title: Tyrosine kinase signal modulation: a matter of H2O2 membrane permeability?
abstract: Abstract H2O2 produced by extracellular NADPH oxidases regulates tyrosine kinase signaling inhibiting phosphatases. How does it cross the membrane to reach its cytosolic targets? Silencing aquaporin-8 (AQP8), but not AQP3 or AQP4, inhibited H2O2 entry into HeLa cells. Re-expression of AQP8 with silencing-resistant vectors rescued H2O2 transport, whereas a C173A-AQP8 mutant failed to do so. Lowering AQP8 levels affected H2O2 entry into the endoplasmic reticulum, but not into mitochondria. AQP8 silencing also inhibited the H2O2 spikes and phosphorylation of downstream proteins induced by epidermal growth factor. These observations lead to the hypothesis that H2O2 does not freely diffuse across the plasma membrane and AQP8 and other H2O2 transporters are potential targets for manipulating key signaling pathways in cancer and degenerative diseases.
authors.affiliation: 1 Divisions of Genetics & Cell Biology and Metabolism, San Raffaele Scientific Institute, OSR & Fondazione Centro San Raffaele , Milano, Italy .
authors.forename: Milena
authors.initials: M
authors.lastname: Bertolotti
authors.forename: Stefano
authors.initials: S
authors.lastname: Bestetti
authors.forename: Jose M
authors.initials: JM
authors.lastname: García-Manteiga
authors.forename: Iria
authors.initials: I
authors.lastname: Medraño-Fernandez
authors.forename: Andrea
authors.initials: A
authors.lastname: Dal Mas
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Malosio
authors.forename: Roberto
authors.initials: R
authors.lastname: Sitia
mesh_terms: D020346:Aquaporins / Q000235:genetics / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000235:genetics; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D020346:Aquaporins; C108330:aquaporin 8; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases
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