Adaptor protein function in breast cancer

衔接蛋白在乳腺癌中的功能

• 批准号: 9889069
• 负责人: LESLIE M SHAW
• 金额: $ 38.69万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-07 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889069
• 关键词: Adaptor Signaling Protein; Amino Acids; Basement membrane; Binding; Binding Proteins; Breast Cancer Patient; Breast Cancer Treatment; Breast Carcinoma; C-terminal; Cancer Patient; Cause of Death; Cells; Complex; Data; Disease; Distant; Distant Metastasis; Docking; Dominant-Negative Mutation; Goals; IRS2 gene; Insulin; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Invaded; Lead; Lobular Carcinoma; Malignant Neoplasms; Mammary Neoplasms; Mediating; Membrane; Metastatic breast cancer; Mus; Mutate; Mutation; N-terminal; Neoplasm Metastasis; Organ; Primary Neoplasm; Protein Conformation; Protein-Serine-Threonine Kinases; Proteins; Recurrence; Role; Secondary to; Signal Transduction; Stains; Stimulus; Structure; Tail; Work; blood glucose regulation; breast cancer progression; breast cancer survival; cancer subtypes; functional outcomes; glucose uptake; in vivo; insight; malignant breast neoplasm; novel; novel strategies; protein function; receptor; recruit; response; tumor; tumor growth

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.

项目摘要 该提案的总体目标是确定胰岛素受体底物2（IRS2）的机制 促进入侵及其在乳腺癌中的作用。 IRS2是一种细胞质适配器蛋白，是钥匙信号传导 胰岛素（IR）和胰岛素样生长因子1（IGF1R）受体的效应子，它们均已实施 在乳腺癌中。缺乏IRS2的小鼠乳腺肿瘤的转移能力显着降低 IRS2表达升高的肿瘤具有增强的肿瘤生长和转移性潜力。从事工作 申请人实验室已经确定，IRS2促进了入侵，这是传播转移性的早期一步 细胞到次生器官。 IRS2促进入侵的意义增强了申请人的最新 发现IRS2在多态性浸润性小叶癌（PILC）中反复突变，一种侵略性 转移性乳腺癌亚型。重要的是，IRS2将上游信号集成到的机制 调解其功能结果仍然未知。确定IRS2如何调节入侵需要 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促进入侵的能力取决于上游IGF1R/IR激活和 PI3K的募集和激活。此外，他们确定了IRS2 C末端内的174个氨基酸区域 入侵所需的尾巴。重要的是，IRS2依赖性调节不需要该区域 葡萄糖吸收，表明IRS2的这两个功能受到独立调节。基本互动 鉴于它以主导的负面方式起作用以抑制侵袭，因此可能发生在该区域内。调查 上游刺激动态改变了IRS2的结构的假设，该假设促进了入侵 促进必需下游信号传导效果的结合申请人将：1）定义结构性基础 IRS2介导的入侵和信号传导。 IRS2中的特定序列参与的假设 改变蛋白质构象和信号传导以促进侵袭的动态分子内相互作用将是 检查； 2）研究IRS2相互作用伙伴及其在促进入侵中的作用。假设是 IRS2内的分子内相互作用导致形成“无序域”环，这些循环组装不同 信号传导子复合物介导功能结果，而这些结合蛋白之一是串行 将检查苏氨酸激酶BMP2K； 3）确定IRS2依赖性侵袭在乳腺癌中的作用 体内进展。选择性靶向IRS2依赖性侵袭的假设将揭示出必不可少的 将检查该特定功能在乳腺癌进展中的作用。 IRS2突变的贡献 还将检查PILC的进展。