Role of Rap1 in cadherin and integrin mediated cross-talk in oral keratinocytes

描述（由申请人提供）：上皮细胞粘附和迁移的破坏是生理和病理过程如胚胎发育、伤口愈合、癌症发展和进展的基础。钙粘素和整合素是粘附和迁移的中心蛋白受体。虽然钙粘蛋白和整合素之间似乎存在着重要的关系，但它们的分子间的相互作用还没有很好的表征，但是ras样蛋白rap 1及其信号级联是一个有前途的研究领域。最近对小鼠甲状腺和人类乳腺细胞的研究支持rap 1在钙粘蛋白和整合素之间的相互作用中的作用。特别是内吞钙粘蛋白刺激rap 1，引发整合素受体。后者结合配体，如纤连蛋白，其触发rad介导的信号传导事件以促进细胞迁移。这些研究表明rap 1通过由内而外的信号机制在连接细胞粘附和迁移中起着关键作用;然而，这在角质形成细胞中尚未研究。与此作用一致，我们在角质形成细胞中的初步研究表明，活性rap 1促进粘附到纤连蛋白，增加迁移的可能机制。E-cadherin刺激的rap 1也可能通过β-连环蛋白的核转运诱导细胞迁移，β-连环蛋白在E-cad被内吞时释放。本申请的中心假设是细胞粘附的破坏刺激rap 1，rap 1通过激活整合素受体和通过p-cat的核转运增强口腔角质形成细胞的细胞迁移。3）E-cad通过α 5 β 1整合素和β-cat激活rap 1在细胞迁移中的作用。这些发现将有助于设计合理的策略来治疗慢性伤口或口腔粘膜肿瘤。

DESCRIPTION (provided by applicant): Disruptions in epithelial cell adhesion and migration are fundamental to physiologic and pathologic processes such as embryonic development, wound healing, development and progression of cancer. Cadherins and integrins are the central protein receptors in adhesion and migration. Although there appears to be an important relationship between cadherins and integrins their molecular cross-talk is not well characterized, but a promising area of research is the ras-like protein rap1 and its signaling cascade. Recent studies in mouse thyroid and human breast cells support a role for rap1 in the cross-talk between cadherins and integrins. Specifically endocytosed cadherin stimulates rap1, which primes integrin receptors. The latter bind ligands, such as fibronectin, which trigger rad-mediated signaling events to facilitate cell migration. These studies suggest that rap1 plays a critical role in linking cell adhesion and migration via an inside-out signaling mechanism; however, this has not been investigated in keratinocytes. Consistent with this role, our preliminary studies in keratinocytes suggest that active rap1 facilitates adhesion to fibronectin, a possible mechanism for increased migration. E-cadherin-stimulated rap1 may also induce cell migration via nuclear transport of p-catenin, which is released when E-cad is endocytosed. The central hypothesis of this application is that disruption of cell adhesion stimulates rap1, which enhances cell migration of oral keratinocytes via activation of integrin receptors and via nuclear transport of p-cat. The goals of the proposed study are to determine 1) whether disruption of cell-cell adhesion and endocytosis of E-cad stimulate rap1; 2) the role of active rap1 in inside-out signaling to a5p1; 3) the role of E-cad stimulated rap1 in cell migration via a5p1 integrin and p-cat. The proposed studies will identify novel signaling mechanisms through which rap1 integrates cell adhesion, and migration signaling networks in oral keratinocytes. These findings will facilitate the design of rational strategies to treat chronic wounds or tumors of the oral mucosa.