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SHIP2依赖性负反馈回路在神经生长因子刺激的PC12细胞神经突发生中的重要作用。

An essential role for the SHIP2-dependent negative feedback loop in neuritogenesis of nerve growth factor-stimulated PC12 cells.

作者信息

Aoki Kazuhiro, Nakamura Takeshi, Inoue Takanari, Meyer Tobias, Matsuda Michiyuki

机构信息

Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

出版信息

J Cell Biol. 2007 Jun 4;177(5):817-27. doi: 10.1083/jcb.200609017. Epub 2007 May 29.

DOI:10.1083/jcb.200609017
PMID:17535963
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2064282/
Abstract

The local accumulation of phosphatidylinositol (3,4,5) trisphosphate (PIP(3)) and resulting activation of Rac1/Cdc42 play a critical role in nerve growth factor (NGF)-induced neurite outgrowth. To further explore the mechanism, we visualized PIP(3), phosphatidylinositol (3,4) bisphosphate, and Rac1/Cdc42 activities by fluorescence resonance energy transfer (FRET) imaging in NGF-stimulated PC12 cells. Based on the obtained FRET images, and with the help of in silico kinetic reaction model, we predicted that PI-5-phosphatase negatively regulates PIP(3) upon NGF stimulation. In agreement with this model, depletion of Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 2 (SHIP2) markedly potentiated NGF-induced Rac1/Cdc42 activation and PIP(3) accumulation and considerably increased the number and the length of neurites in phosphate and tensin homologue-depleted PC12 cells. Further refinement of the computational model predicted Rac1 regulation of PI3-kinase and SHIP2, which was also validated experimentally. We propose that the SHIP2-mediated negative feedback on PIP(3) coordinately works with the PI3-kinase-mediated positive feedback to form an initial protrusive pattern and, later, to punctuate the PIP(3) accumulation to maintain proper neurite outgrowth.

摘要

磷脂酰肌醇（3,4,5）三磷酸（PIP(3)）的局部积累以及由此导致的Rac1/Cdc42激活在神经生长因子（NGF）诱导的神经突生长中起关键作用。为了进一步探究其机制，我们通过荧光共振能量转移（FRET）成像在NGF刺激的PC12细胞中可视化了PIP(3)、磷脂酰肌醇（3,4）二磷酸以及Rac1/Cdc42的活性。基于所获得的FRET图像，并借助计算机动力学反应模型，我们预测PI-5-磷酸酶在NGF刺激后对PIP(3)起负调控作用。与该模型一致，含Src同源2结构域的肌醇多磷酸5-磷酸酶2（SHIP2）的缺失显著增强了NGF诱导的Rac1/Cdc42激活和PIP(3)积累，并显著增加了磷酸酶和张力蛋白同源物缺失的PC12细胞中神经突的数量和长度。对计算模型的进一步优化预测了Rac1对PI3激酶和SHIP2的调控，这也通过实验得到了验证。我们提出，SHIP2介导的对PIP(3)的负反馈与PI3激酶介导的正反馈协同作用，形成初始的突出模式，随后使PIP(3)积累出现间断，以维持适当的神经突生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bda/2064282/c410e395a508/jcb1770817f08.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bda/2064282/c410e395a508/jcb1770817f08.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bda/2064282/4d45e06b8c5c/jcb1770817f02.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7bda/2064282/c410e395a508/jcb1770817f08.jpg

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