Functions of a Rho-specific Guanine Nucleotide Exchange Factor in Neurite Retraction
Functions of a Rho-specific Guanine Nucleotide Exchange Factor in Neurite Retraction
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Rho 特异性鸟嘌呤核苷酸交换因子在神经突收缩中的功能
DOI：
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发表时间：
2000
影响因子：
4.8
通讯作者：
M. Inagaki
中科院分区：
文献类型：
--
作者：
H. Togashi;K. Nagata;Mihoko Takagishi;N. Saitoh;M. Inagaki
Rho/Rho激酶信号通路在神经元细胞响应g12 /13偶联受体激活的神经突缩回和细胞绕圆过程中起重要作用。参与这些过程的鸟嘌呤核苷酸交换因子尚未确定。为了监测Rho激酶的激活状态，我们开发了一个vimentin头/Rho激酶嵌合体，该嵌合体在融合的vimentin头的Ser71位点以Rho依赖的方式进行分子内磷酸化。利用该系统，我们鉴定了一个名为KIAA0380的克隆，该克隆含有g α12/13结合域以及Dbl同源/pleckstrin同源（DH/PH）域串联，作为Rho/Rho激酶信号传导的激活剂。分子解剖分析表明，靠近DH/PH结构域的富含脯氨酸的基序c端对KIAA0380的质膜定位和皮层肌动蛋白重组以及细胞圆缩至关重要。相比之下，KIAA0380的DH/PH结构域位于细胞质中，激活Rho/Rho激酶并诱导应激纤维形成，这与使用p115 Rho鸟嘌呤核苷酸交换因子的结果一致，p115 Rho鸟嘌呤核苷酸交换因子具有与KIAA0380相似的结构，但缺乏富含脯氨酸的基序。这些结果表明，KIAA0380在受到刺激后，通过富含脯氨酸的基序易位到质膜上，并激活Rho/Rho激酶信号。在神经母细胞瘤Neuro2a细胞中，KIAA0380在神经突尖端被观察到，该位置在溶血磷脂酸刺激下诱导皮质肌动蛋白重组。异位表达n端片段抑制溶血磷脂酸诱导的神经突回缩。这些结果表明KIAA0380通过rho依赖性信号在神经突缩回中起重要作用。
The Rho/Rho kinase signaling pathway plays an essential role in neurite retraction and cell rounding in response to G12/13-coupled receptor activation in neuronal cells. The Rho guanine nucleotide exchange factor involved in these processes has not been identified. To monitor the activation state of Rho kinase, we developed a vimentin head/Rho kinase chimera, which is intramolecularly phosphorylated in a Rho-dependent manner at Ser71 of the fused vimentin head. Using this system, we identified a clone termed KIAA0380, which contains the Gα12/13-binding domain as well as a tandem of the Dbl homology/pleckstrin homology (DH/PH) domain, as an activator of Rho/Rho kinase signaling. Molecular dissection analyses revealed that a proline-rich motif C-terminally adjacent to DH/PH domain is essential for plasma membrane localization of KIAA0380 and cortical actin reorganization followed by cell rounding. In contrast, the DH/PH domain of KIAA0380 is localized in the cytoplasm, where it activates Rho/Rho kinase and induces stress fiber formation, consistent with results using p115 Rho guanine nucleotide exchange factor, which has a similar structure to KIAA0380 but lacks a proline-rich motif. These results suggest that upon stimulation, KIAA0380 translocates to the plasma membrane via the proline-rich motif and there activates Rho/Rho kinase signaling. In neuroblastoma Neuro2a cells, KIAA0380 was observed in the tips of neurites, a location where cortical actin reorganization is induced upon stimulation with lysophosphatidic acid. Ectopic expression of the N-terminal fragment inhibited lysophosphatidic acid-induced neurite retraction of Neuro2a cells. These results suggest that KIAA0380 plays an important role in neurite retraction through Rho-dependent signaling.
影响因子：
56.9
作者：
Hart, MJ;Jiang, XJ;Bollag, G
通讯作者：
Bollag, G
中性粒细胞磷脂酶 D 由膜相关 Rho 家族小分子量 GTP 结合蛋白激活。
DOI：
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发表时间：
1993
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bowman,EP;Uhlinger,DJ;Lambeth,JD
通讯作者：
Lambeth,JD