FAK in Stress-activated Signaling and Tumor Invasion

应激激活信号传导和肿瘤侵袭中的 FAK

• 批准号: 7111747
• 负责人: J. Adrian Lunn
• 金额: $ 12.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111747
• 关键词: 3T3 cells; athymic mouse; biological signal transduction; cadherins; colorectal neoplasms; enzyme activity; enzyme mechanism; fibroblasts; focal adhesion kinase; gastrointestinal epithelium; guanine nucleotide binding protein; intercellular connection; metastasis; molecular oncology; neoplasm /cancer invasiveness; neoplasm /cancer transplantation; neoplastic cell; osmosis; phosphorylation; protein binding; protein degradation; stomach neoplasms; stress; xenotransplantation

DESCRIPTION (provided by applicant): My goal ultimately is to establish an independent program of research in gastrointestinal signal transduction focusing on early tumor invasion, and developing and testing novel interventional strategies using xenograft tumor models and transgenic animal models. I also hope to develop more useful, tractable, 3-D culture model systems recapitulating tumor architecture in vitro and ultimately to assay more closely how and why tumors invade, and the relationship of surrounding, non-dysplastic cells on this invasion. Although tumor invasion is multifaceted, I have chosen to focus my studies on a central signal-integrating molecule, FAK, focal adhesion kinase in this process. This proposal is designed in three phases: 1. Stress activation of FAK -- We will extend our studies on hyperosmotic stress-stimulation of FAK in fibroblasts to epithelial and cancer cells. This involves characterization of a novel FAK signaling pathway. Given the distinct cytoskeletal organization within these distinct cell types a detailed study of the role of Rho-family GTPases and their actin regulatory effectors on FAK signaling will be done. 2. We will define FAK domains required for epithelial adherens junction down regulation -- In this specific aim we will use this in vitro model to characterize which functional FAK domains are required for v-Src-mediated and EGF/HGF-stimulated E-cadherin phosphorylation, internalization and degradation, and adherens junction down-regulation. 3. We will establish which FAK domains are required and which are sufficient for tumor cell invasion and metastasis in vivo and in 3-dimensional (3-D) culture systems. Here we will directly test, using a xenograft tumor model in nude mice, whether FAK activation by various stimuli or mutations is sufficient, and which FAK domains are required, for human gastric and colorectal tumor invasion in vivo. Using the FAK molecule as a focal point, this proposal is designed to refine my signal transduction training and to extend my technical expertise to epithelial cell biology and cell-cell junction regulation, advanced cell imaging (in live cells) and to in vivo tumor invasion and metastasis. This K08 award will permit me to establish an independent publishing track record which is so critical to obtaining a future R01.

描述（由申请人提供）：我的最终目标是建立一个独立的胃肠道信号转导研究计划，重点关注早期肿瘤侵袭，并使用异种移植肿瘤模型和转基因动物模型开发和测试新的干预策略。我还希望开发更有用、易于处理的 3D 培养模型系统，在体外重现肿瘤结构，并最终更仔细地分析肿瘤侵袭的方式和原因，以及周围非发育不良细胞与这种侵袭的关系。 尽管肿瘤侵袭是多方面的，但我选择将研究重点放在这个过程中的一个中心信号整合分子FAK，即粘着斑激酶。该提案分三个阶段设计： 1. FAK 的应激激活——我们将把成纤维细胞中 FAK 高渗应激刺激的研究扩展到上皮细胞和癌细胞。这涉及一种新型 FAK 信号通路的表征。鉴于这些不同细胞类型内不同的细胞骨架组织，将详细研究 Rho 家族 GTP 酶及其肌动蛋白调节效应子对 FAK 信号传导的作用。 2. 我们将定义上皮粘附连接下调所需的 FAK 结构域——在此特定目标中，我们将使用此体外模型来表征 v-Src 介导和 EGF/HGF 刺激的 E-钙粘蛋白所需的功能性 FAK 结构域磷酸化、内化和降解以及粘附连接下调。 3. 我们将确定哪些 FAK 结构域是必需的，哪些 FAK 结构域足以在体内和 3 维 (3-D) 培养系统中实现肿瘤细胞的侵袭和转移。在这里，我们将使用裸鼠异种移植肿瘤模型直接测试各种刺激或突变对FAK的激活是否足够，以及哪些FAK结构域对于体内人胃和结直肠肿瘤的侵袭是必需的。该提案旨在以 FAK 分子为焦点，完善我的信号转导训练，并将我的技术专业知识扩展到上皮细胞生物学和细胞-细胞连接调节、高级细胞成像（在活细胞中）和体内肿瘤侵袭和转移。这个 K08 奖项将使我能够建立独立的出版记录，这对于获得未来的 R01 至关重要。