GEFT, a Rho family guanine nucleotide exchange factor, regulates neurite outgrowth and dendritic spine formation
GEFT, a Rho family guanine nucleotide exchange factor, regulates neurite outgrowth and dendritic spine formation
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DOI：
10.1074/jbc.m406216200
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发表时间：
2004-10-29
影响因子：
4.8
通讯作者：
Liu, MY
中科院分区：
文献类型：
--
作者：
Bryan, B;Kumar, V;Liu, MY
小GTP酶的Rho家族控制真核细胞中的广泛的细胞过程，例如正常细胞生长、增殖、分化、基因调节、肌动蛋白细胞骨架组织、细胞命运决定和神经突生长。Rho-GTP酶的活化需要GDP交换为GTP，这是由鸟嘌呤核苷酸交换因子的Dbl家族催化的过程。我们证明，一个新发现的鸟嘌呤核苷酸交换因子，GEFT，广泛表达在大脑中，高度集中在海马，浦肯野和小脑颗粒细胞。外源性表达GEFT可促进海马神经元树突的生长，导致棘比对照组更大。在神经母细胞瘤细胞中，GEFT促进Rac 1，Cdc 42和RhoA的活性GTP结合状态，并主要通过Rac 1增加神经突生长。此外，我们证明了PAK 1和PAK 5，Rac 1/Cdc 42的下游效应子，是GEFT诱导的神经突生长所必需的。AP-1和NF-κ B，两个转录因子参与神经突起的生长和生存，在GEFT表达细胞上调。总之，我们的数据表明，GEFT增强树突棘的形成和神经突生长的原代神经元和神经母细胞瘤细胞，分别通过激活Rac/Cdc 42-PAK信号通路。
The Rho family of small GTPases controls a wide range of cellular processes in eukaryotic cells, such as normal cell growth, proliferation, differentiation, gene regulation, actin cytoskeletal organization, cell fate determination, and neurite outgrowth. The activation of Rho-GTPases requires the exchange of GDP for GTP, a process catalyzed by the Dbl family of guanine nucleotide exchange factors. We demonstrate that a newly identified guanine nucleotide exchange factor, GEFT, is widely expressed in the brain and highly concentrated in the hippocampus, and the Purkinje and granular cells of the cerebellum. Exogenous expression of GEFT promotes dendrite outgrowth in hippocampal neurons, resulting in spines with larger size as compared with control spines. In neuroblastoma cells, GEFT promotes the active GTP-bound state of Rac1, Cdc42, and RhoA and increases neurite outgrowth primarily via Rac1. Furthermore, we demonstrated that PAK1 and PAK5, both downstream effectors of Rac1/Cdc42, are necessary for GEFT-induced neurite outgrowth. AP-1 and NF-kappaB, two transcriptional factors involved in neurite outgrowth and survival, were up-regulated in GEFT-expressing cells. Together, our data suggest that GEFT enhances dendritic spine formation and neurite outgrowth in primary neurons and neuroblastoma cells, respectively, through the activation of Rac/Cdc42-PAK signaling pathways.