Tyrosine Kinase signal modulation: A matter of H2O2 membrane permeability?

Milena Bertolotti; Stefano Bestetti; Jose M. García-Manteiga; Iria Medraño-Fernandez; Andrea Dal Mas; Maria Luisa Malosio; Roberto Sitia

doi:10.1089/ars.2013.5330

Tyrosine Kinase signal modulation: A matter of H2O2 membrane permeability?

Milena Bertolotti, Stefano Bestetti, Jose M. García-Manteiga, Iria Medraño-Fernandez, Andrea Dal Mas, Maria Luisa Malosio, Roberto Sitia

Research output: Contribution to journal › Article

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 H ₂O₂ transport, whereas a C173A-AQP8 mutant failed to do so. Lowering AQP8 levels affected H₂O₂ entry into the endoplasmic reticum, 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. Antioxid. Redox Signal. 19, 1447-1451.

Original language	English
Pages (from-to)	1447-1451
Number of pages	5
Journal	Antioxidants and Redox Signaling
Volume	19
Issue number	13
DOIs	https://doi.org/10.1089/ars.2013.5330
Publication status	Published - Nov 1 2013

ASJC Scopus subject areas

Biochemistry
Cell Biology
Molecular Biology
Physiology
Clinical Biochemistry
Medicine(all)

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title = "Tyrosine Kinase signal modulation: A matter of H2O2 membrane permeability?",

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 H 2O2 transport, whereas a C173A-AQP8 mutant failed to do so. Lowering AQP8 levels affected H2O2 entry into the endoplasmic reticum, 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. Antioxid. Redox Signal. 19, 1447-1451.",

author = "Milena Bertolotti and Stefano Bestetti and Garc{\'i}a-Manteiga, {Jose M.} and Iria Medra{\~n}o-Fernandez and {Dal Mas}, Andrea and Malosio, {Maria Luisa} and Roberto Sitia",

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AU - Bertolotti, Milena

AU - Bestetti, Stefano

AU - García-Manteiga, Jose M.

AU - Medraño-Fernandez, Iria

AU - Dal Mas, Andrea

AU - Malosio, Maria Luisa

AU - Sitia, Roberto

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N2 - 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 H 2O2 transport, whereas a C173A-AQP8 mutant failed to do so. Lowering AQP8 levels affected H2O2 entry into the endoplasmic reticum, 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. Antioxid. Redox Signal. 19, 1447-1451.

AB - 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 H 2O2 transport, whereas a C173A-AQP8 mutant failed to do so. Lowering AQP8 levels affected H2O2 entry into the endoplasmic reticum, 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. Antioxid. Redox Signal. 19, 1447-1451.

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