Research Article Open Access
Volume 2 | Issue 1 | DOI: https://doi.org/10.33696/Signaling.2.033

The Role of Membrane-embedded DUOX2 on Ectodomain Shedding via G protein-coupled Receptor Signaling

  • 1Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325 Kumamoto 861-5598, Japan
  • 2Department of of Neuroscience, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Yoshida-konoe-cho Sakyo-ku Kyoto 606-8501, Japan
+ Affiliations - Affiliations

Corresponding Author

Yasuo Yamaguchi, yamaguti@kumamoto-hsu.ac.jp

Received Date: September 30, 2020

Accepted Date: December 14, 2020


Protease-activated receptors (PARs) and the neurokinin 1 receptor (NK1R) belong to the G protein-coupled receptor (GPCR) family. In this review, we focus on the regulatory mechanism of ectodomain shedding by ADAM10/17 metalloprotease via GPCR signaling. PAR2 and NK1R induce membrane blebbing, resulting in phosphatidylserine externalization in the cellular membrane, which is required for ADAM10/17 metalloprotease activation. Membrane-embedded dual oxidase 2 (DUOX2) has NADPH oxidase and peroxidase domains. NADPH oxidase domain generates hydrogen peroxide (H2O2), while the peroxidase domain produces peroxynitrite (ONOO) through the interaction of nitrogen oxide with superoxide. Both H2O2 and peroxynitrite activate ADAM10/17 metalloproteases. PAR2 signaling activates ADAM10/17 by NADPH-mediated H2O2, leading to the transactivation of DUOX2/EGFR/TLR4 to synergistically upregulate IL-12p40 production after exposure to LPS. In contrast, nitric oxide (NO) synthesis is promoted by NK1R signaling, and DUOX2 generates ONOO-, preferentially activating ADAM10/17 metalloprotease. Ectodomain shedding of membrane-bound fractalkine is mediated by ADAM10/17. Substance P (SP)/NK1R signals enhance shedding of membrane-bound fractalkine, whereas small interfering RNA for DUOX2 further increases membrane-bound fractalkine but decreases soluble fractalkine compared with cells treated with SP alone. Considering the signaling pathway of TGFβ1 (an inhibitor of iNOS mRNA expression), silencing of RNA for TAK-1 upregulates membrane-bound fractalkine tripartite motif 28 (TRIM28)/transcriptional intermediary factor 1β (TIF1β) functions as an E3 ubiquitin ligase and specificity protein 1 negatively regulate TGFβ1 levels to upregulate the generation of peroxynitrite, leading to increased shedding of membrane-bound fractalkine via SP/NK1R signaling. DUOX2 plays a pivotal role for ectodomain shedding through ADAM10/17 activation by GPCR signaling.


GPCR, DUOX2, ADAM family, Peroxynitrite, Shedding

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