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  • The EMBO Journal (2006) 25, 727 - 738
  • doi:10.1038/sj.emboj.7600980

Published online: 2 February 2006

B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK

Claire Letourneux1,2,3, Géraldine Rocher1,2,3 and Françoise Porteu1,2,3

  1. Department of Hematology, Institut Cochin, INSERM U567, Paris, France
  2. CNRS, UMR 8104, Paris, France
  3. Faculté de Médecine René Descartes, Université Paris Descartes, UMR-S 8104, Paris, France

Correspondence to:

Françoise Porteu, Department of Hematology, Institut Cochin, 27 rue du Fg St Jacques, 75014 Paris, France. Tel.: +33 1 40 51 65 15; Fax: +33 1 40 51 65 10; E-mail: porteu@cochin.inserm.fr

Received 20 September 2005; Accepted 10 January 2006

The protein phosphatase 2A (PP2A) acts on several kinases in the extracellular signal-regulated kinase (ERK) signaling pathway but whether a specific holoenzyme dephosphorylates ERK and whether this activity is controlled during mitogenic stimulation is unknown. By using both RNA interference and overexpression of PP2A B regulatory subunits, we show that B56, but not B, family members of PP2A increase ERK dephosphorylation, without affecting its activation by MEK. Induction of the early gene product and ERK substrate IEX-1 (ier3) by growth factors leads to opposite effects and reverses B56-PP2A-mediated ERK dephosphorylation. IEX-1 binds to B56 subunits and pERK independently, enhances B56 phosphorylation by ERK at a conserved Ser/Pro site in this complex and triggers dissociation from the catalytic subunit. This is the first demonstration of the involvement of B56-containing PP2A in ERK dephosphorylation and of a B56-specific cellular protein inhibitor regulating its activity in an ERK-dependent fashion. In addition, our results raise a new paradigm in ERK signaling in which ERK associated to a substrate can transphosphorylate nearby proteins.

  • Keywords:

    • ERK,
    • phosphatases,
    • PP2A,
    • substrates