Protein phosphatase 2A: who shall regulate the regulator?

Biochem Pharmacol. 1999 Feb 15;57(4):321-8. doi: 10.1016/s0006-2952(98)00245-7.


Protein phosphatases are responsible for keeping the signaling output of stimulus-activated protein kinases in check; but protein phosphatases are also themselves targets and conveyors of biological signals. Among the major serine/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 of laboratories has shown that the catalytic activity, substrate specificity, and subcellular targeting of PP2A are regulated by a remarkably diverse range of regulatory subunits and enzyme inhibitors. On the pathological side, DNA tumor viruses subvert PP2A function by producing proteins that compete 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 data indicate that besides classical holoenzyme forms, a fraction of PP2A molecules are associated with novel partners implicated in signal transduction. PP2A biochemically and genetically interacts with the Tap42/alpha4 protein, which is part of a rapamycin-sensitive pathway that connects extracellular stimuli to the initiation of mRNA translation. PP2A also binds to CK2alpha, the catalytic subunit of CK2 (formerly casein kinase 2), and binding is sensitive to mitogenic signaling. The potent effect of quantitatively minor PP2A partners might be explained by a general requirement for docking interactions with substrates under intracellular conditions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Phosphoprotein Phosphatases / chemistry
  • Phosphoprotein Phosphatases / physiology*
  • Protein Kinases / metabolism
  • Protein Phosphatase 2
  • Signal Transduction
  • Sirolimus / pharmacology
  • Substrate Specificity
  • Viral Proteins / pharmacology


  • Viral Proteins
  • Protein Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • Sirolimus