Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling

Juarez, J. C., Manuia, M., Burnett, M. E., Betancourt, O., Boivin, B., Shaw, D. E., Tonks, N. K., Mazar, A. P., Donate, F. (May 2008) Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling. Proc Natl Acad Sci U S A, 105 (20). pp. 7147-7152. ISSN 0027-8424

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URL: http://www.ncbi.nlm.nih.gov/pubmed/18480265
DOI: 10.1073/pnas.0709451105

Abstract

Superoxide dismutase 1 (SOD1) is an abundant copper/zinc enzyme found in the cytoplasm that converts superoxide into hydrogen peroxide and molecular oxygen. Tetrathiomolybdate (ATN-224) has been recently identified as an inhibitor of SOD1 that attenuates FGF-2- and VEGF-mediated phosphorylation of ERK1/2 in endothelial cells. However, the mechanism for this inhibition was not elucidated. Growth factor (GF) signaling elicits an increase in reactive oxygen species (ROS), which inactivates protein tyrosine phosphatases (PTP) by oxidizing an essential cysteine residue in the active site. ATN-224-mediated inhibition of SOD1 in tumor and endothelial cells prevents the formation of sufficiently high levels of H2O2, resulting in the protection of PTPs from H2O2-mediated oxidation. This, in turn, leads to the inhibition of EGF-, IGF-1-, and FGF-2-mediated phosphorylation of ERK1/2. Pretreatment with exogenous H2O2 or with the phosphatase inhibitor vanadate abrogates the inhibition of ERK1/2 phosphorylation induced by ATN-224 or SOD1 siRNA treatments. Furthermore, ATN-224-mediated SOD1 inhibition causes the down-regulation of the PDGF receptor. SOD1 inhibition also increases the steady-state levels of superoxide, which induces protein oxidation in A431 cells but, surprisingly, does not oxidize phosphatases. Thus, SOD1 inhibition in A431 tumor cells results in both prooxidant effects caused by the increase in the levels of superoxide and antioxidant effects caused by lowering the levels of H2O2. These results identify SOD1 as a master regulator of GF signaling and as a therapeutic target for the inhibition of angiogenesis and tumor growth.

Item Type: Paper
Uncontrolled Keywords: angiogenesis cancer redox tetrathiomolybdate ATN-224 DISMUTASE-DEFICIENT MICE SUPEROXIDE-DISMUTASE REVERSIBLE INACTIVATION ESCHERICHIA-COLI EGF RECEPTOR A431 CELLS TETRATHIOMOLYBDATE ANGIOGENESIS INHIBITION CANCER
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein phosphatase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Tonks lab
Depositing User: Matt Covey
Date: May 2008
Date Deposited: 25 Feb 2013 14:44
Last Modified: 08 Nov 2017 21:37
PMCID: PMC2438219
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27628

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