Epithelial cell migration is vital to many important biological processes including wound healing, embryogenesis and tumor invasion. Epithelial cell migration is a complex and coordinated process involving the extracellular matrix, cell surface receptors, intracellular signaling pathways and cytoskeletal rearrangements. The goal of this application is to develop an integrated model of cell migration encompassing the extracellular environment, transmembrane signaling and intracellular events. Recent studies have implicated the alpha-6,beta-4 integrin receptor and its ligand, laminin 5, in cell migration/invasion in many tumors and specialized epithelial tissues. Preliminary studies in this application show that two sites on the beta-4 integrin subunit, the ligand binding site and the TAM signaling motif, perform critical roles in cell migration, affecting the membrane localization of phosphorylated signaling molecules including FAK and p80. Further we show that both gamma-2 and alpha-3 chains of laminin 5 are processed by BMP-1/mTld, and that this processing also performs a critical role in cell migration. The working hypothesis of this application is that processing alters the ability of laminin 5 to interact with integrin receptors, including alpha-6,beta-4, which in turn influences cell migration.
One Specific Aim will elucidate the molecules involved in the signaling pathways which alpha-6,beta-4 integrin, through its beta-4 ligand binding and TAM sequences, utilizes to regulate cell migration. The other Specific Aim will focus on the processing of laminin 5 and its effect on cell migration.
This Specific Aim will study structural changes, alterations of integrin binding sites, and alterations of signaling pathways that result from laminin 5 processing. Also introduced in this application are two nontoxic peptide based inhibitors, which show a high specificity for BMP-1/mTld. Each inhibitor is shown to prevent laminin 5 processing and profoundly inhibit keratinocyte and squamous carcinoma cell migration in vitro. Thus these inhibitors hold promise as nontoxic and specific anti-cancer agents and, as an additional Specific Aim, this application will utilize the inhibitors to study the effects of laminin 5 processing on cell migration in animal model systems of wound healing and tumor invasion.
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