Babraham (Cambridge) [UK], July 25 (ANI): The protein receptor Tyrosine phosphatases are proteins that are found in cell membranes. Although the details of their exact mechanism of action remain unknown, they are known to be tumour suppressors and regulators of cell-cell interactions.
A member of this family, PTPRK, has been linked to multiple cancer forms, most notably colorectal cancer, and human colorectal tumours have PTPRK-inactivating mutations and genetic events. Coeliac disease and PTPRK have also been connected genetically.
The Babraham Institute’s Sharpe lab studied the function and signalling pathways of PTPRK in human and mouse colorectal cancer cells as well as in cell adhesion, growth factor signalling, and tumour suppression. The Journal of Cell Science published their findings, which have implications for our knowledge of the cellular settings that suppress the growth of tumours and the interactions between cells that influence wound healing and possibly cancer spread.
Dr Katie Young, lead author on the paper who undertook this research as a PhD student in the Sharpe lab, said: “Through this work we aimed to investigate the role of PTPRK in the colon, working together several observations in the field and connecting these back to the complex signalling mechanisms behind them. It’s vital that we know more about how receptor protein tyrosine phosphatases sense and transmit signals to ensure the healthy growth of our cells, as well as how errors in these mechanisms cause disease.”
Using human colorectal cancer cell lines, the team found that the deletion of PTPRK altered the appearance of the cells, compared to control cells where PTPRK was functional, and observed that the knockout cells showed impaired wound-healing response, which was likely to be due to the loss of PTPRK affecting coordinated action by cells and their neighbours and defects in cellular polarisation.
Utilising a mouse line where PTPRK had been deleted, the team uncovered a role for PTPRK in colon repair. When inflammation of the colon (colitis) was stimulated, mice lacking PTPRK showed a more severe response, demonstrating either increased susceptibility to damage or decreased repair following inflammation. The knockout mice also developed larger and more invasive tumours in a colorectal cancer model compared to wild-type controls, confirming that PTPRK has a role in suppressing tumour growth and invasion.
Using a catalytic mutant, where the catalytic function of PTPRK was abolished, and a xenograft model where cancer cells were transplanted into mice, the researchers confirmed the function for PTPRK in suppressing tumour growth and demonstrated that this was independent of the protein’s phosphatase activity.
Comparing gene expression profiles between cells with and without PTPRK, the team identified genes that were affected by the loss of PTPRK. These genes are characterised in function as being related to epithelial cell identity (being involved in the epithelial to mesenchymal transition and mesenchymal cell differentiation).
The team hypothesise that PTPRK regulation could be a central factor giving plasticity in epithelial barriers, such as lines the intestines, to facilitate epithelial repair while providing a signal to stop the repair response.
Analysing the xenograft tumour samples, the team quantified tyrosine phosphorylation to determine the signalling mechanisms by which PTPRK suppresses tumour development. Their work suggests that the suppression of epidermal growth factor receptor (EGFR) signalling by PTPRK is a key factor and is mediated separately from its function as a phosphatase.
Dr Hayley Sharpe, group leader in the Signalling research programme at the Institute, said: “The goal of our research was to pull several observations together and begin to fill in the gaps of what we don’t know about PTPRK. It has been assumed that PTPs act as tumour suppressors by countering kinase activity by dephosphorylation on oncogenic phosphotyrosine modifications. Therefore, the non-catalytic role of PTPRK in signalling is really intriguing to us and how it achieves this is an important next question to fully understand its role in tumour suppression.” (ANI)
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