dephosphorylation and inactivation by PTP61F in vitro and in vivo. Furthermore, we demonstrate that Nck interacts with PTP1B and that the Nck/PTP1B complex inducibly associates with the IR for the attenuation of IR activation in mammalian cells. Our studies reveal for the first time that the adaptor protein Dock/Nck attenuates insulin signalling by recruiting PTP61F/PTP1B to its substrate, the IR.
PTP1B（蛋白酪氨酸磷酸酶 1B）是胰岛素受体（IR）激活和葡萄糖动态平衡的负调控因子，但调控 PTP1B 底物选择性和胰岛素信号转导的精确分子机制尚不清楚。在本研究中，我们利用果蝇作为模型生物，确定了 SH3（Src 同源 3/SH2 衔接蛋白）衔接蛋白 Dock（Dreadlocks）及其哺乳动物对应物 Nck 在 PTPs 调控 IR 中的作用。我们证明了 PTP1B 同源物 PTP61F 在体外可使 S2 细胞中的果蝇 IR 去磷酸化，并在体内减弱 IR 诱导的眼过度生长。我们的研究表明，Dock 与 PTP61F 形成稳定的复合物，且 Dock/PTP61F 响应胰岛素与 IR 结合。我们报告称，Dock 是 PTP61F 在体外和体内有效去磷酸化和失活 IR 所必需的。此外，我们证明 Nck 与 PTP1B 相互作用，且 Nck/PTP1B 复合物可诱导与 IR 结合，从而减弱哺乳动物细胞中 IR 的激活。我们的研究首次揭示了衔接蛋白 Dock/Nck 通过将 PTP61F/PTP1B 募集到其底物 IR 上来减弱胰岛素信号转导。
