Hydrogen peroxide and endothelin-1 are novel activators of betacellulin ectodomain shedding.

@article{citeulike:618137, abstract = {The betacellulin precursor (pro-BTC) is a novel substrate for ADAM10-mediated ectodomain shedding. In this report, we investigated the ability of novel physiologically relevant stimuli, including G-protein coupled receptor (GPCR) agonists and reactive oxygen species (ROS), to stimulate pro-BTC shedding. We found that in breast adenocarcinoma MCF7 cells overexpressing pro-BTC, hydrogen peroxide (H(2)O(2)) was a powerful stimulator of ectodomain shedding. The stimulation of pro-BTC shedding by H(2)O(2) was blocked by the broad-spectrum metalloprotease inhibitor TAPI-0 but was still functional in ADAM17 (TACE)-deficient stomach epithelial cells indicating the involvement of a distinct metalloprotease. H(2)O(2)-induced pro-BTC shedding was blocked by co-culturing cells in the anti-oxidant N-acetyl-L-cysteine but was unaffected by culture in calcium-deficient media. By contrast, calcium ionophore, which is a previously characterized activator of pro-BTC shedding, was sensitive to calcium depletion but was unaffected by co-culture with the anti-oxidant, identifying a clear distinction between these stimuli. We found that in vascular smooth muscle cells overexpressing pro-BTC, the GPCR agonist endothelin-1 (ET-1) was a strong inducer of ectodomain shedding. This was blocked by a metalloprotease inhibitor and by overexpression of catalytically inactive E385A ADAM10. However, overexpression of wild-type ADAM10 or ADAM17 led to an increase in ET-1-induced pro-BTC shedding providing evidence for an involvement of both enzymes in this process. This study identifies ROS and ET-1 as two novel inducers of pro-BTC shedding and lends support to the notion of activated shedding occurring under the control of physiologically relevant stimuli. J. Cell. Biochem. (c) 2006 Wiley-Liss, Inc.}, address = {Cooperative Research Centre for Tissue Growth and Repair, School of Biological Sciences, Flinders University, Australia.}, author = {Sanderson, Michael P P. and Abbott, Catherine A A. and Tada, Hiroko and Seno, Masaharu and Dempsey, Peter J J. and Dunbar, Andrew J J. }, citeulike-article-id = {618137}, doi = {http://dx.doi.org/10.1002/jcb.20968}, issn = {0730-2312}, journal = {J Cell Biochem}, keywords = {test}, month = {May}, posted-at = {2006-05-08 18:30:45}, priority = {2}, title = {Hydrogen peroxide and endothelin-1 are novel activators of betacellulin ectodomain shedding.}, url = {http://dx.doi.org/10.1002/jcb.20968}, year = {2006} }

TY - JOUR ID - citeulike:618137 L3 - citeulike-article-id:618137 N2 - The betacellulin precursor (pro-BTC) is a novel substrate for ADAM10-mediated ectodomain shedding. In this report, we investigated the ability of novel physiologically relevant stimuli, including G-protein coupled receptor (GPCR) agonists and reactive oxygen species (ROS), to stimulate pro-BTC shedding. We found that in breast adenocarcinoma MCF7 cells overexpressing pro-BTC, hydrogen peroxide (H(2)O(2)) was a powerful stimulator of ectodomain shedding. The stimulation of pro-BTC shedding by H(2)O(2) was blocked by the broad-spectrum metalloprotease inhibitor TAPI-0 but was still functional in ADAM17 (TACE)-deficient stomach epithelial cells indicating the involvement of a distinct metalloprotease. H(2)O(2)-induced pro-BTC shedding was blocked by co-culturing cells in the anti-oxidant N-acetyl-L-cysteine but was unaffected by culture in calcium-deficient media. By contrast, calcium ionophore, which is a previously characterized activator of pro-BTC shedding, was sensitive to calcium depletion but was unaffected by co-culture with the anti-oxidant, identifying a clear distinction between these stimuli. We found that in vascular smooth muscle cells overexpressing pro-BTC, the GPCR agonist endothelin-1 (ET-1) was a strong inducer of ectodomain shedding. This was blocked by a metalloprotease inhibitor and by overexpression of catalytically inactive E385A ADAM10. However, overexpression of wild-type ADAM10 or ADAM17 led to an increase in ET-1-induced pro-BTC shedding providing evidence for an involvement of both enzymes in this process. This study identifies ROS and ET-1 as two novel inducers of pro-BTC shedding and lends support to the notion of activated shedding occurring under the control of physiologically relevant stimuli. J. Cell. Biochem. (c) 2006 Wiley-Liss, Inc. JF - J Cell Biochem SN - 0730-2312 AD - Cooperative Research Centre for Tissue Growth and Repair, School of Biological Sciences, Flinders University, Australia. TI - Hydrogen peroxide and endothelin-1 are novel activators of betacellulin ectodomain shedding. KW - test AU - Sanderson, Michael P AU - Abbott, Catherine A AU - Tada, Hiroko AU - Seno, Masaharu AU - Dempsey, Peter J AU - Dunbar, Andrew J PY - 2006/05/04/ UR - http://dx.doi.org/10.1002/jcb.20968 ER -