ADAM17, induced by Augmenter of Liver Regeneration via G protein-coupled receptor activation, transactivates epidermal growth factor-receptor and reduces classical IL-6 signaling

URN zum Zitieren dieses Dokuments:: urn:nbn:de:bvb:355-epub-792246
DOI zum Zitieren dieses Dokuments:: 10.5283/epub.79224

Voigt, Christoph ; Menzel, Sophie ; Dayoub, Rania

; Kubitza, Marion ; Schmutzler, Florian ; Buechler, Christa

; Eggenhofer, Elke

; Melter, Michael

; Weiss, Thomas S.

Lizenz: Creative Commons Namensnennung 4.0 International
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Veröffentlichungsdatum dieses Volltextes: 14 Apr 2026 09:24

Alternative Links zum Volltext:DOI Verlag

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Zusammenfassung

Background:
Liver regeneration is orchestrated by various cytokines and growth factors, and any imbalance in this process may contribute to liver disease development. Augmenter of Liver Regeneration (ALR), an anti-apoptotic and anti-inflammatory co-mitogen supports regeneration, yet the molecular mechanisms by which ALR regulates proliferation and inflammation remain poorly understood.

Methods:
Hepatoma cell lines, primary mouse and human hepatocytes, and mice subjected to ischemia–reperfusion injury, were treated with recombinant ALR. Various specific inhibitors, small interfering RNA, immunoprecipitation, Western blot, qRT-PCR and ELISA techniques were utilized to analyze the underlying signaling pathways.

Results:
ALR induces the phosphorylation of the EGF-receptor (EGF-R), which subsequently activates the MAPK and PI3K/Akt pathways. EGF-R phosphorylation is triggered by EGF-R ligands, such as TGFα, amphiregulin and HB-EGF, which are released from plasma membranes by the sheddase a disintegrin and metalloproteinase 17 (ADAM17) upon ALR activation. Furthermore, ALR-activated ADAM17 cleaves the membrane-tethered IL-6-receptor α (gp80), thereby reducing IL-6-induced STAT3 phosphorylation and the expression of its target genes (e.g. ICAM-1) in vitro and in vivo. The induction of ADAM17 involves the phosphorylation of protein kinase C (PKC) and the tyrosine kinase Src, as well as the activation of a G protein-coupled receptor (GPCR) by ALR. ALR transduction across plasma membranes is achieved by activating a Gαq/11-coupled GPCR, which is known to induce ADAM17 via cytosolic relay molecules PKC and Src.

Conclusion:
Activation of ADAM17 by ALR: i) transactivates EGF-R signaling upon release of membrane-bound EGF-R ligands, and ii) attenuates classical IL-6 signaling upon gp80 shedding. ALR supports liver regeneration by inducing EGF-R-dependent proliferative (MAPK) and anti-apoptotic (PI3K/Akt) pathways, and reduces IL-6-induced inflammatory gene expression.

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