FOCAL ADHESION KINASE SIGNALING

焦点粘附激酶信号传导

• 批准号: 2795936
• 负责人: J THOMAS PARSONS
• 金额: $ 25.78万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2795936
• 关键词: RNase protection assay; SDS polyacrylamide gel electrophoresis; affinity chromatography; biological signal transduction; cell adhesion; cell differentiation; cell growth regulation; cell migration; cell motility; electrospray ionization mass spectrometry; extracellular matrix; gene targeting; guanosinetriphosphatase activating protein; guanosinetriphosphatases; immunoprecipitation; in situ hybridization; laboratory mouse; laboratory rabbit; mass spectrometry; phosphorylation; protein binding; protein protein interaction; protein structure function; protein tyrosine kinase; tissue /cell culture; yeast two hybrid system

The long term goal of the proposed research is to understand how signal transduction cascades initiated by extracellular matrix-integrin interactions regulate cell adhesion, cell motility, cell growth and differentiation. Our goal is to understand how such signaling pathways are organized (wired) in normal cells and to ultimately define the cellular alterations (both genetic and environmental) that lead to abnormal adhesion signaling in cancer cells. Studies over the past five years have identified two major classes of signaling molecules that participate in and regulate adhesion signaling, protein tyrosine kinases and members of the family of small GTPases. How these two classes of regulatory proteins function to organize the complex signaling required for cell adhesion and movement is a central theme of this proposal. The proposed studies focus specifically on the role of focal adhesion kinase in mediating signals from the extracellular matrix through the beta- integrin receptors. The three aims emphasize the identification and characterization of molecules that directly interact with FAK and link both upstream and downstream signaling components; defining the role of FAK and interacting partners in mediating signals that regulate cell motility and growth; and finally studying how cells utilize a potentially novel mechanism to regulate adhesion signaling during development. The specific aims are: 1) Using our base of knowledge about the structural organization of the domains of FAK and the related protein tyrosine kinase PYK2, identify new structural and functional linkages by defining new binding/interacting partners for FAK; 2) examine the functional role of FAK in the regulation of cell migration, focusing initially on fibronectin induced motility. We will also explore the role of FAK in the regulation of cell motility using FAK null fibroblasts derived from mice containing a conditional deletion of FAK (Cre-mediate deletion of a FAK exon flanked by lox P sites); 3) explore the possible in vivo regulation of adhesion signaling by the cell/tissue type-specific expression of the C-terminal domain of FAK, FRNK FAK-related Non-Kinase) and examine the consequences of knocking out FRNK on the course and extent of normal development of the mouse.

拟议研究的长期目标是了解信号如何 由细胞外基质整合素启动的转导级联 相互作用调节细胞粘附、细胞运动性、细胞生长和 分化 我们的目标是了解这些信号通路 在正常细胞中组织（连接），并最终定义 细胞改变（遗传和环境），导致 癌细胞中异常的粘附信号。 过去五年的研究 多年来已经确定了两种主要的信号分子， 参与和调节粘附信号传导，蛋白酪氨酸激酶 和小GTP酶家族的成员。 这两类 调节蛋白的功能是组织所需的复杂信号传导， 对于细胞粘附和运动是该提议的中心主题。的 建议的研究特别关注粘着斑激酶的作用， 在介导信号从细胞外基质通过β- 整合素受体 这三个目标强调识别和 表征与FAK直接相互作用并连接 上游和下游信令组件;定义 FAK及其相互作用伙伴介导细胞信号调节 运动性和生长;最后研究细胞如何利用 调节粘附信号传导的潜在新机制 发展 具体目标是：1）利用我们的知识基础 关于FAK域的结构组织和相关的 蛋白酪氨酸激酶PYK 2，鉴定新的结构和功能 通过为FAK定义新的结合/相互作用伴侣来连接; 2） 检查FAK在细胞迁移调节中的功能作用， 最初集中于纤连蛋白诱导的运动性。 我们还将 探讨FAK在细胞运动调节中的作用 来源于含有条件性缺失的小鼠的空成纤维细胞， FAK（Cre介导的侧翼为lox P位点的FAK外显子缺失）; 3） 探索粘附信号转导的可能体内调节， FAK C-末端结构域的细胞/组织类型特异性表达， FRNK FAK相关的非激酶），并检查敲除的后果 FRNK对小鼠正常发育的过程和程度的影响。