Adaptor protein function in breast cancer

项目摘要 这项提议的总体目标是确定胰岛素受体底物2(IRS2)的机制。 促进侵袭及其在乳腺癌中的作用。IRS2是一种细胞质接头蛋白，它是一种关键的信号转导 胰岛素(IR)和胰岛素样生长因子-1(IGF1R)受体的效应因子，这两种受体都已被涉及 在乳腺癌方面。缺乏irs2的小鼠乳腺肿瘤转移能力显著降低。 IRS2表达升高的肿瘤具有更强的肿瘤生长和转移潜能。工作地点： 申请人的实验室已经确定IRS2促进侵袭，这是转移性肿瘤扩散的早期步骤 从细胞到次级器官。IRS2促进侵袭的意义因申请人最近的 发现IRS2在多形性浸润性小叶癌(PILC)中反复突变， 转移性乳腺癌亚型。重要的是，IRS2将上行信号集成到 其功能转归尚不清楚。要确定IRS2如何监管入侵，需要一个 了解其结构，以及该结构如何决定功能。申请人的初步数据 确定IRS2促进侵袭的能力依赖于上游IGF1R/IR的激活和 PI3K的招募和激活。此外，他们还在IRS2的C末端确定了174个氨基酸区域 入侵所需的尾巴。重要的是，这个区域不是依赖IRS2的调控所必需的 葡萄糖摄取，表明IRS2的这两个功能是独立调节的。基本互动 很可能发生在这个地区，因为它以一种占主导地位的负面方式来抑制入侵。去调查 假设IRS2的结构被促进入侵的上游刺激动态改变 促进必要的下游信号效应器的结合申请人将：1)定义以下结构基础 IRS2介导的侵袭和信号转导。IRS2中的特定序列参与的假设 改变蛋白质构象和信号以促进入侵的动态分子内相互作用将是 研究；2)调查IRS2相互作用的伙伴及其在促进入侵中的作用。假设 IRS2内的分子内相互作用导致形成“无序结构域”环，这些环组装成不同的 信号亚复合体调节功能结果，这些结合蛋白之一是丝氨酸 苏氨酸激酶BMP2K，将被检测；3)确定依赖IRS2的侵袭在乳腺癌中的作用 在体内的进展。假设选择性靶向IRS2依赖的侵袭将揭示一个重要的 这一特殊功能在乳腺癌进展中的作用将被研究。IRS2基因突变的作用 TO PILC进展也将被检查。

Project Summary The overall goal of this proposal is to determine the mechanism by which Insulin Receptor Substrate 2 (IRS2) promotes invasion and its role in breast cancer. IRS2 is a cytoplasmic adaptor protein that is a key signaling effector of the insulin (IR) and insulin-like growth factor-1 (IGF1R) receptors, both of which have been implicated in breast cancer. Mouse mammary tumors that lack Irs2 are significantly diminished in their ability to metastasize and tumors with elevated Irs2 expression have enhanced tumor growth and metastatic potential. Work from the applicant’s lab has established that IRS2 promotes invasion, an early step in the dissemination of metastatic cells to secondary organs. The significance of IRS2 promoting invasion is heightened by the applicant’s recent discovery that IRS2 is recurrently mutated in pleomorphic invasive lobular carcinoma (PILC), an aggressive, metastatic breast cancer subtype. Importantly, the mechanism by which IRS2 integrates upstream signals to mediate its functional outcomes remains unknown. Determining how IRS2 regulates invasion requires an understanding of its structure, and how this structure determines function. The applicant’s preliminary data establish that the ability of IRS2 to promote invasion is dependent upon upstream IGF1R/IR activation and the recruitment and activation of PI3K. In addition, they identified a 174-amino acid region within the IRS2 C-terminal tail that is required for invasion. Importantly, this region is not required for the IRS2-dependent regulation of glucose uptake, revealing that these two functions of IRS2 are independently regulated. Essential interactions likely occur within this region given that it acts in a dominant negative manner to inhibit invasion. To investigate the hypothesis that the structure of IRS2 is dynamically altered by upstream stimuli that promote invasion to facilitate binding of essential downstream signaling effectors the applicant will: 1) Define the structural basis for IRS2-mediated invasion and signaling. The hypothesis that specific sequences within IRS2 participate in dynamic intramolecular interactions that alter protein conformation and signaling to promote invasion will be examined; 2) Investigate IRS2 interacting partners and their role in promoting invasion. The hypothesis that intramolecular interactions within IRS2 lead to the formation of “disordered domain” loops that assemble distinct signaling sub-complexes to mediate functional outcomes, and that one of these binding proteins is the serine threonine kinase BMP2K, will be examined; 3) Establish the role of IRS2-dependent invasion in breast cancer progression in vivo. The hypothesis that selective targeting of IRS2-dependent invasion will reveal an essential role for this specific function in breast cancer progression will be examined. The contribution of IRS2 mutations to PILC progression will also be examined.