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Feedback regulation of MAPK signalling by an RNA-binding protein

Nature volume 424, pages 961–965 (2003)Cite this article

Abstract

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.

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Figure 1: Identification of Rnc1, a new KH-type RNA-binding protein.
Figure 2: Rnc1 modulates MAPK signalling through regulation of the MAPK phosphatase Pmp1.
Figure 3: Rnc1 binds Pmp1 mRNA in vitro and in vivo.
Figure 4: Pmk1-mediated phosphorylation regulates the ability of Rnc1 to bind and stabilize Pmp1 mRNA.

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Acknowledgements

We thank M. Yanagida and T. Toda for their gift of strains and plasmids, S. Nakielny and M. Sakaue for discussions, and M. Takeuchi for technical assistance. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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  1. Susie O. Sio

    Present address: Department of Pharmacology, College of Medicine, University of the Philippines Manila, Manila, 1000, Philippines

Authors and Affiliations

  1. Division of Molecular Pharmacology and Pharmacogenomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, 650-0017, Kobe, Japan

    Reiko Sugiura, Ayako Kita, Yasuhito Shimizu, Susie O. Sio & Takayoshi Kuno

  2. Faculty of Health Science, Kobe University School of Medicine, 7-10-2 Tomogaoka, Suma-ku, 654-0142, Kobe, Japan

    Hisato Shuntoh

Authors
  1. Reiko Sugiura
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Correspondence to Reiko Sugiura.

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Sugiura, R., Kita, A., Shimizu, Y. et al. Feedback regulation of MAPK signalling by an RNA-binding protein. Nature 424, 961–965 (2003). https://doi.org/10.1038/nature01907

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