The goal of this research is to define the mechanisms whereby the Abl family of nonreceptor tyrosine kinases and associated adaptor proteins regulate intercellular adhesion, with emphasis on their role in the regulation of cell-cell adhesion during metastasis and angiogenesis. Dynamic regulation of the actin cytoskeleton is required for cell-cell adhesion, which is critical for cell morphogenesis, tissue integrity, cell migration, cell survival and growth. Disruption of cell-cell adhesion is linked to tumor invasion and other pathological conditions. Actin polymerization provides the driving force for the formation of adherens junctions, which are specialized sites of cell-cell contact that link cadherins on the cell surface to the actin cytoskeleton via the catenins. Adherens junctions are regulated by tyrosine phosphorylation, and we have recently demonstrated a critical role for the Abl family of tyrosine kinases in the formation and turnover of adherens junctions. Moreover, we have identified a requirement for a functional Abi/Wave/Nap1 protein complex in the formation of cell-cell junctions. This protein complex, which has been linked to Rac- dependent actin polymerization, is comprised of two Abl-binding proteins, Abi and Wave, as well as Nap1 and PIR121/Sra. A fundamental gap in knowledge exists regarding the mechanisms whereby tyrosine kinases regulate cell-cell adhesion, and the identification of signaling pathways linking cadherin engagement to de novo actin polymerization. We will test the hypothesis that the activities of Abl family kinases and their targets are play critical roles in the regulation of cell-cell adhesion during cancer progression and angiogenic remodeling.
The specific aims of this proposal are: 1) define the mechanisms whereby Abl kinases regulate the formation and turnover of adherens junctions, and determine whether Abl family kinase activity contributes to altered epithelial intercellular adhesion during invasion and metastasis;2) examine whether Abl kinases regulate endothelial cell-cell adhesion and angiogenesis;and 3) elucidate the mechanisms whereby the Abi/Wave/Nap1 complex regulates adherens junctions and examine the role of Abi proteins in metastasis. Results from the proposed studies will provide insights into the mechanisms whereby tyrosine kinases and actin regulatory proteins modulate cell-cell adhesion during cancer progression, metastasis, and angiogenic sprouting.
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