SIGNALING THROUGH CELL SURFACE RECEPTORS ON ENDOTHELIAL CELLS

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The goal of this to understand the molecular basis for endothelial cell responses to external events, including local injury and inflammation. To accomplish this we will continue our work on two groups of cell surface receptors that can initiate intracellular signaling in endothelial cells: the protease-activated receptors (PARs) and Eph kinases. The protease-activated receptors are a subfamily of G protein coupled receptors that are activated by proteolysis of the receptor that are activated by proteolysis of the receptor N-terminus. Four members of this family have been identified to date. Eph kinase receptors are a large family of membrane-bound tyrosine kinases whose ligands are also cell surface proteins. Both of these receptors families was chosen because of their relevance to endothelial cell growth and function. Protease-activated receptors because of their role in mediating responses to the proteolytic enzymes that accumulate at high concentrations at sites of injury and inflammation. Eph receptors were selected based upon the hypothesis that they play a role in cell-cell interactions between endothelial cells, leukocytes and platelets, as well as mediating interactions between endothelial cells. It is our belief that comparisons among these receptor families in term of surface expression and distribution, the signaling pathways that are initiated by receptor activation, crosstalk between the receptors and adaptations to the local environment including changes in flow and shear, will provide insights into endothelial cell biology and pathology at a level of organization beyond that which comes from concentration on any one receptor family. This is, in fact, the theme that unites the three parts of this proposal-and relates it to the other 4 proposals within this program project, each of which deals with the responses of endothelial cells, smooth muscle cells or platelets to changes in their local environment via cell surface receptors or integrins.