Epithelial cells assemble adhesive and communicating cell junctions at substrate and cell-cell contacts. In epidermis, cell junctions integrate individual keratinocytes into tissue with barrier and communicating functions. Quiescent keratinocytes anchor to laminin 5 in the basement membrane (BM) via integrin a6134 in hemidesmosomes (HD) and integrin alpha-3beta-1 in focal adhesions (FAs). Cell-cell interactions are mediated by at least three types of intercellular junctions: adherens junctions (AJs), desmosomes and gap junctions (GJs). Connexin 43 (Cx43) is the predominant constituent of GJs in the epidermis. Wounding of quiescent epidermis disrupts cell junctions and activates migration of an epidermal cell outgrowth over exposed dermal collagen and fibronectin with deposition of laminin 5 in repair of the BM. The outgrowth contains both leading and following keratinocytes that are distinct based on substrate ligands, integrin adhesion, cell signaling, and GJs. We have identified a form of communication between adhesive and cell-cell junctions in the epidermis and have suggested two hypotheses based on our findings. We hypothesize that PI3K-dependent adhesion on laminin 5, but not Rho-dependent adhesion on collagen, promotes assembly of GJs. Second, that cell confluence in quiescent tissues inhibits adhesion to collagen and fibronectin but does not inhibit adhesion to BM laminin 5. We propose to test these hypotheses in two steps: 1. Map components and structures that link communication between laminin 5 and GJs in the following keratinocytes. 2. Elucidate the mechanisms that these components utilize to affect adhesion and junctional communication. These studies will provide an understanding of components and mechanisms critical for regulating epithelial morphogenesis in development, wound repair and tumor invasion.
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