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Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN

The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that...

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Detalles Bibliográficos
Autores principales: Singh, Karmveer, Maity, Pallab, Krug, Linda, Meyer, Patrick, Treiber, Nicolai, Lucas, Tanja, Basu, Abhijit, Kochanek, Stefan, Wlaschek, Meinhard, Geiger, Hartmut, Scharffetter-Kochanek, Karin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309668/
https://www.ncbi.nlm.nih.gov/pubmed/25520316
http://dx.doi.org/10.15252/emmm.201404082
Descripción
Sumario:The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions ([Image: see text]) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of [Image: see text]-dismutating mitochondrial Sod2. The [Image: see text]-dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced [Image: see text] led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated [Image: see text]-induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with [Image: see text], PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.