The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling
The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling
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DOI：
10.1111/j.1356-9597.2004.00701.x
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发表时间：
2004-01-01
期刊：
影响因子：
2.1
通讯作者：
Arnheiter, H
中科院分区：
文献类型：
--
作者：
Kasai, K;Takahashi, M;Arnheiter, H
Sonic hedgehog（Shh）是一种分泌型形态发生蛋白，在脊椎动物发育过程中对细胞命运决定、细胞增殖和模式化至关重要。细胞内Shh信号转导由Smoothened（Smo），一种属于G蛋白偶联受体家族的七跨膜蛋白转导。Galphai被认为是负责转导Shh信号的四个Galpha亚基家族中的一个，而一些证据表明可能涉及其他信号通路。我们发现，G12家族的异源三聚体G蛋白和小GTdR RhoA参与Shh/Smo介导的细胞反应，包括刺激靶基因启动子和抑制神经母细胞瘤细胞的轴突生长。我们还发现，G12/RhoA通路负责Smo诱导的GLI 3的核输入，GLI 3被认为是将Shh信号传递到核。此外，G12特异性GTP酶激活蛋白在大鼠神经管中的错误表达导致运动神经元和神经元间发育的扰动，模仿Shh信号传导减少的影响。这些结果表明，Shh信号传导部分是通过激活G12家族偶联信号传导途径介导的。RhoA是许多信号转导途径中的关键分子开关，它的参与可能有助于解释Shh如何触发各种细胞反应。
Sonic hedgehog (Shh) is a secreted morphogen crucial for cell fate decision, cellular proliferation, and patterning during vertebrate development. The intracellular Shh signalling is transduced by Smoothened (Smo), a seven-transmembrane spanning protein that belongs to the G-protein coupled receptor family. Among four families of Galpha subunits, Galphai has been thought to be responsible for transducing Shh signalling, while several lines of evidence indicated that other signalling pathways may be involved. We found that the G12 family of heterotrimeric G proteins and the small GTPase RhoA are involved in Shh/Smo-mediated cellular responses, including stimulation of target gene promoter and inhibition of neurite outgrowth of neuroblastoma cells. We also found that the G12/RhoA pathway is responsible for Smo-induced nuclear import of GLI3 which is thought to transduce Shh signals to nucleus. Furthermore, misexpression of a G12-specific GTPase-activating protein in rat neural tubes leads to pertubation of motor neurone and interneurone development, mimicking the effects of decreased Shh signalling. These results show that Shh signalling is mediated in part by activating G12 family coupled signalling pathways. The participation of RhoA, a pivotal molecular switch in many signal transduction pathways, may help explain how Shh can trigger a variety of cellular responses.