Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β
Smad-dependent GADD45β expression mediates delayed activation of p38 MAP kinase by TGF-β
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DOI：
10.1093/emboj/cdf643
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发表时间：
2002-12-02
期刊：
影响因子：
11.4
通讯作者：
Saito, H
中科院分区：
文献类型：
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作者：
Takekawa, M;Tatebayashi, K;Saito, H
转化生长因子-β(TGF-β)与其特异性受体结合后，通过磷酸化激活转录因子Smad。转化生长因子-β也可激活p38MAPK通路，但早期激活和延迟激活似乎有不同的机制。在这份报告中，我们证明了GADD45β依赖于Smad的表达是转化生长因子-β延迟激活p38的原因。GADD45beta蛋白结合并激活MTK1(=MEKK4)，MTK1是MAPKKK家族的成员，也是p38 MAPK级联的上游激活剂。转化生长因子-β诱导的GADD45β表达和延迟的p38激活都需要有功能的Smad蛋白。反义抑制GADD45β的表达可抑制转化生长因子β诱导的延迟的p38激活，而过表达GADD45β则通过MTK1激活p38 MAPK。血管生成抑制因子血栓反应蛋白-1(TSP-1)的表达是由转化生长因子-β通过Smad依赖的p38活化诱导的。因此，GADD45β表达介导的转化生长因子-β诱导的p38活化可能在转化生长因子-β的生物学效应中起重要作用。
Transforming growth factor-beta (TGF-beta), when bound to its specific receptor, activates the transcription factor Smad by phosphorylation. TGF-beta also activates the p38 MAPK pathway, but there seem to be disparate mechanisms for the early p38 activation and delayed p38 activation. In this report, we demonstrate that Smad-dependent expression of GADD45beta is responsible for the delayed activation of p38 by TGF-beta. The GADD45beta protein binds and activates MTK1 (=MEKK4), which is a member of the MAPKKK family kinases and an upstream activator of the p38 MAPK cascade. Both TGF-beta-induced GADD45beta expression and the delayed p38 activation require functional Smad proteins. Antisense inhibition of GADD45beta expression suppresses the TGF-beta-induced delayed p38 activation, whereas overexpression of GADD45beta activates the p38 MAPK via MTK1. Expression of the angiogenesis inhibitor thrombospondin-1 (TSP-1) is induced by TGF-beta via Smad-dependent p38 activation. Thus TGF-beta-induced p38 activation, mediated by GADD45beta expression, may play an important role in the biological effects of TGF-beta.