Protein Tyrosine Phosphatase T/Paxillin – An Unappreciated Pathway of Colon Carcinogenesis
Joseph Willis, Yujun Hao, Anthony Scott, Yiqing Zhao, Dawn Dawson, Sanford Markowitz, Zhenghe Wang. Case Medical Center, Cleveland, OH; Case Comprehensive Cancer Center, Cleveland, OH; Case Western Reserve University, Cleveland, OH
Background: Protein tyrosine phosphatase T (PTPRT) is the most frequently mutated tyrosine phosphatase in cancer - having been identified in a number of differing human cancer types. Paxillin is an adaptor protein involved in cell adhesion, migration, proliferation and apoptosis. We recently discovered that paxillin is a substrate of PTPRT, that PTPRT directly dephosphorylates a previously unappreciated paxillin phospho-tyrosine site Y88 (pY88). We noted that the PTPRT system complex acts as a tumor suppressor and that over expression of pY88 occurs in colon cancers (CCs). This study investigates the extent of pY88 expression, site of activity of the PTPTRT/paxillin pathway in CC and a possible therapeutic option for chemotherapeutic modulation via Src kinase since pY88 is a known phosphorylation site for this enzyme.
Design: Immunohistochemistry was performed on a range of CCs and matching controls with anti-pY88 antibody. Cell fractionation studies of CC cell lines to independently identify the site of pY88 cellular localization was performed. Finally, CC cell cultures with variable pY88 expression were exposed to Src tyrosine kinase inhibition using a specific inhibitor 'Dasatinib' and the effects observed.
Results: 74% of Stage IV, 53% of Stage III, and 37% of Stage I & II CCs show strong pY88 paxillin IHC staining. No association with tumor grade was found. Immunohistochemistry and cell fractionation analyses consistently showed that pY88 accumulates in cancer nuclei. CC cell lines harboring high levels of pY88 paxillin are hyper-sensitive to Src kinase inhibitor 'Dasatinib' in tissue culture.
Conclusions: Our data suggest that paxillin Y88 phosphorylation may play a significant role in colon cancer progression and demonstrate its preferred localization to the nucleus. This is consistent with its newly discovered carcinogenic functions. Interestingly, as postulated from the known association of pY88 with the Src kinase pathway, over expression of paxillin pY88 may be a marker of colon cancer susceptibility to a Src kinase inhibitor chemotherapeutic effect.
Monday, March 19, 2012 1:00 PM
Poster Session II # 120, Monday Afternoon