The human Rho-GEF trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth
The human Rho-GEF trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth
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DOI：
10.1016/s0960-9822(02)00658-9
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发表时间：
2002-02-19
期刊：
影响因子：
9.2
通讯作者：
Debant, A
中科院分区：
文献类型：
--
作者：
Estrach, S;Schmidt, S;Debant, A
Rho-GTP酶通过调节肌动蛋白细胞骨架动力学来控制广泛的生理过程[1]。对神经元细胞系的大量研究已经确定Rac、Cdc 42和RhoG激活神经突延伸，而RhoA介导神经突收缩[25]。鸟嘌呤核苷酸交换因子（GEF）通过加速GDP/GTP交换激活Rho-GTP酶（6）。Trio显示两个Rho-GEF结构域，GEFD 1，通过RhoG激活Rac通路，和GEFD 2，作用于RhoA，并含有许多信号传导基序，其对Trio功能的贡献尚未研究[7-9]。果蝇和秀丽隐杆线虫的遗传分析表明，Trio通过GEFD 1依赖性过程参与轴突导向和细胞运动，表明其Rho-GEFs的活性受到严格调控[10-14]。在这里，我们表明，人类Trio诱导PC 12细胞中的神经突起生长在GEFD 1依赖的方式。有趣的是，血影蛋白重复序列和SH 3 -1结构域的三是必不可少的GEFD 1介导的神经突生长，揭示了一个意想不到的作用，这些图案在三功能。此外，我们证明Trio诱导的神经突生长是由RhoG的GEFD 1依赖性激活介导的，先前已证明RhoG是NGF（神经生长因子）途径的一部分[4]。不同Trio突变体的表达干扰了NGF诱导的神经突生长，表明Trio可能是RhoG在该途径中的上游调节因子。此外，我们还发现，在NGF刺激下，Trio蛋白会积累。因此，Trio是第一个被鉴定的参与NGF分化信号传导的Rho-GEF。
Rho-GTPases control a wide range of physiological processes by regulating actin cytoskeleton dynamics [1]. Numerous studies on neuronal cell lines have established that Rac, Cdc42, and RhoG activate neurite extension, while RhoA mediates neurite retraction [25]. Guanine nucleotide exchange factors (GEFs) activate Rho-GTPases by accelerating GDP/GTP exchange (6]. Trio displays two Rho-GEF domains, GEFD1, activating the Rac pathway via RhoG, and GEFD2, acting on RhoA, and contains numerous signaling motifs whose contribution to Trio function has not yet been investigated [7-9]. Genetic analyses in Drosophila and in Caenorhabditis elegans indicate that Trio is involved in axon guidance and cell motility via a GEFD1-dependent process, suggesting that the activity of its Rho-GEFs is strictly regulated [10-14]. Here, we show that human Trio induces neurite outgrowth in PC12 cells in a GEFD1-dependent manner. Interestingly, the spectrin repeats and the SH3-1 domain of Trio are essential for GEFD1-mediated neurite outgrowth, revealing an unexpected role for these motifs in Trio function. Moreover, we demonstrate that Trio-induced neurite outgrowth is mediated by the GEFD1-dependent activation of RhoG, previously shown to be part of the NGF (nerve growth factor) pathway [4]. The expression of different Trio mutants interferes with NGF-induced neurite outgrowth, suggesting that Trio may be an upstream regulator of RhoG in this pathway. In addition, we show that Trio protein accumulates under NGF stimulation. Thus, Trio is the first identified Rho-GEF involved in the NGF-differentiation signaling.