Song Eun Joo, Hong Hye-Min, Yoo Young Sook
Bioanalysis and Biotransformation Research Center, Life Sciences Research Division, Korea Institute of Science and Technology, P.O. BOX 131, Cheongryang, Seoul 130-650, Republic of Korea.
Int J Biochem Cell Biol. 2009 Mar;41(3):539-45. doi: 10.1016/j.biocel.2008.04.022. Epub 2008 May 24.
The ubiquitin-proteasome pathway regulates many biological processes, including protein degradation, receptor endocytosis, protein sorting, subnuclear trafficking and neuronal differentiation. While proteasome inhibition is known to induce neurite outgrowth, the signaling mechanisms that mediate these effects have not been defined. In this study, we investigated the underlying mechanisms that link proteasome inhibition with neurite generation. We found that the proteasome inhibitors, MG132 and lactacystin, induced neurite outgrowth and also activated extracellular signal-regulated kinase/mitogen activated protein kinase and phosphatidylinositol-3-kinase/AKT pathways. These proteasome inhibitors also induced phosphorylation and ubiquitination of TrkA receptors, indicating that proteasome inhibition activates the major pathways of TrkA signaling. However, in contrast to nerve growth factor stimulation, which induces internalization of surface TrkA receptors, proteasome inhibitor-induced neurite outgrowth did not require TrkA receptor internalization. These results indicate that the ubiquitin-proteasome system regulates neurite formation through posttranslational modification of TrkA receptors.
泛素-蛋白酶体途径调节许多生物学过程，包括蛋白质降解、受体内吞作用、蛋白质分选、核内运输和神经元分化。虽然已知蛋白酶体抑制可诱导神经突生长，但介导这些效应的信号机制尚未明确。在本研究中，我们调查了将蛋白酶体抑制与神经突生成联系起来的潜在机制。我们发现蛋白酶体抑制剂MG132和乳胞素可诱导神经突生长，并激活细胞外信号调节激酶/丝裂原活化蛋白激酶和磷脂酰肌醇-3-激酶/AKT途径。这些蛋白酶体抑制剂还诱导TrkA受体的磷酸化和泛素化，表明蛋白酶体抑制激活了TrkA信号传导的主要途径。然而，与诱导表面TrkA受体内化的神经生长因子刺激相反，蛋白酶体抑制剂诱导的神经突生长不需要TrkA受体内化。这些结果表明，泛素-蛋白酶体系统通过TrkA受体的翻译后修饰来调节神经突形成。
