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 IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions (O-2(center dot-)) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of O-2(center dot-)-dismutating mitochondrial Sod2. The O-2(center dot-)-dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of alpha 1(I), alpha 1(III), and alpha 2(I) collagen, the hallmarks of skin ageing. Enhanced O-2(center dot-) 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 O-2(center dot-)-induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with O-2(center dot-), PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.