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Araf kinase antagonizes Nodal-Smad2 activity in mesendoderm development by directly phosphorylating the Smad2 linker region

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  • Xingfeng Liu

    (State-Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Cong Xiong

    (State-Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Shunji Jia

    (State-Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Yu Zhang

    (State-Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Ye-Guang Chen

    (State-Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University)

  • Qiang Wang

    (Institute of Zoology, Chinese Academy of Sciences)

  • Anming Meng

    (State-Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University
    Institute of Zoology, Chinese Academy of Sciences)

Abstract

Smad2/3-mediated transforming growth factor β signalling and the Ras-Raf-Mek-Erk cascade have important roles in stem cell and development and tissue homeostasis. However, it remains unknown whether Raf kinases directly crosstalk with Smad2/3 signalling and how this would regulate embryonic development. Here we show that Araf antagonizes mesendoderm induction and patterning activity of Nodal/Smad2 signals in vertebrate embryos by directly inhibiting Smad2 signalling. Knockdown of araf in zebrafish embryos leads to an increase of activated Smad2 with a decrease in linker phosphorylation; consequently, the embryos have excess mesendoderm precursors and are dorsalized. Mechanistically, Araf physically binds to and phosphorylates Smad2 in the linker region with S253 being indispensable in a Mek/Erk-independent manner, thereby attenuating Smad2 signalling by accelerating degradation of activated Smad2. Our findings open avenues for investigating the potential significance of Raf regulation of transforming growth factor β signalling in versatile biological and pathological processes in the future.

Suggested Citation

  • Xingfeng Liu & Cong Xiong & Shunji Jia & Yu Zhang & Ye-Guang Chen & Qiang Wang & Anming Meng, 2013. "Araf kinase antagonizes Nodal-Smad2 activity in mesendoderm development by directly phosphorylating the Smad2 linker region," Nature Communications, Nature, vol. 4(1), pages 1-11, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2762
    DOI: 10.1038/ncomms2762
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