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

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Abstract

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 signallingin vitroand in a murine ageing modelin vivois suppressed in response to accumulation of superoxide anions (Symbol) in mitochondria, either by chemical inhibition of complex I or by genetic silencing ofSymbol-dismutating mitochondrial Sod2. TheSymbol-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. EnhancedSymbolled 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 abrogatedSymbol-induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events withSymbol, PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.

Synopsis

New insight into a previously unreported mitochondrial superoxide anion (Symbol)-dependent activation of PTP1B and PTEN with subsequent repression of IGF-1 signalling, and its implications for skin ageing and other pathologies with aberrant IGF-1 signalling.

New insight into a previously unreported mitochondrial superoxide anion (Symbol)-dependent activation of PTP1B and PTEN with subsequent repression of IGF-1 signalling, and its implications for skin ageing and other pathologies with aberrant IGF-1 signalling.

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