Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1
Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1
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DOI：
10.1038/39348
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发表时间：
1997-10-09
期刊：
影响因子：
64.8
通讯作者：
Massague, J
中科院分区：
文献类型：
--
作者：
Kretzschmar, M;Doody, J;Massague, J
生长因子TGF-β、骨形态发生蛋白（BMP）和相关因子调节细胞增殖、分化和凋亡，控制大多数组织的发育和维持（1，2）。它们的信号通过受体蛋白丝氨酸/苏氨酸激酶（RS/TK）磷酸化肿瘤抑制SMAD蛋白来传递（3-10），导致SMAD蛋白的核积累（5，9，11，12）和转录活性（6，12，13）。在这里，我们报告说，Smad 1，它介导的BMP信号，也是一个目标的促有丝分裂生长因子信号通过表皮生长因子和肝细胞生长因子受体蛋白酪氨酸激酶（RTK）。磷酸化发生在连接Smad 1的抑制和效应结构域的区域内的特定丝氨酸处，并且由有丝分裂原活化蛋白激酶的Erk家族催化。与BMP刺激的Smad 1磷酸化作用（影响羧基末端丝氨酸并诱导Smad 1的核积累）相反（6），ERK介导的磷酸化作用特异性抑制Smad 1的核积累。因此，Smad 1通过RTK和RS/TK接收相反的调节输入，正是这种平衡决定了细胞核中Smad 1活性的水平，因此可能决定了Smad 1在控制细胞命运中的作用。
The growth factor TGF-beta, bone morphogenetic proteins (BMPs) and related factors regulate cell proliferation, differentiation and apoptosis, controlling the development and maintenance of most tissues(1,2). Their signals are transmitted through the phosphorylation of the tumour-suppressor SMAD proteins by receptor protein serine/threonine kinases (RS/TKs)(3-10), leading to the nuclear accumulation(5,9,11,12) and transcriptional activity of SMAD proteins(6,12,13). Here we report that Smad1, which mediates BMP signals, is also a target of mitogenic growth-factor signalling through epidermal growth factor and hepatocyte growth factor receptor protein tyrosine kinases (RTKs). Phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of Smad1, and is catalysed by the Erk family of mitogen-activated protein kinases. In contrast to the BMP-stimulated phosphorylation of Smad1, which affects carboxy-terminal serines and induces nuclear accumulation of Smad1(6), Erk-mediated phosphorylation specifically inhibits the nuclear accumulation of Smad1. Thus, Smad1 receives opposing regulatory inputs through RTKs and RS/TKs, and it is this balance that determines the level of Smad1 activity in the nucleus, and so possibly the role of Smad1 in the control of cell fate.