Background <p>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.</p> Methods <p>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.</p> Results <p>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 Gα_q/11-coupled GPCR, which is known to induce ADAM17 via cytosolic relay molecules PKC and Src.</p> Conclusion <p>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.</p>