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 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions () in mitochondria, either by chemical inhibition of complex I or by genetic silencing of -dismutating mitochondrial Sod2. The -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 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 -induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with , PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.
Highlights
To study the effect of different reactive oxygen species (ROS) species such as superoxide anion (O2À) and hydrogen peroxide (H2O2) on the Insulin-like growth factors (IGFs)-1/AKT axis, murine dermal fibroblast (MDFs) were treated with rotenone, an established inhibitor of complex I of the mitochondrial electron transport chain (Li et al, 2003) or with exogenous H2O2
As we have observed that rotenone inhibited insulin-like growth factor-1 (IGF-1)-induced autophosphorylation of tyrosine residues (Tyr 1135 and 1136) of IGF-1 receptor b subunit (IGF-1Rb) (Fig 2B), we further explored the possibility whether the activation of specific tyrosine phosphatases is responsible for the observed IGF-1Rb dephosphorylation
The major finding of this report is that accumulation of mitochondrial O2À led to IGF-1 resistance by tilting the delicate balance of regulatory kinases and phosphatases towards enhanced activities of Protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homologue (PTEN), key phosphatases of the IGF-1 signalling pathway
Summary
Insulin-like growth factors (IGFs) play essential roles in the regulation of cell growth, proliferation, stem cell maintenance and synthesis of extracellular matrix proteins (Baker et al, 1993; Le Roith, 1997; Papaconstantinou, 2009; Piecewicz et al, 2012) and—if dysregulated—result in connective tissue and organ atrophy with enhanced ageing or cancer progression (Baker et al, 1993; Pollak et al, 2004; Govoni et al, 2007b; Laviola et al, 2008; Anisimov & Bartke, 2013). Similar to other growth factors, IGF-1 signalling is initiated by the autophosphorylation of the IGF-1 receptor b subunit (IGF-1Rb), which is followed by a series of kinase-dependent phosphorylations of downstream effectors such as phosphoinositide-3-kinase (PI3K), AKT (protein kinase B), and p70S6 ribosomal protein kinase (p70S6K)—a prerequisite for synthesis of extracellular matrix—and other proteins. This in conjunction with the IGF-1-initiated Ras-dependent upregulation of cyclin D1 promotes cell cycle progression and growth essential for overall tissue homeostasis (Pollak et al, 2004; Samani et al, 2007).
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