ZFIN ID: ZDB-PUB-130710-82
IGF-1 Receptor Antagonism Inhibits Autophagy
Renna, M., Figueira-Bento, C., Fleming, A., Menzies, F.M., Siddiqi, F.H., Ravikumar, B., Puri, C., Garcia-Arencibia, M., Sadiq, O., Corrochano, S., Carter, S., Brown, S.D., Acevedo-Arozena, A., and Rubinsztein, D.C.
Date: 2013
Source: Human molecular genetics   22(22): 4528-44 (Journal)
Registered Authors: Fleming, Angeleen
Keywords: none
MeSH Terms:
  • Animals
  • Autophagy/drug effects*
  • Cell Line
  • Enzyme Inhibitors/pharmacology
  • HeLa Cells
  • Humans
  • Insulin-Like Growth Factor I/antagonists & inhibitors*
  • Insulin-Like Growth Factor I/metabolism
  • Macrolides/pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Multiprotein Complexes/genetics
  • Multiprotein Complexes/metabolism
  • Neurodegenerative Diseases/drug therapy
  • Neurodegenerative Diseases/pathology
  • Protein Kinase C/genetics
  • Protein Kinase C/metabolism
  • Receptor, IGF Type 1/antagonists & inhibitors*
  • Receptor, IGF Type 1/genetics*
  • Signal Transduction/drug effects*
  • Signal Transduction/genetics
  • TOR Serine-Threonine Kinases/genetics
  • TOR Serine-Threonine Kinases/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 23804751 Full text @ Hum. Mol. Genet.
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ABSTRACT

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 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 PKCα/β. This perturbs the actin cytoskeleton dynamics and decreases the rate of clathrin-dependent endocytosis, which impacts on 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 in clinically relevant conditions, such as neurodegenerative diseases, where autophagy stimulation is considered beneficial.

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