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First published online 14 January 2004
doi: 10.1242/dev.00987

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C. elegans SUR-6/PR55 cooperates with LET-92/protein phosphatase 2A and promotes Raf activity independently of inhibitory Akt phosphorylation sites

Gautam Kao^1,*, Simon Tuck², David Baillie³ and Meera V. Sundaram^1,

¹ Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA
² UCMP, Umea University, SE-901 87 Umeå, Sweden
³ Department of Biological Sciences, Simon Fraser University, Burnaby B.C. V5A 1S6, Canada

Author for correspondence (e-mail: sundaram{at}mail.med.upenn.edu)

Accepted 4 November 2003

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 of C. 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.

Key words: PP2A, PR55, Raf, PAR-1, Vulva, C. elegans

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