Harnessing surface phosphatases to define and modulate signal transduction in cancer

Receptor tyrosine kinases (RTKs) are molecular switches that are essential for cell signalling. Aberrant activation of RTKs has disastrous consequences, often leading to tumour growth. I propose a new framework to determine critical aspects of RTK signalling by investigating the contribution of receptor protein tyrosine phosphatases (RPTPs) and harnessing phosphatase activity in a controlled manner using engineered ligands. RTK activity is affected by phosphatases, including RPTPs. However, the specificity and activity of many RPTPs remain unexplored and their impact on RTK signalling is unknown. I developed a systematic screen to determine the specificity of RPTPs against a representative subset of 15 RTKs that, combined, are associated with a third of all tumours. I aim to identify which RPTPs suppress RTK activity and to develop a novel platform to explore this regulatory mechanism. I will generate synthetic bispecific proteins that recruit membrane phosphatases to RTKs, resulting in enforced kinase dephosphorylation and inhibition. These molecules will allow me to address critical questions on RTK regulation and to explore the interplay between RTKs and RPTPs at the cell surface. In addition, this approach will pave the way towards a new class of molecules for oncogene suppression with strong potential for therapeutic applications.