INTERACTION BETWEEN THE INSULIN RECEPTOR AND TRAP

工作总结：许多信号中间产物和膜相关糖蛋白可以通过与胰岛素受体的不同区域相互作用来调节该受体的功能。鉴于细胞内还原/氧化电位在胰岛素调节中的重要作用，我们推测胰岛素受体与相关蛋白之间的相互作用可能受到受体胞浆硫醇(S)反应性的影响。在这项研究中，我们研究了不同的受体结构域和特定的胰岛素受体半胱氨酸残基在这种联系中的作用。结果表明，野生型人胰岛素受体β亚基与硫醇反应膜相关蛋白TRAP形成了一个大的复合体，其特性有待进一步阐明。一系列实验表明，人类胰岛素受体膜旁区域附近的一个半胱氨酸残基负责这种相互作用。已知的信号中间体不是受体-陷阱复合体的一部分。因此，识别陷阱的工作正在进行中。此外，氧化剂和抗氧化剂对胰岛素受体-TRAP异源复合体的形成和细胞分布的影响目前正在评估中。由于TRAP在未受刺激的细胞和经胰岛素处理的细胞中都与胰岛素受体的胞浆结构域相关，因此它可能是一种辅助蛋白，与胰岛素受体发生结构性的相互作用，使细胞质膜上的信号中间产物能够对胰岛素的攻击做出反应。

Summary of work: A number of signaling intermediates and membrane-associated glycoproteins can regulate the insulin receptor function by interacting with different regions of this receptor. Because of the important role that intracellular reduction/oxidation potential plays in the modulation of insulin action, we postulated that the interaction between the insulin receptor and associated proteins may be affected by the reactivity of the receptor cytoplasmic thiol(s). In this study, we examined the role of various receptor domains and specific insulin receptor cysteine residues in this association. The results showed the formation of a large complex between the wild-type human insulin receptor beta-subunit and TRAP, a thiol reactive membrane-associated protein, whose identity remains to be elucidated. A series of experiments revealed that a single cysteine residue near the juxtamembrane region of the human insulin receptor is responsible for this interaction. Known signaling intermediates are not part of the receptor-TRAP complex. Hence, work is underway to identify TRAP. Also, the effects of oxidants and antioxidants on the formation and cellular distribution of the insulin receptor-TRAP heterocomplex is currently evaluated. Since TRAP is associated with the insulin receptor cytoplasmic domain both in unstimulated cells and cells treated with insulin, it may represent an accessory protein that interacts constitutively with the insulin receptor, enabling recruitment of signaling intermediates at the plasma membrane in response to insulin challenge.