scholarly journals Mitochondrial Reactive Oxygen Species Mediate GPCR–induced TACE/ADAM17-dependent Transforming Growth Factor-α Shedding

2009 ◽  
Vol 20 (24) ◽  
pp. 5236-5249 ◽  
Author(s):  
Timothy J. Myers ◽  
Leann H. Brennaman ◽  
Mary Stevenson ◽  
Shigeki Higashiyama ◽  
William E. Russell ◽  
...  

Epidermal growth factor receptor (EGFR) activation by GPCRs regulates many important biological processes. ADAM metalloprotease activity has been implicated as a key step in transactivation, yet the regulatory mechanisms are not fully understood. Here, we investigate the regulation of transforming growth factor-α (TGF-α) shedding by reactive oxygen species (ROS) through the ATP-dependent activation of the P2Y family of GPCRs. We report that ATP stimulates TGF-α proteolysis with concomitant EGFR activation and that this process requires TACE/ADAM17 activity in both murine fibroblasts and CHO cells. ATP-induced TGF-α shedding required calcium and was independent of Src family kinases and PKC and MAPK signaling. Moreover, ATP-induced TGF-α shedding was completely inhibited by scavengers of ROS, whereas calcium-stimulated shedding was partially inhibited by ROS scavenging. Hydrogen peroxide restored TGF-α shedding after calcium chelation. Importantly, we also found that ATP-induced shedding was independent of the cytoplasmic NADPH oxidase complex. Instead, mitochondrial ROS production increased in response to ATP and mitochondrial oxidative complex activity was required to activate TACE-dependent shedding. These results reveal an essential role for mitochondrial ROS in regulating GPCR-induced growth factor shedding.

2003 ◽  
Vol 89 (2) ◽  
pp. 254-261 ◽  
Author(s):  
Craig D. Albright ◽  
Rudolf I. Salganik ◽  
Corneliu N. Craciunescu ◽  
Mei-Heng Mar ◽  
Steven H. Zeisel

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