title: Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN.
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 (O2∙-) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of O2∙--dismutating mitochondrial Sod2. The O2∙--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 O2∙- 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 O2∙--induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with O2∙-, PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies.
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany Aging Research Center (ARC), Ulm, Germany.
authors.forename: Karmveer
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany Aging Research Center (ARC), Ulm, Germany.
authors.forename: Pallab
authors.initials: P
authors.lastname: Maity
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany Aging Research Center (ARC), Ulm, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Krug
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany Aging Research Center (ARC), Ulm, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Meyer
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Treiber
authors.affiliation: Department of Gene Therapy, University of Ulm, Ulm, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Lucas
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Basu
authors.affiliation: Department of Gene Therapy, University of Ulm, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kochanek
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany Aging Research Center (ARC), Ulm, Germany.
authors.forename: Meinhard
authors.initials: M
authors.lastname: Wlaschek
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany Aging Research Center (ARC), Ulm, Germany Institute of Molecular Medicine and Stem Cell Aging, University of Ulm, Ulm, Germany Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.affiliation: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany Aging Research Center (ARC), Ulm, Germany karin.scharffetter-kochanek@uniklinik-ulm.de.
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D007334:Insulin-Like Growth Factor I; D051059:PTEN Phosphohydrolase; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017526:Receptor, IGF Type 1; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C516609:Ptpn1 protein, mouse; C487757:Pten protein, mouse
keywords: IGF‐1; ageing; phosphatase; reactive oxygen species; superoxide anions