Role of Vinculin in Epithelial Cell Junctions

描述（由申请人提供）：本研究的长期目标是研究细胞-细胞和细胞-基质粘附介导的事件的细胞骨架调节以及这种调节在肿瘤疾病中被破坏的机制。细胞之间的粘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-细胞接触不仅在正常细胞生长和运动中具有重要功能，而且还涉及在癌变和转移过程中发生的失调。细胞有好几种连接邻近细胞的机制。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，如间隙连接、紧密连接、粘附连接、桥粒和半桥粒，每种结构都有不同的功能。尽管上皮细胞-细胞连接具有明显的稳定性，但它是细胞中高度动态的区域，对细胞外环境的提示作出反应。对这些线索的反应所伴随的形态变化是由潜在的肌动蛋白细胞骨架介导的，其特征和完整性由激酶、磷酸酶和小gtp酶控制。据报道，将细胞-细胞连接连接到肌动蛋白细胞骨架的一个重要磷酸化蛋白是血管蛋白。多年来，人们广泛研究了血管蛋白在基质黏附部位的作用，但血管蛋白在细胞-细胞接触部位的功能仍未得到充分研究。这个建议就是为了回答这个问题。假设是血管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，并将研究血管蛋白动力学及其磷酸化在粘附体和紧密连接功能中的作用。

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.