ALR induces EGF-receptor transactivation and impairs classical IL-6 signaling by activation of sheddase ADAM17

ALR (Augmenter of Liver Regeneration), an anti-apoptotic and anti-inflammatory co-mitogen, is released upon and supportive for liver regeneration. Molecular details of how ALR addresses proliferation and inflammation are rare. Hepatoma cell lines were treated with recombinant human ALR (rALR) and/or specific inhibitors, followed by analysis of respective signaling pathways using immunoprecipitation, Western Blot, qRT-PCR and ELISA techniques. We present evidence for 1) rALR, irrespective of direct receptor binding, phosphorylates EGFR at cytoplasmic sites and subsequently activates downstream mediators Erk1/2 and Akt. 2) rALR abates IL-6-induced STAT3 phosphorylation and thereby reduces STAT3 target gene expression e.g. involved in inflammation (ICAM-1) and iron homeostasis (hepcidin, Transferrin-receptor, ZIP14). 3) rALR attenuates IL-6-induced STAT3 phosphorylation independent of EGFR activation and involvement of cytoplasmatic regulatory proteins (SOCS1/3, PIAS, JAK1/2, SHP1/2). 4) rALR enhances membrane tethered mature ADAM17/TACE expression thereby increasing its sheddase activity and subsequently release of membrane-bound EGFR ligands such as TGFα and soluble IL-6R subunit α (sgp80) from IL-6R. 5) rALR induces a G-protein coupled receptor (GPCR) and consequently phosphorylation of src, which in turn activates sheddase ADAM17. In conclusion, rALR activates sheddase ADAM17/TACE via GPCR and src, thereby releasing TGFα as well as sgp80. TGFα binds to and activates EGFR and its downstream signaling pathways (MAPK, PI3K/Akt) responsible for cell proliferation. Reduction of functional IL-6 receptor complex by IL-6R shedding leads to reduced STAT3 target gene expression with consequences for inflammation. ALR triggers ADAM17 thereby inducing EGFR trans-signaling and IL-6R shedding, and potentially other ADAM17 targets including their subsequent pathways.

Publication History

Article published online:
20 January 2025