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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Smad inhibition by the Ste20 kinase Misshapen
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Smad inhibition by the Ste20 kinase Misshapen

机译：Ste20激酶Misshapen对Smad的抑制作用

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摘要

The level of TGF-fVbone morphogenetic protein (BMP) signaling through Smad is tightly regulated to ensure proper embryonic pat terning and homeostasis. Here we show that Smad activation by TGF-β/BMP is blocked by a highly conserved phosphorylation event in the α-helix 1 region of Smad [T312 in Drosophila Smadi (MAD)], α-helix 1 phosphorylation reduces Smad interaction with TGF-β/BMP receptor kinase and affects all receptor-activated Smads except Smad3. Tissue culture and transgenic studies in Drosophila further demonstrate that the biological activity of MAD is repressed by T312 phosphorylation in vivo. Through RNAi screening of the kinome, we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for a-helix 1 phosphorylation. Targeted expression of an active form of Msn in the wing imaginal disk disrupted activation of endogenous MAD by Dpp and expression of the Dpp/MAD target gene. Msn kinases be long to the Ste20 kinase family that has been shown to act as MAP kinase kinase kinase kinase (MAP4K). Our findings thus reveal a function of Msn independent of its impact on MAP kinase cas cades. This Smad inhibition mechanism by Msn likely has important implications for development and disease.
机译：通过Smad传递的TGF-fVbone形态发生蛋白（BMP）信号的水平受到严格调节，以确保适当的胚胎模式和体内平衡。在这里，我们显示TGF-β/ BMP激活Smad会被Smad的α-螺旋1区域[果蝇Smadi（MAD）中的T312]高度保守的磷酸化事件所阻断，α-螺旋1的磷酸化作用会降低Smad与TGF-的相互作用β/ BMP受体激酶，影响除Smad3以外的所有受体激活的Smad。果蝇中的组织培养和转基因研究进一步证明，MAD的生物活性在体内被T312磷酸化所抑制。通过RNAi筛选的激酶，我们已经确定了Misshapen（Msn）和哺乳动物直系同源基因TNIK，MINK1和MAP4K4是负责a-螺旋1磷酸化的激酶。机翼假想盘中Msn活性形式的靶向表达破坏了Dpp对内源性MAD的激活以及Dpp / MAD靶基因的表达。 Msn激酶属于Ste20激酶家族，已被证明可充当MAP激酶激酶激酶（MAP4K）。因此，我们的发现揭示了Msn的功能，与其对MAP激酶级联的影响无关。 Msn的这种Smad抑制机制可能对发育和疾病具有重要意义。

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