title: Raf-1-associated protein phosphatase 2A as a positive regulator of kinase activation.
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.
authors.affiliation: Vienna Biocenter, Institute of Microbiology and Genetics, Dr. Bohr Gasse 9, A 1030 Vienna, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Abraham
authors.forename: K
authors.initials: K
authors.lastname: Podar
authors.forename: M
authors.initials: M
authors.lastname: Pacher
authors.forename: M
authors.initials: M
authors.lastname: Kubicek
authors.forename: N
authors.initials: N
authors.lastname: Welzel
authors.forename: B A
authors.initials: BA
authors.lastname: Hemmings
authors.forename: S M
authors.initials: SM
authors.lastname: Dilworth
authors.forename: H
authors.initials: H
authors.lastname: Mischak
authors.forename: W
authors.initials: W
authors.lastname: Kolch
authors.forename: M
authors.initials: M
authors.lastname: Baccarini
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019908:Proto-Oncogene Proteins c-raf; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2