Regulating the regulators

According to a modest estimation, one third of the known eukaryotic proteins can be phosphorylated. Protein kinases are members of a large superfamily and incorporate the phosphate moiety into the serine (Ser), threonine (Thr) or tyrosine (Tyr) residues of their target proteins. In comparison, protein phosphatases are less numerous but more diverse. They can be classified into four independent protein families according to their substrate specificities, catalytic mechanisms and amino acid sequences (Figure 1). The phosphatases specific for Ser and Thr side chains were first identified in classical biochemical studies, but their subsequent cloning revealed significant structural differences between the family members, which led to their division into the phosphoprotein phosphatase (PPP) and metal-ion-dependent protein phosphatase (PPM) subfamilies. Molecular cloning and genetic studies also led to the discovery of the so-called novel PPP enzymes. Despite the fact that both PPP and PPM subfamily members utilize the same binuclear metal assisted catalytic mechanism, they appear to have emerged through convergent evolution. Tyr-specific protein phosphatases (PTPs) have been identified since and are composed of transmembrane (receptor-like) and cytosolic (nonreceptor) subfamilies. These phosphatases not only counterbalance the effects of receptor and cytosolic protein Tyr kinases but also transmit information through the plasma membrane. Thus, they are of paramount importance in cellular signaling. Like the broad-substrate-specificity or dual-specificity protein phosphatases (DSPs), PTPs contain a highly conserved cysteine residue that is essential for the catalytic reaction. In contrast to the relatively well studied processes of Ser/Thr and Tyr phosphorylation, histidine (His) phosphorylation in eukaryotes is an emerging field, and a unique protein phosphatase responsible for His dephosphorylation (PHP) has been identified recently. In order to counteract the large number of protein kinases, protein phosphatases exhibit broad substrate specificity and interact with numerous regulatory and targeting proteins that control the activities of phosphatases by changing the conformation and location of these enzymes. Since the discovery of protein phosphorylation–dephosphorylation as a possible regulatory device in the mid-1950s, there has been a steady expansion of the field. The latest developments were summarized and new research directions were identified at this EMBO Conference on ‘Protein Phosphorylation and Protein Phosphatases’ held in Marburg, Germany.