Tissue kallikrein mediates neurite outgrowth through epidermal growth factor receptor and flotillin-2 pathway in vitro
Tissue kallikrein mediates neurite outgrowth through epidermal growth factor receptor and flotillin-2 pathway in vitro
复制标题
体外组织激肽释放酶通过表皮生长因子受体和 flotillin-2 途径介导神经突生长
DOI：
10.1016/j.cellsig.2013.10.010
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发表时间：
2014-02-01
影响因子：
4.8
通讯作者：
Dong, Qiang
中科院分区：
文献类型：
--
作者：
Lu, Zhengyu;Cui, Mei;Dong, Qiang
组织激肽释放酶（TK）以前被证明通过缓激肽受体发挥其大部分生物学作用。在这项研究中，我们假设TK介导的轴突生长是独立的缓激肽受体。为了验证这一假设，我们在培养的原代神经元和人SH-SY 5 Y细胞中研究了TK诱导的神经突生长及其信号机制。我们发现TIC刺激可增加原代神经元突起数量和平均突起长度，这一作用可被表皮生长因子受体（EGFR）抑制剂或下调剂、小干扰RNA（siRNA）、细胞外信号调节激酶（ERK）1/2抑制剂阻断。此外，TIC诱导的轴突生长与EGFR和ERK 1/2激活相关，EGFR拮抗剂或RNA干扰和flotilin-2敲低可抑制EGFR和ERK 1/2激活。有趣的是，缓激肽受体的抑制对EGFR和ERK 1/2磷酸化没有显著影响。在本研究中，我们的数据还表明，EGFR和flotillin-2形成组成型复合物，在TIC刺激中易位到核周围。上述结果为TIC通过EGFR、flotillin-2和ERK 1/2信号通路促进神经突起生长提供了实验依据。(C)2013 Elsevier Inc. All rights reserved.
Tissue kallikrein (TK) was previously shown to take most of its biological effects through bradykinin receptors. In this study, we assumed that TK mediated neurite outgrowth was independent of bradykinin receptors. To test the hypothesis, we investigated TK-induced neurite outgrowth and its signaling mechanisms in cultured primary neurons and human SH-SY5Y cells. We found that TIC stimulation could increase the number of processes and mean process length of primary neurons, which were blocked by epidermal growth factor receptor (EGFR) inhibitor or down-regulation, small interfering RNA for flotillin-2 and extracellular signal-regulated kinase (ERK) 1/2 inhibitor. Moreover, TIC-induced neurite outgrowth was associated with EGFR and ERK1/2 activation, which were inhibited by EGFR antagonist or RNA interference and flotillin-2 knockdown. Interestingly, inhibition of bradykinin receptors had no significant effects on EGFR and ERK1/2 phosphorylation. In the present research, our data also suggested that EGFR and flotillin-2 formed constitutive complex that translocated to around the nuclei in the TIC stimulation. In sum, our findings provided evidence that TIC could promote neurite outgrowth via EGFR, flotillin-2 and ERK1/2 signaling pathway in vitro. (C) 2013 Elsevier Inc. All rights reserved.