Mechanisms of Hemidesmosome Disassembly: Role of a6b4 integrin phosphorylation

描述(由申请人提供)：我们的总体目标是了解细胞黏附和迁移在侵袭和转移中的作用。在癌变过程中，上皮来源的恶性细胞离开正常范围，侵入邻近的间质，最终转移到远处组织。了解允许细胞脱离正常范围的机制将对设计阻止细胞扩散的治疗或预防措施具有重要价值。这就是为什么我们关注通常阻止其移动的上皮细胞的主要锚之一：半桥粒(HD)。在早期阶段，癌细胞失去其高密度脂蛋白，因此可能更具流动性。我们的目标是了解这些结构是如何以及为什么被拆解的。我们专注于hd的一个组成部分：a6b4整合素。这种分子将细胞固定在基底膜上，是HD的主要组织者。在以前的研究中，我们已经确定了几个磷酸化位点，当激活时，会导致HD的解体。我们的目标之一是了解磷酸化是如何完成HD拆卸的。我们提出了一种基于磷酸化触发的a6b4整合素构象变化的HD拆解机制。此外，我们还探讨了磷酸酶在调节HD拆卸的信号通路中的作用

DESCRIPTION (provided by applicant): Our general goal is to understand the role of cell adhesion and migration in invasion and metastasis. During carcinoma progression, malignant cells of epithelial origin leave their normal confines to invade the adjacent stroma and eventually metastasize to distant tissues. Understanding the mechanisms that allow cells to leave their normal confines would be of great value in designing therapeutic or preventive measures to block cell dissemination. That is why we focus on one of the main anchors of epithelial cells that normally prevent their movement: the hemidesmosome (HD). At early stages, carcinoma cells lose their HDs and are therefore potentially more mobile. Our goal is to understand how and why these structures are disassembled. We focus on one of the HD components: the a6b4 integrin. This molecule anchors the cell to the basement membrane and is the primary organizer of the HD. In previous studies we have identified several phosphorylation sites that when activated, induce the disassembly of the HD. One of our objectives is to understand how phosphorylation accomplishes HD disassembly. We propose a mechanism of HD disassembly that is based on conformational changes of the a6b4 integrin triggered by phosphorylation. Additionally we explore the role of phosphatases in the signaling pathway the regulates HD disassembly