Cell communication, proliferation, and motility are governed by a complex web of protein-protein interactions and phosphorylation events at the cell cortex. Protein tyrosine kinases and protein tyrosine phosphatases (PTPs) provide critical control points for these processes and thus play central roles in normal development as well as diseases such as cancer. The fly Drosophila melanogaster provides a powerful model system to study the role of PTPs in development and signal transduction. The investigator has sequenced clones encoding two novel Drosophila PTPs, named Pez and Meg after two of their human orthologs. Pez and Meg are members of the FERM-PTP family, modular proteins of unknown biological function that contain amino-terminal FERM (4.1, ezrin, radixin, moesin-related) domains, carboxy-terminal PTP domains, and distinct protein-protein interaction motifs in their central portions. Most other FERM domain proteins are structural components and/or regulators of the membrane cytoskeleton or focal adhesions. Thus the domain structures of Pez and Meg suggest that they participate in multiprotein complexes important in cell motility or adhesion, and therefore could play a role in tumor metastasis. To test this hypothesis, mutations will be generated in the Pez gene and their effects on proliferation, motility, adhesion, and differentiation will be examined by a variety of phenotypic assays available in Drosophila. Further, Pez substrates will be pursued by expressing a """"""""substrate trapping"""""""" mutant form of Pez. Trapped substrates will identified by genetic and biochemical approaches. These experiments are designed to elucidate the biological function of Pez and identify the signaling pathways) in which Pez resides. This work will initiate a long term molecular genetic investigation of the role of the membrane cytoskeleton in signaling and cell movement.
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