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Smad2/3-mediated TGF-signaling and the Ras-Raf-Mek-Erk cascade play important roles in stem cell and development and tissue homeostasis.However,it remains unknown whether Raf kinases directly crosstalk with Smad2/3 signaling and how this would regulate embryonic development.We show that Araf antagonizes mesendoderm induction and patterning activity of Nodal/Smad2 signals in vertebrate embryos by directly inhibiting Smad2 signaling.Knockdown of araf in zebrafish embryos leads to an increase of activated Smad2 with a decrease of linker phosphorylation while activated Smad1/5/8 levels are dramatically reduced;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 signaling by accelerating degradation of activated Smad2.Our findings open avenues for investigating the potential significance of Raf regulation of TGF- signaling in versatile biological and pathological processes in the ? future.