Investigating the role of R2B receptor tyrosine phosphatases in developmental signalling pathways (360G-Wellcome-207154_Z_17_Z)

Tyrosine phosphorylation is a key post translational modification that is often dysregulated in disease. The balanced actions of kinases and phosphatases are required for cellular homeostasis. However, the substrates and functions of phosphatases are poorly understood. The receptor tyrosine phosphatase PTPRK was identified as a recurrent fusion partner of the oncogene RSPO3 – an amplifier of the Wnt pathway. Additionally, PTPRK was identified in a forward genetic screen for modulators of APC min driven intestinal tumorigenesis. Given these genetic links, and hints in the literature that PTPRK can dephosphorylate beta catenin, a Wnt transcriptional activator, we plan to investigate the signalling cross-talk between PTPRK and Wnt signaling. First, this project aims to discover whether Wnt signalling influences the regulation of PTPRK at the messenger RNA and protein level. Second, we plan to test how depletion of PTPRK affects Wnt signaling output using luciferase reporter assays and western blotting. The outcome of this project will be a comprehensive assessment of the interplay between PTPRK and Wnt signalling, with important implications for the role of PTPRK in colorectal cancer, which is one of the current focusses of the Sharpe Lab.