Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation

J Biol Chem. 2000 Jul 21;275(29):22300-4. doi: 10.1074/jbc.M003259200.

Abstract

The Raf-1 kinase plays a key role in relaying proliferation signals elicited by mitogens or oncogenes. Raf-1 is regulated by complex and incompletely understood mechanisms including phosphorylation. A number of studies have indicated that phosphorylation of serines 259 and 621 can inhibit the Raf-1 kinase. We show that both serines are hypophosphorylated during early mitogenic stimulation and that hypophosphorylation correlates with peak Raf-1 activation. Concentrations of okadaic acid that selectively inhibit protein phosphatase 2A (PP2A) induce phosphorylation of these residues and prevent maximal activation of the Raf-1 kinase. This effect is mediated via phosphorylation of serine 259. The PP2A core heterodimer forms complexes with Raf-1 in vivo and in vitro. These data identify PP2A as a positive regulator of Raf-1 activation and are the first indication that PP2A may support the activation of an associated kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Enzyme Activation
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Phosphatase 2
  • Proto-Oncogene Proteins c-raf / metabolism*
  • Signal Transduction

Substances

  • Proto-Oncogene Proteins c-raf
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2