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.
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.