Identificador persistente para citar o vincular este elemento: http://hdl.handle.net/10553/42994
Título: IGF-1 receptor antagonism inhibits autophagy
Autores/as: Renna, Maurizio
Bento, Carla F.
Fleming, Angeleen
Menzies, Fiona M.
Siddiqi, Farah H.
Ravikumar, Brinda
Puri, Claudia
Garcia-Arencibia, Moises 
Sadiq, Oana
Corrochano, Silvia
Carter, Sarah
Brown, Steve D.M.
Acevedo-Arozena, Abraham
Rubinsztein, David C.
Clasificación UNESCO: 32 Ciencias médicas
Palabras clave: Actins
Signal transduction
Autophagy
Endocytosis
Insulin-like growth factor i, et al.
Fecha de publicación: 2013
Editor/a: 0964-6906
Publicación seriada: Human Molecular Genetics 
Resumen: 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.
URI: http://hdl.handle.net/10553/42994
ISSN: 0964-6906
DOI: 10.1093/hmg/ddt300
Fuente: Human Molecular Genetics [ISSN 0964-6906], v. 22 (22), p. 4528-4544
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