Rab22 controls NGF signaling and neurite outgrowth in PC12 cells.
Rab22 controls NGF signaling and neurite outgrowth in PC12 cells.
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DOI：
10.1091/mbc.e11-03-0277
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发表时间：
2011-10
影响因子：
3.3
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Wang L;Liang Z;Li G
Rab22 是一种小型 GTP 酶，位于早期内体上并调节早期内体分选。这项研究报告称，Rab22 通过将 NGF 和激活/磷酸化受体 (pTrkA) 分类到信号内体中以维持细胞内的信号转导，从而促进 PC12 细胞中 NGF 信号依赖的神经突生长和基因表达。 Rab22 是一种小型 GTP 酶，位于早期内体上并调节早期内体分选。这项研究报告称，Rab22 通过将 NGF 和激活/磷酸化受体 (pTrkA) 分类到信号内体中以维持细胞内的信号转导，从而促进 PC12 细胞中神经生长因子 (NGF) 信号依赖性神经突生长和基因表达。 NGF 结合诱导 pTrkA 内吞到含有 Rab22 的内体中。通过小发夹 RNA (shRNA) 敲低 Rab22 可阻断 NGF 诱导的 pTrkA 内吞作用进入内体、基因表达 (VGF) 和神经突生长。人 Rab22 的过度表达可以挽救 Rab22 shRNA 的抑制作用，表明 Rab22 在 NGF 信号转导中具有特定功能，而不是脱靶效应。此外，Rab22 效应子 Rabex-5 对于 NGF 诱导的神经突生长和基因表达是必需的，shRNA 介导的 Rabex-5 敲低的抑制作用证明了这一点。通过在细胞中过度表达 Rabex-5 的 Rab22 结合域来破坏 Rab22-Rabex-5 相互作用也会阻止 NGF 诱导的神经突生长，这表明 Rab22-Rabex-5 相互作用在 NGF 信号内体的生物发生中发挥着关键作用，以维持神经突生长的信号。这些数据为早期内体 Rab GTPase 作为 NGF 信号转导和细胞分化的正调节因子提供了第一个证据。
Rab22 is a small GTPase that is localized on early endosomes and regulates early endosomal sorting. This study reports that Rab22 promotes NGF signaling–dependent neurite outgrowth and gene expression in PC12 cells by sorting NGF and the activated/phosphorylated receptor (pTrkA) into signaling endosomes to sustain signal transduction in the cell. Rab22 is a small GTPase that is localized on early endosomes and regulates early endosomal sorting. This study reports that Rab22 promotes nerve growth factor (NGF) signaling-dependent neurite outgrowth and gene expression in PC12 cells by sorting NGF and the activated/phosphorylated receptor (pTrkA) into signaling endosomes to sustain signal transduction in the cell. NGF binding induces the endocytosis of pTrkA into Rab22-containing endosomes. Knockdown of Rab22 via small hairpin RNA (shRNA) blocks NGF-induced pTrkA endocytosis into the endosomes and gene expression (VGF) and neurite outgrowth. Overexpression of human Rab22 can rescue the inhibitory effects of the Rab22 shRNA, suggesting a specific Rab22 function in NGF signal transduction, rather than off-target effects. Furthermore, the Rab22 effector, Rabex-5, is necessary for NGF-induced neurite outgrowth and gene expression, as evidenced by the inhibitory effect of shRNA-mediated knockdown of Rabex-5. Disruption of the Rab22–Rabex-5 interaction via overexpression of the Rab22-binding domain of Rabex-5 in the cell also blocks NGF-induced neurite outgrowth, suggesting a critical role of Rab22–Rabex-5 interaction in the biogenesis of NGF-signaling endosomes to sustain the signal for neurite outgrowth. These data provide the first evidence for an early endosomal Rab GTPase as a positive regulator of NGF signal transduction and cell differentiation.