The broad objective of this renewal application remains an analysis of the role of cell-matrix interactions in the process of tumor cell malignancy. The specific focus is on signaling events mediated by the avb3 and avb5 integrins, which have been shown to play a role in angiogenesis and the migratory properties of tumor cells in vivo and in vitro. Although both avb3 and avb5 promote cell attachment to vitronectin, only avb3 directly leads to motility. However, cytokine or phorbol ester stimulation results in avb5-dependent cell motility.
Aims 1 and 2 of this proposal will test the hypothesis that avb3 and avb5 differ in their ability to activate protein kinase C, focal adhesion kinase, and MAP kinase after cell attachment to vitronectin. A requirement for activation of the MAP kinase pathway for cell motility and invasion will also be investigated.
Aims 3 and 4 will extend preliminary studies demonstrating the specific binding of the collagenase matrix metalloproteinase 2 (MMP-2) to avb3 in a functionally active form on the cell surface.
Aim 3 will characterize the structural basis of this interaction and Aim 4 will determine its potential biological relevance in two models of tumor relevance in vivo. These studies will elucidate key molecular events in integrin-mediated signal transduction leading to post-ligand binding events that are important for the invasive behavior of transformed cells.
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