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.
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