FOCAL ADHESION TYROSINE KINASES AND CELL SIGNALING

本研究的长期目标是了解由细胞外基质-整合素相互作用引发的信号转导级联如何调节细胞粘附、细胞运动、细胞生长和分化。我们的目标是了解这些信号通路是如何在正常细胞中组织（连接）的，并最终确定导致癌细胞中异常粘附信号的细胞改变（遗传和环境）。过去五年的研究已经确定了两大类参与和调节粘附信号蛋白酪氨酸激酶和小gtpase家族成员的信号分子。这两类调节蛋白如何组织细胞粘附和运动所需的复杂信号是本提案的中心主题。提出的研究特别关注焦点粘附激酶在通过β -整合素受体介导细胞外基质信号中的作用。这三个目标强调直接与FAK相互作用的分子的识别和表征，并将上游和下游信号元件连接起来；确定FAK及其相互作用伙伴在调节细胞运动和生长的介导信号中的作用；最后，研究细胞在发育过程中如何利用一种潜在的新机制来调节粘附信号。具体目标是：1。利用我们对FAK结构域结构组织的基础知识，我们将寻求定义由c端蛋白相互作用基序介导的新的结构和功能联系；2. 确定FAK在组织局灶复合体和局灶黏附中的功能作用，并确定FAK如何在响应生长因子和细胞基质分子的情况下调节细胞迁移；和3。探讨FAK、FRNK (FAK相关NonKinase) c端结构域的细胞组织类型特异性表达对粘附信号传导的体内调控，并检查敲除FRNK对小鼠正常发育过程和程度的影响。

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, we will seek to define new structural and functional linkages mediated by C-terminal protein interaction motifs; 2. determine the functional role of FAK in the organization of focal complexes and focal adhesions and determine how FAK contributes to the regulation of cell migration in response to growth factors and cell matrix molecules; and 3. explore the possible in vivo regulation of adhesion signaling by the cell1tissue type-specific expression of the C-terminal domain of FAK, FRNK ( FAK-related NonKinase) and examine the consequences of knocking out FRNK on the course and extent of normal development of the mouse.