REGULATION AND DYNAMICS OF HEMIDESMOSOME DISASSEMBLY

这项工作的总体目标是了解癌侵袭的分子基础。 半桥粒是大多数上皮细胞中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。大多数癌细胞会脱落半桥粒。 细胞迁移需要破坏半桥粒。 我们研究的重点是了解半桥粒的解体是如何调节的，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节半桥粒解体的分子基础。 我们将主要集中在半桥粒的组成部分之一，整联蛋白α 6 β 4，因为这种整联蛋白是半桥粒的关键组织者，以前已经表明，它可以从半桥粒动员使用PKC依赖性机制，包括丝氨酸磷酸化的β 4亚基。 最近的数据表明，整合素内吞作用是重要的细胞迁移。 我们假设PKC α通过调节α 6 β 4整联蛋白的解离和内化来调节半桥粒的解体，允许α 6 β 4整联蛋白在细胞内向富含肌动蛋白的突起转运，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.