Protein Tyrosine Dephosphorylation & Signal Transduction

Cold Spring Harbor Laboratory, Cold Spg Hbr NY

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Abstract

DESCRIPTION (provided by applicant): The broad, long-term objectives of this project are to characterize the structure, regulation and physiological function of members of the protein tyrosine phosphatase (PTP) family of enzymes. In the area of tyrosine phosphorylation-dependent signal transduction, drug discovery efforts to date have emphasized the protein tyrosine kinases (PTKs). However, protein tyrosine phosphorylation is reversible and, therefore, there is the potential to manipulate signal transduction pathways at the level of both PTKs and PTPs. The composition of the PTP family has been determined and significant progress has been made in elucidating the physiological functions of these enzymes. Tumor-derived mutations have been identified in multiple PTP genes and examples of PTPs as either the products of oncogenes or tumor suppressors have been established. Although the PTPs have been garnering attention as potential therapeutic targets, they remain largely an untapped resource. In the previous funding period, a broad array of tools and technologies has been developed to permit a systematic analysis of PTP function from the perspective of the family as a whole. This competitive renewal has been focused on a functional analysis of specific PTPs in models of breast cancer. The hypothesis to be tested is that PTPs function as specific regulators of tyrosine phosphorylation-dependent signaling pathways and thus manipulation of PTP function in cell and animal models will reveal new insights into the critical signaling events that underlie the disease. The overall goal is to define functional links between particular PTPs and specific signaling pathways in breast cancer, with a view to establishing how disruption of such functions affects the etiology of the disease and to reveal novel therapeutic targets from among the PTPs themselves or from the signaling pathways they regulate. The Specific Aims of this research program are: 1: To characterize the role of PTP1B in regulating signaling by HER2, 2: To characterize the function of PTPs in the control of HER2-induced cell migration and invasion, focusing on PTPRG, PTPRR and PTPN23, 3: To identify and characterize PTPs that modify HER2 signaling in 3D culture, focusing initially on PTPRO and PTPRJ/DEP-1, 4: To determine how loss of expression of PTPs contributes to tumorigenesis in vivo.