Cell communication is critical in orchestrating a proportionate response to external factors, such as growth factors and during essential processes, such as junctional remodelling. Plasma membrane-localised receptor PTPs (RPTP) are well positioned to sense external environmental cues, such as cell-cell contact, and transmit signals via their intracellular domains. Using unbiased approaches we find RPTP, PTPRK binds and dephosphorylates key junctional regulators in epithelial cells. Consequently, PTPRK knockout (KO) epithelial cells exhibit impaired morphology and junctional integrity. In parallel, we find Ptprk KO mice are more susceptible to DSS-induced colitis and exhibit increased growth and invasion in a colorectal cancer model. These observations support its putative role as a tumour suppressor in several cancer types and its association with inflammatory bowel disease. Strikingly, we find that the ability of PTPRK to supress tumour growth in a colorectal cancer xenograft model does not require its catalytic activity. We employ the use of multi-omics to discover that this phenotype could be attributed to an enhanced susceptibility to growth factor stimulation, particularly epidermal growth factor.