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Int J Biochem Cell Biol. 2009 Mar;41(3):539-45. doi: 10.1016/j.biocel.2008.04.022. Epub 2008 May 24.

Proteasome inhibition induces neurite outgrowth through posttranslational modification of TrkA receptor.

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  • 1Bioanalysis 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.


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.

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