Phosphorylation of proteins on tyrosine residues is a key mechanism in the execution of a wide range of signal transduction events. The net level of tyrosine phosphorylation reflects a dynamic balance between the opposing actions of tyrosine kinases and protein tyrosine phosphatases (PTPases). PTPase deregulation is being implicated in a variety of clinical situations, including diabetes and cancer. Hence, PTPases also constitute an attractive and intensely explored target for pharmacological intervention. So-called receptor tyrosine phosphatases (R-PTPases) are of particular interest, due to their location at the cell membrane, and the presence of extracellular domains which may perform a regulatory role.

Our recent studies have concentrated on the analysis of RPTP* as a widely expressed model for the R-PTPase family. We have made the surprising observation that RPTP* is itself a substrate for tyrosine phosphorylation, leading to its controlled association with Grb2, an adaptor protein previously implicated in the regulation of Ras function by tyrosine kinases. We have shown that such association with adaptor proteins is one of the mechanisms by which the cell controls PTPase function. Further work on the role of RPTP* in growth factor signaling also demonstrated that a single phosphatase can, in the same cell, exert opposite (positive vs. negative) effects on different signaling pathways, for instance antagonizing the responses to fibroblast growth factor, but actually enhancing cellular responses to epidermal growth factor. One way in which RPTP* exerts its potentiating effects on cell signaling is by activating tyrosine kinases of the Src family. Thus, our recently generated mouse knock-out of RPTP* shows decreased c-src kinase activity and function, and mimics aspects of the phenotype of a c-src null mutation. These studies furthermore point at an important role for RPTP* in the control of cell-matrix interaction and integrin signaling. By contrast, other R-PTPases, such as RPTPk, appear to affect cell-cell adhesive interactions.