IGF-1 receptor antagonism inhibits autophagy
| العنوان: | IGF-1 receptor antagonism inhibits autophagy |
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| المؤلفون: | Sarah Carter, Angeleen Fleming, Abraham Acevedo-Arozena, Carla F. Bento, Fiona M. Menzies, Claudia Puri, Moisés García-Arencibia, Oana Sadiq, David C. Rubinsztein, Maurizio Renna, Brinda Ravikumar, Farah H. Siddiqi, Steve D.M. Brown, Silvia Corrochano |
| المساهمون: | Renna, Maurizio, Bento, Carla F., Fleming, Angeleen, Menzies, Fiona M., Siddiqi, Farah H., Ravikumar, Brinda, Puri, Claudia, Garcia-Arencibia, Moise, Sadiq, Oana, Corrochano, Silvia, Carter, Sarah, Brown, Steve D. M., Acevedo-Arozena, Abraham, Rubinsztein, David C., Fleming, Angeleen [0000-0003-3721-7126], Siddiqi, Farah [0000-0001-9185-0163], Rubinsztein, David [0000-0001-5002-5263], Apollo - University of Cambridge Repository |
| المصدر: | Human Molecular Genetics |
| بيانات النشر: | Oxford University Press (OUP), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Autophagosome, Mechanistic Target of Rapamycin Complex 2, mTORC1, Biology, HeLa Cell, Endocytosis, mTORC2, Cell Line, Receptor, IGF Type 1, Mice, 03 medical and health sciences, 0302 clinical medicine, Genetic, Autophagy, Genetics, Enzyme Inhibitor, Animals, Humans, Enzyme Inhibitors, Insulin-Like Growth Factor I, Molecular Biology, Protein Kinase C, Zebrafish, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Neurodegenerative Disease, TOR Serine-Threonine Kinase, Animal, TOR Serine-Threonine Kinases, Neurodegenerative Diseases, Articles, General Medicine, Actin cytoskeleton, Hedgehog signaling pathway, Cell biology, Mice, Inbred C57BL, Multiprotein Complexes, Models, Animal, Multiprotein Complexe, Macrolide, Macrolides, Signal transduction, 030217 neurology & neurosurgery, Human, HeLa Cells, Signal Transduction |
| الوصف: | Inhibition of the insulin/insulin-like growth factor signalling pathway increases lifespan and protects against neurodegeneration in model organisms, and has been considered as a potential therapeutic target. This pathway is upstream of mTORC1, a negative regulator of autophagy. Thus, we expected autophagy to be activated by insulin-like growth factor-1 (IGF-1) inhibition, which could account for many of its beneficial effects. Paradoxically, we found that IGF-1 inhibition attenuates autophagosome formation. The reduced amount of autophagosomes present in IGF-1R depleted cells can be, at least in part, explained by a reduced formation of autophagosomal precursors at the plasma membrane. In particular, IGF-1R depletion inhibits mTORC2, which, in turn, reduces the activity of protein kinase C (PKCα/β). This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts autophagosome precursor formation. Finally, with important implications for human diseases, we demonstrate that pharmacological inhibition of the IGF-1R signalling cascade reduces autophagy also in zebrafish and mice models. The novel link we describe here has important consequences for the interpretation of genetic experiments in mammalian systems and for evaluating the potential of targeting the IGF-1R receptor or modulating its signalling through the downstream pathway for therapeutic purposes under clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial. |
| وصف الملف: | application/pdf |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::503172b46149b3e7978a17c382f57d3fTest https://doi.org/10.1093/hmg/ddt300Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....503172b46149b3e7978a17c382f57d3f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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