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Letters to Nature

Nature 424, 961-965 (21 August 2003) | doi:10.1038/nature01907; Received 10 February 2003; Accepted 11 July 2003

Feedback regulation of MAPK signalling by an RNA-binding protein

Reiko Sugiura1, Ayako Kita1, Yasuhito Shimizu1, Hisato Shuntoh2, Susie O. Sio1,3 & Takayoshi Kuno1

  1. Division of Molecular Pharmacology and Pharmacogenomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
  2. Faculty of Health Science, Kobe University School of Medicine, 7-10-2 Tomogaoka, Suma-ku, Kobe 654-0142, Japan
  3. Present address: Department of Pharmacology, College of Medicine, University of the Philippines Manila, Manila 1000, Philippines

Correspondence to: Reiko Sugiura1 Email: sugiurar@med.kobe-u.ac.jp

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Mitogen-activated protein kinases (MAPKs) are evolutionarily conserved enzymes that convert extracellular signals into various outputs such as cell growth, differentiation and cell death1, 2, 3, 4. MAPK phosphatases selectively inactivate MAPKs by dephosphorylating critical phosphothreonine and phosphotyrosine residues5, 6. The transcriptional induction of MAPK phosphatase expression by various stimuli, including MAPK activation, has been well documented as a negative-feedback mechanism of MAPK signalling7, 8. Here we show that Rnc1, a novel K-homology-type RNA-binding protein in fission yeast, binds and stabilizes Pmp1 messenger RNA9, the MAPK phosphatase for Pmk1 (refs 10, 11). Rnc1 therefore acts as a negative regulator of Pmk1 signalling. Notably, Pmk1 phosphorylates Rnc1, causing enhancement of the RNA-binding activity of Rnc1. Thus, Rnc1 is a component of a new negative-feedback loop that regulates the Pmk1 pathway through its binding to Pmp1 mRNA. Our findings—the post-transcriptional mRNA stabilization of a MAPK phosphatase mediated by an RNA-binding protein—provide an additional regulatory mechanism for fine-tuning of MAPK signalling pathways.