Protein tyrosine phosphatases (PTPases) are a largely understudied class of putative tumor suppressors. A critical step in tumor progression is the loss of cell-cell contacts leading to a highly invasive phenotype. Increased tyrosine kinase signaling at cell-cell contacts contributes to the invasion of colon carcinomas through disruption of adherens junctions. Cadherin engagement promotes cell-cell adhesion and contact inhibition of cell motility through regulation of Rho GTPases. p120 catenin is a tyrosine phosphorylated cadherin binding protein that regulates Rho GTPase activity. Binding of p120ctn to cadherins stabilizes adherens junctions. Elevated RTK signaling increases cytoplasmic p120ctn and leads to cell scattering and invasion by delocalizing Rho GTPase activity from adherens junctions to the leading edge. The delocalization of p120ctn is associated with aggressive colon cancer. However, the mechanisms that control tyrosine phosphorylation of p120ctn and how this affects junctional integrity, Rho GTPase activity and subsequent invasion of colon carcinoma cells are poorly understood. PTP-PEST is a cytoplasmic PTPase that, like p120ctn, regulates cell motility through Rho GTPases. Our preliminary evidence indicates that PTP-PEST targets p120ctn in colon carcinoma cells. In addition, the PTP-PEST gene is mutated in colon cancer cells leading to a loss of functional protein. How loss of PTP-PEST expression correlates with motility and Rho GTPase activity is not known. Our long-term goal is to understand how PTP-PEST contributes to colon cancer progression. The purpose of this proposal is to investigate how PTP-PEST controls Rho GTPase activity in adherens junctions to limit colon carcinoma invasion and how changes in PTP-PEST expression influence invasive potential.
The specific aims of this proposal are: 1) Determine how localization of PTP-PEST affects integrity of adherens junctions and cell motility 2) Elucidate how PTP- PEST modulates Rac1 and RhoA activity downstream of cadherin engagement and 3) Examine how PTP- PEST expression affects the invasive and metastatic potential of colon carcinoma cells. A major barrier to effective treatment of colon cancer is a need for targeted therapies. Our work will establish PTP-PEST as a potential candidate for the treatment of colon cancer as a suppressor of invasion. Completion of the proposed aims will lead to a better understanding of the cellular and biochemical mechanisms by which PTP- PEST functions to control colon carcinoma invasion. Moreover, our studies will lay a foundation for future studies investigating PTP-PEST as a potential biomarker and as a candidate for gene therapy based approaches to circumvent colon carcinoma invasion. ? ? ?
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