Araf kinase antagonizes Nodal-Smad2 activity in mesendoderm development by directly phosphorylating the Smad2 linker region.
Araf kinase antagonizes Nodal-Smad2 activity in mesendoderm development by directly phosphorylating the Smad2 linker region.
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DOI：
10.1038/ncomms2762
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发表时间：
2013
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Smad 2/3介导的转化生长因子β信号传导和Ras-Raf-Mek-Erk级联在干细胞和发育以及组织稳态中具有重要作用。然而，Raf激酶是否直接与Smad 2/3信号转导交叉以及这将如何调节胚胎发育仍然是未知的。在这里，我们表明，Araf拮抗中内胚层诱导和图案活动的Nodal/Smad 2信号在脊椎动物胚胎中直接抑制Smad 2信号。敲除斑马鱼胚胎中的Araf导致激活的Smad 2增加，接头磷酸化减少;因此，胚胎具有过量的中内胚层前体并背侧化。在机制上，Araf以Mek/Erk非依赖性方式与S253不可或缺的接头区中的Smad 2物理结合并磷酸化，从而通过加速活化的Smad 2的降解来减弱Smad 2信号传导。我们的发现为将来研究Raf调节转化生长因子β信号转导在多种生物和病理过程中的潜在意义开辟了途径。 通过SMAD转录因子的TGF-β信号传导已经涉及胚胎中内胚层发育。Liu及其同事揭示了Ras调节的激酶Raf通过磷酸化和促进SMAD 2的降解来防止过度的中内胚层形成。
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. TGF-β signalling through SMAD transcription factors has been implicated in embryonic mesendoderm development. Liu and colleagues reveal that the Ras-regulated kinase Raf prevents excessive mesendoderm formation by phosphorylating and promoting the degradation of SMAD2.
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影响因子：
64.5
作者：
Lin, Xia;Duan, Xueyan;Feng, Xin-Hua
通讯作者：
Feng, Xin-Hua
影响因子：
4.8
作者：
Jia, Shunji;Ren, Zhen;Meng, Anming
通讯作者：
Meng, Anming
影响因子：
2.7
作者：
Alexander, J;Rothenberg, M;Stainier, DYR
通讯作者：
Stainier, DYR
影响因子：
64.8
作者：
Kretzschmar, M;Doody, J;Massague, J
通讯作者：
Massague, J
影响因子：
10.5
作者：
Kretzschmar, M;Doody, J;Massagué, J
通讯作者：
Massagué, J