The long term objectives of the project are to test the hypothesis that receptor protein tyrosine phosphatases (RPTPs) play a role in controlling signaling responses initiated by cell contact. As normal cells in culture approach confluence and adjacent cells touch each other, growth is inhibited. The proposal concentrates on three RPTPs that display features of cell adhesion molecules in their extracellular segments. These RPTPs may sense cell-cell contact directly, and trigger net dephosphorylation of tyrosyl residues in proteins at the membrane, thus countering the growth promoting effects of protein tyrosine kinases. There are three specific aims to the proposal. (1) To characterize PTP as a modulator of the adhesive properties of the cadherin-catenin complex. (2) To characterize the role of DEP-1 in controlling signaling responses initiated by cell contact. (3) To characterize the RPTP ceLAR from C. elegans. A combination of biochemistry, molecular and cell biology, and genetic approaches will be taken to characterize these RPTPs. Tyrosine phosphorylation antagonizes the adhesive function of cadherins, promoting a metastatic, invasive phenotype. The role of PTP, which is associated with cadherin-catenin complexes in vivo, in maintaining normal adhesive function will be tested. Expression of DEP-1 is elevated in confluent relative to sparse cell cultures. It will be tested as a potential mediator of contact inhibition of cell growth. PTP and DEP-1 are highly expressed in endothelial cells; their involvement in growth, migration and differentiation of these cells will be examined, potentially providing new insights into the control of angiogenesis. Disruption of ceLAR results in a phenotype consistent with defective cell-cell adhesion. Genetic approaches will be taken to the characterization of the phenotype and the signaling events controlled by this PTP. The health relatedness of the project is that the results should provide important insights into normal growth control and how the process is abrogated in tumors.
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