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粘附和迁移在侵袭和转移中的作用。在癌进展过程中，上皮来源的恶性细胞离开其正常范围侵入相邻间质并最终转移到远处组织。了解允许细胞离开其正常范围的机制将在设计治疗或预防措施以阻止细胞传播方面具有重要价值。这就是为什么我们专注于上皮细胞的主要锚之一，通常阻止他们的运动：半桥粒（HD）。在早期阶段，癌细胞失去了它们的HD，因此潜在地更具移动的性。我们的目标是了解这些结构是如何以及为什么被分解的。我们专注于HD组件之一：a6b4整联蛋白。这种分子将细胞锚定在基底膜上，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，激活时，诱导拆卸的HD。我们的目标之一是了解磷酸化是如何完成HD拆卸。我们提出了一种机制，HD拆卸是基于构象变化的α 6 β 4整合素磷酸化引发的。此外，我们还探讨了磷酸酶在调节HD分解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