FOCAL ADHESION TYROSINE KINASES AND CELL SIGNALING

该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参与和调节粘附信号蛋白酪氨酸激酶和小GTP酶家族成员的两大类信号分子。这两类调节蛋白如何发挥作用来组织细胞粘附和运动所需的复杂信号传导是本提案的中心主题。拟议的研究重点特别是粘着斑激酶介导的信号从细胞外基质通过β-整联蛋白受体的作用。这三个目标强调识别和表征直接与FAK相互作用并连接上游和下游信号组分的分子;定义FAK和相互作用伙伴在介导调节细胞运动和生长的信号中的作用;最后研究细胞如何利用潜在的新机制来调节发育过程中的粘附信号。具体目标是：1.利用我们对FAK结构域的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在局灶复合体和局灶粘附的组织中的功能作用，并确定FAK如何有助于响应生长因子和细胞基质分子的细胞迁移的调节;以及3.探索通过FAK，FRNK（FAK相关非激酶）的C-末端结构域的细胞1组织类型特异性表达对粘附信号传导的可能体内调节，并检查敲除FRNK对小鼠正常发育的过程和程度的后果。

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.