Protein phosphatases and the regulation of mitogen-activated protein kinase signalling

The magnitude and duration of signalling through mitogen- and stress-activa ted kinases are critical determinants of biological effect. This reflects a balance between the activities of upstream activators and a complex regula tory network of protein phosphatases. These mitogen-activated protein kinas e phosphatases include both dual-specificity (threonine/tyrosine) and tyros ine-specific enzymes, and recent evidence suggests that a single mitogen-ac tivated protein kinase isoform may be acted upon by both classes of protein phosphatase. In both cases, substrate selectivity is determined by specifi c protein-protein interactions mediated through noncatalytic amino-terminal mitogen-activated protein kinase binding domains. Future challenges includ e the determination of exactly how this network of protein phosphatases int eracts selectively with mitogen-activated protein kinase signalling complex es to achieve precise regulation of these key pathways in mammalian cells.