Iria Medraño Fernandez

How cells decipher, amplify and turn off signals originating from tyrosine kinase receptors are central issues in cancer biology. Evidence is accumulating that redox-based circuits are pivotal modulators of these processes. H2O2 is the most stable and abundant reactive oxygen species (ROS) in living cells and, at high concentrations, is toxic and causes cell death. However, at lower concentrations, it is an essential second messenger acting in several physiological pathways.

We have shown that AQP8 is needed to channel H2O2 across the cellular membranes otherwise poorly permeable to this oxidant. In fact, silencing aquaporin-8 (AQP8) inhibits H2O2 entry, and consequently tyrosine phosphorylation induced by several tyrosine kinase receptors (TKR). These data confirm that uptake of H2O2 by living cells acts as a rheostat of tyrosine kinase signaling and demonstrate that AQP8 guarantees efficient H2O2 transport across membranes, a feature that could also be shared by other aquaporins.

We have also discovered that AQP8-dependent H2O2 transport is itself a target of regulation: diverse cellular stresses reversibly inhibit it, transiently limiting the sensitivity to growth factors via reversible redox modifications of AQP8.

These results are of great interest in relation to cancer. It is well known that tumors develop and progress in a stressful microenvironment in which physical and chemical parameters and cell components are altered. This induces cell stress and entails production of ROS. In turn, ROS cause DNA damage and affect intracellular signaling pathways controlling cell proliferation, survival, cell motility and invasiveness.

On these bases, I am characterizing the mechanisms that inhibit the peroxiporin activity of AQP8 under stress and my aim is focused on describe how H2O2 transport regulation can influence tumor growth and progression to identify new therapeutical approaches.

Publications

1. Different redox sensitivity of endoplasmic reticulum associated degradation clients suggests a novel role for disulphide bonds in secretory proteins. Medraño-Fernandez I, Fagioli C, Mezghrani A, Otsu M, Sitia R. Biochem Cell Biol. 2014 Apr;92(2):113-8.

2. Response to Marinelli and Marchissio. Bertolotti M, Bestetti S, Medraño-Fernandez I, Sitia R. Antioxid Redox Signal. 2013 Sep 10;19(8):897.

3. Tyrosine kinase signal modulation: a matter of H2O2 membrane permeability? Bertolotti M, Bestetti S, García-Manteiga JM, Medraño-Fernandez I, Dal Mas A, Malosio ML, Sitia R. Antioxid Redox Signal. 2013 Nov 1;19(13):1447-51.

4. RIAM (Rap1-interacting adaptor molecule) regulates complement-dependent phagocytosis.

Medraño-Fernandez I, Reyes R, Olazabal I, Rodriguez E, Sanchez-Madrid F, Boussiotis VA, Reche PA, Cabañas C, Lafuente EM. Cell Mol Life Sci. 2013 Jul;70(13):2395-410.

5. Rap1-GTP-interacting adaptor molecule (RIAM) protein controls invasion and growth of melanoma cells. Hernández-Varas P, Coló GP, Bartolomé RA, Paterson A, Medraño-Fernández I, Arellano-Sánchez N, Cabañas C, Sánchez-Mateos P, Lafuente EM, Boussiotis VA, Strömblad S, Teixidó J. J Biol Chem. 2011 May 27;286(21):18492-504.

6. RIAM. Lafuente EM, Patsoukis N, Medraño-Fernández I, Boussiotis VA.

UCSD-Nature Molecule Pages 2010 on-line resource

7. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Vilchez D, Ros S, Cifuentes D, Pujadas L, Vallès J, García-Fojeda B, Criado-García O, Fernández-Sánchez E, Medraño-Fernández I, Domínguez J, García-Rocha M, Soriano E, Rodríguez de Córdoba S, Guinovart JJ. Nat Neurosci. 2007 Nov;10(11):1407-13.

8. Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. Fernández-Sánchez ME, Criado-García O, Heath KE, García-Fojeda B, Medraño-Fernández I, Gomez-Garre P, Sanz P, Serratosa JM, Rodríguez de Córdoba S. Hum Mol Genet. 2003 Dec 1;12(23):3161-71.