The Insulin Receptor Isoform-A and Cancer

胰岛素样生长因子系统参与促进癌症生长和抵抗化疗治疗的存活。胰岛素样生长因子-I和-II通过细胞表面受体（IGF-1 R）起作用。许多努力已经应用于通过IGF-1 R阻断胰岛素样生长因子的作用。然而，最近已经确定了胰岛素样生长因子参与癌症的第二种机制。胰岛素样生长因子-II也可以通过胰岛素受体的替代形式促进癌症生长和存活。我们将与我们的国际合作者一起，汇集一个由生物化学家和蛋白质结构生物学家组成的团队，他们是了解胰岛素和胰岛素样生长因子系统中蛋白质相互作用的世界领导者。由于对这种替代途径知之甚少，我们建议定义胰岛素样生长因子-II与替代胰岛素受体亚型结合的机制。我们将使用成熟和新颖的技术相结合，绘制相互作用。这些知识将允许设计特异性抑制剂来阻断胰岛素样生长因子-II促进癌细胞生长和存活的作用，而不破坏胰岛素受体的代谢作用。

The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via an alternative form of the insulin receptor. We will join with our international collaborator to bring together a team of biochemists and protein structural biologists who are world leaders in understanding protein interactions in the insulin and insulin-like growth factor systems. As relatively little is known about this alternate pathway we propose to define the mechanism of binding of insulin-like growth factor-II to the alternate insulin receptor isoform. Using a combination of well-established and novel techniques we will map the interaction. This knowledge will allow design of specific inhibitors to block the action of insulin-like growth factor-II in promotion of cancer cell growth and survival without disruption of the metabolic actions of the insulin receptor.