title: Araf kinase antagonizes Nodal-Smad2 activity in mesendoderm development by directly phosphorylating the Smad2 linker region.
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.
authors.affiliation: State-Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Xingfeng
authors.initials: X
authors.lastname: Liu
authors.forename: Cong
authors.initials: C
authors.lastname: Xiong
authors.forename: Shunji
authors.initials: S
authors.lastname: Jia
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.forename: Anming
authors.initials: A
authors.lastname: Meng
mesh_terms: D000818:Animals; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008648:Mesoderm / Q000201:enzymology / Q000378:metabolism*; D055457:Nodal Protein; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051899:Smad2 Protein; D015027:Zebrafish / Q000196:embryology
chemical_list: D055457:Nodal Protein; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D011494:Protein Kinases