Role of Vinculin in Epithelial Cell Junctions

描述(申请人提供)：这项研究的长期目标是研究细胞-细胞和细胞-基质黏附介导的事件的细胞骨架调节，以及在肿瘤疾病中这种调节被颠覆的机制。细胞之间的黏附对于正常组织结构的建立和维持是必不可少的。因此，细胞间的接触不仅在细胞的正常生长和运动中起着至关重要的作用，而且还与癌变和转移过程中发生的失调有关。单元格有几种链接到其邻居的机制。这些所谓的“细胞连接”由蛋白质组成，这些蛋白质组装成各种结构，如缝隙连接、紧密连接、黏附连接、桥粒和半桥粒，每种结构都有不同的功能。尽管它们表面上是稳定的，但上皮细胞-细胞连接是细胞的高度动态区域，对细胞外环境的信号做出反应。伴随着对这些线索的反应而来的形态变化是由潜在的肌动蛋白细胞骨架介导的，它们的特征和完整性由激酶、磷酸酶和小的GTP酶控制。据报道，一种将细胞-细胞连接与肌动蛋白细胞骨架联系起来的重要的磷酸化蛋白质是纽蛋白。多年来，纽蛋白在基质黏附部位的作用已被广泛研究，但纽蛋白在细胞-细胞接触部位的作用仍未得到很大程度的探讨。这项提议就是为了回答这个问题。该假说认为纽蛋白是上皮细胞连接的重要调节因子。这一假设将得到验证，纽蛋白动力学及其磷酸化在黏附和紧密连接功能中的作用也将得到检验。

DESCRIPTION (provided by applicant): The long-term goal of this research is to investigate the cytoskeletal regulation of cell-cell and cell-matrix adhesion-mediated events and the mechanism by which this regulation is subverted in neoplastic disease. The adhesion of cells to one another Is essential for the establishment and maintenance of normal tissue architecture. As such cell-cell contacts not only have an essential function in normal cell growth and motility but are also involved in cases of dysregulation that occur during carcinogenesis and metastasis. Cells have several mechanisms for linking to their neighbors. These so-called "cell junctions" consist of proteins that assemble into a variety of structures such as gap junctions, tight junctions, adherens junctions, desmosomes and hemidesmosomes, each with a different function. Despite their apparent stability, epithelial cell-cell junctions are highly dynamic regions of a cell that respond to cue from the extracellular environment. The morphological changes accompanying the response to these cues are mediated by the underlying actin cytoskeleton and their characteristics and integrity is controlled by kinases, phosphatases and small GTPases. A prominent phosphorylated protein that is reported to link cell-cell junctions to the actin cytoskeleton is vinculin. The role of vinculin at sites of adhesion to the matrix has been widely studied for many years, but the function of vinculin at sites of cell-cell contact remains largely unexplored. This proposal is directed towards answering this question. The hypothesis is that vinculin is an important regulator of epithelial cell junctions. This hypothesis will be tested and the role of vinculin dynamics and its phosphorylation in adherens and tight junction function will be examined.