Protein Tyrosine Phosphatase Receptor Type F Promotes Wnt Signaling in Colorectal Cancer

Abstract

Colorectal cancer is the second leading cause of cancer deaths in the United States. A major mechanism behind the formation of colon cancer is the activation of Wnt signaling through a mutation in the APC or β‐catenin gene, which leads to accumulation of active β‐catenin. Aberrant signaling of the Wnt pathway has been linked to the initiation and progression of colorectal cancer. A major mechanism of control for the Wnt signaling pathway is protein phosphorylation. A fine balance between phosphorylation and dephosphorylation exist to keep the cell balanced depending on its needs. Protein phosphatases are important in regulating signaling pathways by dephosphorylating a large number of cellular substrates. In this study, we investigated the functional importance of PTPRF, a member of protein tyrosine phosphatase receptor type 2A, in regulating Wnt signaling in colon cancer. Bioinformatics analysis indicated that PTPRF is highly expressed in the intestinal epithelium. Silencing PTPRF in colon cancer cells resulted in a decrease in the expression of Wnt target genes. As a consequence, the rate of cell proliferation was significantly decreased in PTPRF knockdown cells. To determine the molecular mechanism, we examined the internalization process of Wnt‐Fzd‐LRP6 receptor complex, a key mode of regulation for the Wnt pathway. Specifically, we monitored the time course of LRP6‐GFP tracking in control and PTPRF knockdown cells upon Wnt stimulation. Our preliminary confocal microscopy results showed that the amount of LRP6‐GFP protein detected at the cell surface was decreased basally and the time course of LRP6‐GFP endocytosis was altered upon Wnt treatment in PTPRF knockdown cells. Interestingly, we found that PTPRF was co‐localized with LRP6‐GFP at both endocytic vesicles and plasma membrane in colon cancer cells, and Wnt treatment promoted internalization of PTPRF. Taken together, our study has identified PTPRF as a novel regulator of Wnt signaling by controlling the endocytosis of LRP6 receptor in colorectal cancer.Support or Funding InformationThis work was supported by R01CA133429 and R01CA208343.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.