Mitochondrial reactive oxygen species mediate GPCR-induced TACE/ADAM17-dependent transforming growth factor-alpha shedding.

Myers TJ, Brennaman LH, Stevenson M, Higashiyama S, Russell WE, Lee DC, Sunnarborg SW
Mol Biol Cell. 2009 20 (24): 5236-49

PMID: 19846666 · PMCID: PMC2793298 · DOI:10.1091/mbc.e08-12-1256

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-alpha (TGF-alpha) shedding by reactive oxygen species (ROS) through the ATP-dependent activation of the P2Y family of GPCRs. We report that ATP stimulates TGF-alpha proteolysis with concomitant EGFR activation and that this process requires TACE/ADAM17 activity in both murine fibroblasts and CHO cells. ATP-induced TGF-alpha shedding required calcium and was independent of Src family kinases and PKC and MAPK signaling. Moreover, ATP-induced TGF-alpha shedding was completely inhibited by scavengers of ROS, whereas calcium-stimulated shedding was partially inhibited by ROS scavenging. Hydrogen peroxide restored TGF-alpha 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.

MeSH Terms (19)

ADAM17 Protein ADAM Proteins Adenosine Triphosphate Animals Calcium CHO Cells Cricetinae Cricetulus ErbB Receptors HL-60 Cells Humans Mice Mitochondria NADPH Oxidases Reactive Oxygen Species Receptors, G-Protein-Coupled Receptors, Purinergic P2 Transcriptional Activation Transforming Growth Factor alpha

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