PUBLICATION

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

Authors
Liu, X., Xiong, C., Jia, S., Zhang, Y., Chen, Y.G., Wang, Q., and Meng, A.
ID
ZDB-PUB-130423-15
Date
2013
Source
Nature communications   4: 1728 (Journal)
Registered Authors
Jia, Shunji, Meng, Anming, Wang, Qiang, Xiong, Cong, Zhang, Yu
Keywords
none
MeSH Terms
  • Animals
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Mesoderm/enzymology
  • Mesoderm/metabolism*
  • Nodal Protein
  • Phosphorylation
  • Protein Kinases/genetics
  • Protein Kinases/metabolism*
  • Smad2 Protein
  • Zebrafish/embryology
PubMed
23591895 Full text @ Nat. Commun.
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.

Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping