FOCAL ADHESION TYROSINE KINASES AND CELL SIGNALING

这项研究的长期目标是了解细胞外基质-整合素相互作用引发的信号转导级联反应如何调节细胞黏附、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在正常细胞中是如何组织(连接)的，并最终确定导致癌细胞异常黏附信号的细胞变化(包括遗传和环境)。过去五年的研究已经确定了两类主要的信号分子，它们参与和调节黏附信号蛋白酪氨酸激酶和小GTP酶家族的成员。这两类调节蛋白如何发挥功能来组织细胞黏附和运动所需的复杂信号是这项提案的中心主题。建议的研究主要集中在粘着斑激酶通过β-整合素受体在细胞外基质信号传递中的作用。这三个目标强调识别和表征直接与FAK相互作用并连接上下游信号成分的分子；确定FAK及其相互作用伙伴在调节细胞运动和生长的信号中的作用；以及最后研究细胞如何利用一种潜在的新机制来调节发育过程中的黏附信号。具体目标是：1.利用我们对FAK结构域结构组织的知识基础，我们将寻求定义由C-末端蛋白质相互作用基序介导的新的结构和功能连接；2.确定FAK在焦点复合体和焦点粘连组织中的功能作用，并确定FAK如何在响应生长因子和细胞基质分子的反应中调节细胞迁移；3.探讨FAK、FRANK(FAK-Related NonKinase)C-末端结构域的细胞类型特异性表达对黏附信号的可能调节作用，并检测FRNK基因敲除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.