Loss, Omar;
Wu, Chun Ting;
Riccio, Antonella;
Saiardi, Adolfo;
(2013)
Modulation of inositol polyphosphate levels regulates neuronal differentiation.
Molecular Biology of the Cell
, 24
(18)
pp. 2981-2989.
10.1091/mbc.E13-04-0198.
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Abstract
The binding of neurotrophins to tropomyosin receptor kinase receptors initiates several signaling pathways, including the activation of phospholipase C-γ, which promotes the release of diacylglycerol and inositol 1,4,5-trisphosphate (IP3). In addition to recycling back to inositol, IP3 serves as a precursor for the synthesis of higher phosphorylated inositols, such as inositol 1,3,4,5,6-pentakisphosphate (IP5) and inositol hexakisphosphate (IP6). Previous studies on the effect of neurotrophins on inositol signaling were limited to the analysis of IP 3 and its dephosphorylation products. Here we demonstrate that nerve growth factor (NGF) regulates the levels of IP5 and IP6 during PC12 differentiation. Furthermore, both NGF and brain-derived neurotrophic factor alter IP5 and IP6 intracellular ratio in differentiated PC12 cells and primary neurons. Neurotrophins specifically regulate the expression of IP5-2 kinase (IP5-2K), which phosphorylates IP5 into IP6. IP5-2K is rapidly induced after NGF treatment, but its transcriptional levels sharply decrease in fully differentiated PC12 cells. Reduction of IP5-2K protein levels by small interfering RNA has an effect on the early stages of PC12 cell differentiation, whereas fully differentiated cells are not affected. Conversely, perturbation of IP5-2K levels by overexpression suggests that both differentiated PC12 cells and sympathetic neurons require low levels of the enzyme for survival. Therefore maintaining appropriate intracellular levels of inositol polyphosphates is necessary for neuronal survival and differentiation. © 2013 Loss et al.
| Type: | Article |
|---|---|
| Title: | Modulation of inositol polyphosphate levels regulates neuronal differentiation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1091/mbc.E13-04-0198 |
| Publisher version: | https://doi.org/10.1091/mbc.E13-04-0198 |
| Language: | English |
| Additional information: | © 2013 Loss et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cell Biology, NERVE GROWTH-FACTOR, 1,3,4,5,6-PENTAKISPHOSPHATE 2-KINASE, NEUROTROPHIC FACTOR, SIGNALING PATHWAYS, RETROGRADE SIGNAL, DENDRITIC GROWTH, FACTOR RECEPTOR, MESSENGER-RNA, PC12 CELLS, HEXAKISPHOSPHATE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10162531 |
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