C. elegans SUR-6/PR55 cooperates with LET-92/protein phosphatase 2A and promotes Raf activity independently of inhibitory Akt phosphorylation sites
2004 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 131, no 4, 755-765 p.Article in journal (Refereed) Published
Protein phosphatase 2A (PP2A) can both positively and negatively influence the Ras/Raf/MEK/ERK signaling pathway, but its relevant substrates are largely unknown. In C. elegans, the PR55/B regulatory subunit of PP2A, which is encoded by sur-6, positively regulates Ras-mediated vulval induction and acts at a step between Ras and Raf. We show that the catalytic subunit (C) of PP2A, which is encoded by let-92, also positively regulates vulval induction. Therefore SUR-6/PR55 and LET-92/PP2A-C probably act together to dephosphorylate a Ras pathway substrate. PP2A has been proposed to activate the Raf kinase by removing inhibitory phosphates from Ser259 from Raf-1 or from equivalent Akt phosphorylation sites in other Raf family members. However, we find that mutant forms ofC. elegans LIN-45 RAF that lack these sites still require sur-6. Therefore, SUR-6 must influence Raf activity via a different mechanism. SUR-6 and KSR (kinase suppressor of Ras) function at a similar step in Raf activation but our genetic analysis suggests that KSR activity is intact in sur-6 mutants. We identify the kinase PAR-1 as a negative regulator of vulval induction and show that it acts in opposition to SUR-6 and KSR-1. In addition to their roles in Ras signaling, SUR-6/PR55 and LET-92/PP2A-C cooperate to control mitotic progression during early embryogenesis.
Place, publisher, year, edition, pages
Cambridge: Company of Biologists Limited , 2004. Vol. 131, no 4, 755-765 p.
Animals, Animals; Genetically Modified, Caenorhabditis elegans/embryology/*enzymology/genetics, Caenorhabditis elegans Proteins/metabolism, Drosophila Proteins, Female, Mutation, Phosphoprotein Phosphatase/genetics/*metabolism, Phosphorylation, Protein-Serine-Threonine Kinases/metabolism, Protein-Tyrosine-Phosphatase/metabolism, Proto-Oncogene Proteins/*metabolism, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-raf/*metabolism, Vulva/embryology
IdentifiersURN: urn:nbn:se:umu:diva-17951DOI: 10.1242/dev.00987PubMedID: 14724126OAI: oai:DiVA.org:umu-17951DiVA: diva2:157624