Ser/Thr specific protein phosphatase

In mammals, at least eight types of Ser/Thr-specific protein phosphatases have been identified, and these are classified according to their substrate specificities, metal requirements, and sensitivities to natural or synthetic inhibitors. Four groups of the Ser/ Thr phosphatases, the protein phosphatases (PP) 1, 2A, 2B and C2, have been studied in detail. PP-1, PP-2A and PP-2B, which is also known as calcineurin, are highly homo-... 

PPI is a major dass of eukaryotic Ser/Thr-specific protein phosphatases that regulate diverse cellular processes such as cell cycle progression, muscle contraction, carbohydrate metabolism, protein synthesis, transcription, and neuronal signaling. Its action is modulated and regulated by assodation with subunits induding various inhibitor proteins and multiple targeting subunits of which nearly 30 proteins have now been identified (review Aggen et al., 2000). The activity of the inhibitory proteins can be controlled via phosphorylation by protein kinase A as outlined in Fig. 7.16. 

The current state of Ser/Thr phosphorylation of a protein is determined by the relative activity of Ser/Thr-specific protein kinase and protein phosphatase. It is therefore imderstandable that the cell has had to develop special mechanisms to balance the two activities with one another, and, when needed, to allow kinase or phosphatase activity to dominate. One of the best investigated examples of coordinated activity of protein kinases and protein phosphatases is the regulation of glycogen metabolism in skeletal muscle. Glycogen metabolism is an example of how two different signals, namely a cAMP signal and a Ca signal meet in one metabolic pathway and control the activity of one and the same enzyme. 

The extent of tyrosine phosphorylation of signal proteins is determined both by the activity of the tyrosine kinases and also the activity of tyrosine-specific protein phosphatases. If the total activity of both enzymes in the cell is considered, it is found that there is a preponderance of protein tyrosine phosphatase activity compared to tyrosine kinase activity. In contrast, the activities of the Ser/Thr-specific protein kinases and protein phosphatases are approximately balanced. It is estimated that the activity of the protein tyrosine phosphatases is about 3-4 orders of magnitude higher than the activity of the protein tyrosine kinases. With this relationship between the activities, it is not surprising that the net level of tyrosine phosphorylation in the cell is very low and that tyrosine phosphorylation is often only transient. Consequently, it took a relatively long time until the importance of tyrosine phosphorylation for signal transduction was assessed correctly. 

Another mechanism of regulation of protein tyrosine phosphatases is via Ser/Thr phosphorylation. Specific phosphorylation of protein tyrosine phosphatases by Ser/ Thr-specific protein kinases of types A and C has been reported (see Neel and Tonks, 1997). This observation indicates the possibility that signal transductions via Ser/Thr kinases and via Tyr kinases/phosphatases may cooperate and that different signal pathways may be crosslinked in this way. 

Under physiological conditions, phosphate esters of Ser and Thr residues are stable and only show a low rate of spontaneous hydrolysis. Thus, the cell requires its own tools for regulated cleavage of phosphate residues, to terminate and damp signals mediated by protein phosphorylation. This role is performed by specific protein phosphatases. 

We know of Ser/Thr phosphate specific protein phosphatases (referred to in the following as Ser/Thr phosphatases) and Tyr phosphate specific protein phosphatases. The latter are dealt with in Chapter 8. 

---