Role of Desmosomal Adhesion in Carcinogenesis

描述(申请人提供)：桥粒是细胞间的粘连连接，在维持组织结构、完整性和功能方面起着关键作用。桥粒蛋白(Desmogleins，DSG)1-4是桥粒的跨膜成分，是多种人类自身免疫性、感染性和遗传性疾病的靶分子，在细胞间黏附、皮肤屏障功能和毛囊发育中发挥重要作用。然而，这些桥粒蛋白是否能在正常和疾病条件下调节细胞信号仍然知之甚少。在人类中，DSG2基因的基因突变导致遗传性致心律失常的右室发育不良/心肌病。对Dsg2缺失小鼠的研究证实了Dsg2在胚胎发育以及干细胞生长和存活过程中的重要性。此外，Dsg2在某些上皮性恶性肿瘤中过度表达，提示它在细胞增殖和分化中发挥作用，有利于肿瘤的发展。我们最近提供了强有力的证据表明，Dsg2在表皮角质形成细胞中的过表达解除了与体内生长速度增加、锚定非依赖性细胞存活和皮肤肿瘤发展相关的多个信号通路的调控。这些令人信服的结果要求深入研究桥粒钙粘附素在上皮细胞生物学和皮肤肿瘤发展中的新作用。我们实验室的长期目标是在分子和细胞水平上阐明桥粒介导的信号，特别是在皮肤发育过程中正常和致病信号之间的差异。我们的中心假设是桥粒蛋白可以激活与桥粒结构和黏附功能无关的信号事件。我们认为，桥粒蛋白在桥粒中的功能不足以解释其不同的生物学效应。因此，这项建议的总体目标是阐明Dsg2激活的影响上皮细胞生长、存活和恶性转化的细胞和分子机制。这一目标将通过三个特定的目标来实现：1)评估Dsg2在不同细胞群中表达时对信号和恶性转化的影响，特别是在祖细胞和分化上皮细胞中的表达；2)评估Dsg2的蛋白分解过程在上皮细胞生长和存活中的作用；以及3)确定小窝蛋白-1在Dsg2介导的信号和恶性转化中的作用。这项拟议的工作具有创新性，因为它利用了我们最近发现的Dsg2的“致癌”作用，以及初步数据显示Dsg2的复杂蛋白分解过程以及Dsg2与小凹-1的定位，小窝是参与许多关键生长和生存信号通路的专门脂筏。这些结果将加深我们对桥粒钙粘附素和桥粒相关疾病的病理学的理解，并将有助于为桥粒功能受损引起的获得性和遗传性疾病的治疗找到新的方向。 公共卫生相关性：这一应用将有助于确定桥粒钙粘附素在调节上皮细胞-细胞黏附以及细胞生长和存活中的作用。特别是，我们将重点研究桥粒芯糖蛋白2，它在几种皮肤癌中表达上调。确定桥粒芯糖蛋白2影响肿瘤生长和发展的分子机制有可能确定癌症治疗的新靶点。

DESCRIPTION (provided by applicant): Desmosomes are intercellular adhesive junctions that play pivotal roles in maintaining tissue architecture, integrity and function. Desmogleins (Dsg) 1-4 are the transmembrane components of desmosomes and are the target molecules in several human autoimmune, infectious and heritable diseases highlighting their roles in cell-cell adhesion, skin barrier function, and hair follicle development. However, whether these desmogleins can mediate cell signaling under normal and diseased conditions is still poorly understood. In human, genetic mutations in the DSG2 gene results in inherited arrhythmogenic right ventricular dysplasia/cardiomyopathy. Studies of the Dsg2 null mice attest to the importance of Dsg2 during embryonic development and in stem cell growth and survival. Furthermore, Dsg2 is over-expressed in certain epithelial malignancies suggesting a role in cell proliferation and differentiation that favor of tumor development. We recently provide strong evidence that overexpression of Dsg2 in epidermal keratinocytes deregulates multiple signaling pathways associated with increased growth rate, anchorage-independent cell survival, and the development of skin tumors in vivo. These compelling results call for an in-depth investigation of novel roles of desmosomal cadherins in epithelial cell biology and skin tumor development. The long-term goal of our laboratory is to elucidate desmosome-mediated signaling at the molecular and cellular level; particularly, the differences between normal and pathogenic signaling during skin development. Our central hypothesis is that desmogleins can activate signaling events that are independent of desmosomal structure and adhesive function. We argue that the function of desmogleins strictly within the context of the desmosome is not sufficient to explain their diverse biologic effects. Thus the overall goal for this proposal is to elucidate the cellular and molecular mechanisms activated by Dsg2 that impact epithelial cell growth, survival and malignant transformation. This goal will be pursued in three Specific Aims designed to: 1) Assess the effects of Dsg2 on signaling and malignant transformation when expressed in different cell populations specifically progenitor and differentiating epithelial cells; 2) Assess the role of proteolytic processing of Dsg2 in epithelial cell growth and survival; and 3) Determine the role of caveolin-1 in Dsg2-mediated signaling and malignant transformation. The proposed work is innovative because it capitalizes on our recent discovered "oncogenic" role of Dsg2 and preliminary data showing complex proteolytic processing of Dsg2 and localization of Dsg2 with caveolin-1 to the caveolae, specialized lipid rafts that are involved in many key growth and survival signaling pathways. The results obtained here will enhance our understanding of desmosomal cadherins and the pathology of desmosome-associated diseases and will help identify new directions for therapeutic treatments of acquired and inherited diseases resulting from impaired desmosome function. PUBLIC HEALTH RELEVANCE: This application will help define the roles of desmosomal cadherins in modulating, not only epithelial cell-cell adhesion, but also cell growth and survival. In particular, we will focus on desmoglein 2, which is up regulated in several skin cancers. Determining the molecular mechanisms by which desmoglein 2 affects tumor growth and development has the potential of identifying new targets for therapeutic cancer treatments.