Protein Tyrosine Pseudophosphatase Signalling Mechanisms

Phosphatases are remarkably diverse, having evolved up to 10 distinct protein folds to mediate the removal of phosphate from substrates. Their functions are correspondingly wide ranging and a number are important clinical targets. As for kinases, several phosphatase classes comprise catalytically dead members. The classical protein tyrosine phosphatases (PTPs) are a subclass that utilise a cysteine nucleophile for catalysis and are critical for the control of cellular phosphotyrosine levels. Of the 49 human PTP domains, 19 possess sequence variants in key catalytic motifs defining them as pseudophosphatase domains. Strikingly, in all but two cases the catalytic cysteine remains intact. This is in contrast to other pseudophosphatases such as the pseudo‐dual specificity phosphatase (DUSP) MK‐Styx, which is inactivated by loss of its catalytic cysteine. We find that, like many pseudokinases, pseudoPTPs can mediate protein‐protein interactions, providing scaffolding functions, but also substrate recruitment to active PTP domains. Finally, given the striking conservation of cysteine residues in the pseudoPTPs, we have also explored a potential role for redox regulation in their signalling mechanisms.