Tyrosine phosphorylation is a fundamental regulatory mechanism, occurring exclusively in multicellular eukaryotes. This signaling mechanism is regulated by the balanced action of tyrosine kinases and protein tyrosine phosphatases (PTPs). The first PTP was purified in 1988 (1), approximately 10 years after the discovery of tyrosine kinases. The following years witnessed a rapid development that established PTPs as a family of highly specific and tightly regulated signaling proteins. It is now well established that PTPs equal tyrosine kinases in importance for the regulation of tyrosine phosphorylation (2–5). It is also predicted that, like tyrosine kinases, PTPs may emerge as drug targets for many major diseases, including conditions associated with endothelial pathology (6).

THE FAMILY OF PROTEIN TYROSINE PHOSPHATASES

Protein Tyrosine Phosphatase Subfamilies

A recent survey identified a total of 107 genes encoding PTPs in the human genome, of which 105 have mouse orthologues (3). Of these 107 genes, 38 belong to the subtype of classical PTPs, which display a specificity for dephosphorylation of tyrosine residues. Other major subgroups include the dual-specificity phosphatases (61 genes), the myotubularins (16 genes), and the non–cysteine-based Eya family of phosphatases (4 genes). This chapter is restricted to discussing the classical PTPs, hereafter only referred to as PTPs (Figure 84.1).

Structure of the Protein Tyrosine Phosphatase Domain and Catalytic Mechanism

The conserved catalytic domain of PTPs consists of approximately 280 amino acid residues, of which 22 are perfectly conserved among the 38 human PTPs (7). Six of the conserved residues are part of the active-site sequence V/I H C S X G X G R. In addition to this PTP signature motif, three conserved regions contribute to the formation of the catalytic site.