Hevin Regulation of Cell Migration

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DESCRIPTION (provided by applicant): Extracellular matrix (ECM) structure is a known determinant of cell behavior and is in turn regulated by signals from its adjacent cells. Matricellular proteins such as hevin play an important role in regulating cell/ECM communication and ECM structure by acting as adapters, and therefore are critical regulators of numerous pathologies such as tumor growth and its associated angiogenesis. The hypothesis of this proposal is that hevin functions as a regulator of cell migration by inducing a state of adhesion permissive for migration. The specific aims geared to address this hypothesis are focused on elucidating one or more of the mechanisms through which hevin functions. First, we will investigate the role of the hevin/collagen I interaction in deadhesion, and second, we will examine the mechanism of hevin-induced focal adhesion disassembly. To address the first specific aim, we will evaluate hevin/collagen I binding and its effect on collagen fibril synthesis, structure, and interaction with alpha2beta1-integrin in dermal fibroblasts. To address the second specific aim, we will investigate the signaling pathways involved in regulating focal adhesion disassembly and cell migration by hevin in bovine aortic endothelial cells and dermal fibroblasts.