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: 6916528
• 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/6916528
• 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）：我的目标最终是在胃肠道信号转导的独立研究计划上，重点是早期肿瘤侵袭，并使用异种移植肿瘤模型和转基因动物模型制定和测试新型的介入策略。我还希望开发更有用的，可进行的3-D培养模型系统，在体外概括肿瘤结构，并最终更仔细地测定肿瘤的侵袭以及在这种侵袭中周围的非塑性细胞的关系。 尽管肿瘤浸润是多方体的，但我选择将研究集中在此过程中的中央信号整合分子，FAK，局灶性粘附激酶上。该提案分为三个阶段：1。FAK的应力激活 - 我们将扩展有关成纤维细胞中FAK的过度渗透应力刺激的研究，以至上皮细胞和癌细胞。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中的独特的细胞骨架组织将对Rho-Family GTPases及其肌动蛋白调节效应子在FAK信号传导上的作用进行详细研究。 2。我们将定义上皮粘附所需的FAK结构域 - 在此特定目的中，我们将使用此体外模型来表征V-SRC介导的功能性FAK域以及EGF/HGF/HGF刺激的e-钙粘着蛋白磷酸化，内在化，内在化和脱位，以及脱落和脱水剂的结局。 3。我们将确定需要哪些FAK结构域，哪些足以用于体内肿瘤细胞侵袭和转移，以及在3维（3-D）培养系统中。在这里，我们将使用裸鼠中的异种移植肿瘤模型直接测试，无论是通过各种刺激或突变而激活的FAK激活，并且需要哪些FAK结构域，用于体内的人类胃和结直肠肿瘤侵袭。该建议将使用FAK分子作为焦点，旨在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 - 细胞连接调控，晚期细胞成像（在活细胞中）以及体内肿瘤侵入和转移。该K08奖将使我能够建立独立的发布记录，这对于获得未来R01至关重要。