REGULATION AND DYNAMICS OF HEMIDESMOSOME DISASSEMBLY

这项工作的总体目标是了解癌症侵袭的分子基础。半桥粒是大多数上皮细胞稳定附着的分子基础，因为这些多蛋白结构在基膜和细胞角蛋白网络之间提供了牢固的联系。大多数癌细胞的半桥体松动。半桥粒需要被破坏，细胞才能迁移。我们研究的重点是了解半桥粒的拆解是如何调节的，以及它的动力学是什么。我们推测，半桥粒关键成分的磷酸化是调控半桥粒拆解的分子基础。我们将主要关注半桥粒的一个组成部分，整合素α6β4，因为这种整合素是半桥粒的关键组织者，而且以前已经证明，它可以通过PKC依赖的机制从半桥粒中动员起来，这种机制包括β4亚基的丝氨酸磷酸化。最近的数据表明，整合素的内吞作用对细胞迁移很重要。我们假设PKCα通过调节α6β4整合素的解离和内化来调节半桥粒的分解，允许α6β4整合素在细胞内运输到富含肌动蛋白的突起，在那里它起着迁移的作用。

The general goal of this work is to understand the molecular basis of carcinoma invasion. Hemidesmosomes are the molecular basis for stable attachment in most epithelial cells, because these multiprotein structures provide a firm link between the basal lamina and the cytokeratin network. Most carcinoma cells loose their hemidesmosomes. Hemidesmosomes need to be disrupted for a cell to migrate. The focus of our study is to understand how the disassembly of the hemidesmosome is regulated and what its dynamics are. We hypothesize that phosphorylation of key hemidesmosomal components is the molecular basis for regulating hemidesmosome disassembly. We will focus mostly on one of the hemidesmosome components, the integrin alpha6beta4, because this integrin is the key organizer of hemidesmosomes and it has been previously shown that it can be mobilized from hemidesmosomes using a PKC-dependent mechanism that includes serine phosphorylation of the beta4 subunit. Recent data suggest that integrin endocytosis is important for cell migration. We hypothesize PKC alpha regulates the disassembly of the hemidesmosome by regulating both the dissociation and internalization of the alpha6beta4 integrin, allowing the alpha6beta4 integrin to be transported intracellularly towards actin rich protrusions, where it functions in migration.