Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
Mol Cell Neurosci. 2010 Apr;43(4):403-13. doi: 10.1016/j.mcn.2010.01.007. Epub 2010 Feb 1.
Activation of nascent receptor tyrosine kinases within the secretory pathway has been reported, yet the consequences of intracellular activation are largely unexplored. We report that overexpression of the Trk neurotrophin receptors causes accumulation of autoactivated receptors in the ER-Golgi intermediate compartment. Autoactivated receptors exhibit inhibited Golgi-mediated processing and they inhibit Golgi-mediated processing of other co-expressed transmembrane proteins, apparently by inducing fragmentation of the Golgi apparatus. Signaling from G protein-coupled receptors is known to induce Trk transactivation. Transactivation of nascent TrkB in hippocampal neurons resulting from exposure to the neuropeptide PACAP caused Golgi fragmentation, whereas BDNF-dependent activation of TrkB did not. TrkB-mediated Golgi fragmentation employs a MEK-dependent signaling pathway resembling that implicated in regulation of Golgi fragmentation in mitotic cells. Neuronal Golgi fragments, in the form of dendritically localized Golgi outposts, are important determinants of dendritic growth and branching. The capacity of transactivated TrkB to enhance neuronal Golgi fragmentation may represent a novel mechanism regulating neural plasticity.
已报道新生受体酪氨酸激酶在分泌途径中的激活，但细胞内激活的后果在很大程度上仍未得到探索。我们报告称，过度表达神经营养因子受体 Trk 会导致内质网-高尔基体中间隔室中自动激活的受体积累。自动激活的受体表现出抑制的高尔基体介导的加工，并且它们抑制其他共表达的跨膜蛋白的高尔基体介导的加工，显然是通过诱导高尔基体装置的碎片化。已知 G 蛋白偶联受体的信号转导会诱导 Trk 的转激活。暴露于神经肽 PACAP 会导致新生 TrkB 在海马神经元中的转激活，从而导致高尔基体碎片化，而 BDNF 依赖性的 TrkB 激活则不会。TrkB 介导的高尔基体碎片化采用类似于有丝分裂细胞中高尔基体碎片化调节所涉及的 MEK 依赖性信号通路。以树突状定位的高尔基体突出物形式存在的神经元高尔基体片段是树突生长和分支的重要决定因素。转激活的 TrkB 增强神经元高尔基体碎片化的能力可能代表一种调节神经可塑性的新机制。
