Protein phosphatase 2A: Who shall regulate the regulator?

Protein phosphatases are responsible for keeping the signaling output of st imulus-activated protein kinases in check; but protein phosphatases are als o themselves targets and conveyors of biological signals. Among the major s erine/threonine phosphatases, protein phosphatase 2A (PP2A) appears to play a privileged role in the regulation of cell growth and division. How PP2A is regulated is an intriguing question. This review will focus on the role of local protein-protein interactions in PP2A control. Work from a number o f laboratories has shown that the catalytic activity; substrate specificity , and subcellular targeting of PP2A are regulated by a remarkably diverse r ange of regulatory subunits and enzyme inhibitors. On the pathological side , DNA tumor viruses subvert PP2A function by producing proteins that compet e with specific regulatory subunits. By interfering with PP2A, these viral proteins can elicit changes in the activity of specific signal transduction pathways, such as the mitogen-activated protein kinase cascade. Recent dat a indicate that besides classical holoenzyme forms, a fraction of PP2A mole cules are associated with novel partners implicated in signal transduction. PP2A biochemically and genetically interacts with the Tap42/alpha 4 protei n, which is part of a rapamycin-sensitive pathway that connects extracellul ar stimuli to the initiation of mRNA translation. PP2A also binds to CK2 al pha, the catalytic subunit of CK2 (formerly casein kinase 2), and binding i s sensitive to mitogenic signaling. The potent effect of quantitatively min or PP2A partners might be explained by a general requirement for docking in teractions with substrates under intracellular conditions. (C) 1999 Elsevie r Science Inc.