REGULATION AND DYNAMICS OF HEMIDESMOSOME DISASSEMBLY

这项工作的总体目标是了解肿瘤侵袭的分子基础。半粒体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底层和细胞角蛋白网络之间提供了牢固的联系。大多数癌细胞的半粒酶脱落。半粒酶需要被破坏才能使细胞迁移。我们研究的重点是了解半染色体的分解是如何调节的，以及它的动力学是什么。我们假设关键半粒染色体组分的磷酸化是调节半粒染色体解体的分子基础。我们将主要关注其中一种半端粒成分，即整合素alpha6beta4，因为这种整合素是半端粒的关键组织者，之前的研究表明，它可以通过pkc依赖机制从半端粒中动员起来，其中包括beta4亚基的丝氨酸磷酸化。最近的数据表明，整合素内吞作用对细胞迁移很重要。我们假设PKC α通过调节alpha6beta4整合素的分离和内化来调节半染色体的分解，允许alpha6beta4整合素在细胞内运输到富含肌动蛋白的突起，在那里它在迁移中起作用。

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.