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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Hepatoma cell lines, primary mouse and human hepatocytes, and mice subjected to ischemia\u2013reperfusion 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 TGF\u03b1, 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 \u03b1 (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 G\u03b1\n                      <jats:sub>q\/11<\/jats:sub>\n                      -coupled GPCR, which is known to induce ADAM17 via cytosolic relay molecules PKC and Src.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-026-02782-7","type":"journal-article","created":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T11:14:44Z","timestamp":1772882084000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["ADAM17, induced by Augmenter of Liver Regeneration via G protein-coupled receptor activation, transactivates epidermal growth factor-receptor and reduces classical IL-6 signaling"],"prefix":"10.1186","volume":"24","author":[{"given":"Christoph","family":"Voigt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Menzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rania","family":"Dayoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Kubitza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Schmutzler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa","family":"Buechler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Eggenhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Melter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S.","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,7]]},"reference":[{"issue":"1","key":"2782_CR1","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41575-020-0342-4","volume":"18","author":"GK Michalopoulos","year":"2021","unstructured":"Michalopoulos GK, Bhushan B. 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Biomed Res Intern 2018;2018: 381242438.","DOI":"10.1155\/2018\/3812424"}],"container-title":["Cell Communication and Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12964-026-02782-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-026-02782-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-026-02782-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:34:00Z","timestamp":1781638440000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12964-026-02782-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,7]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2782"],"URL":"https:\/\/doi.org\/10.1186\/s12964-026-02782-7","relation":{},"ISSN":["1478-811X"],"issn-type":[{"value":"1478-811X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,7]]},"assertion":[{"value":"18 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Experimental procedures were performed according to the guidelines of the charitable state controlled foundation HTCR (Human Tissue and Cell Research, Regensburg, Germany), with the written informed patient's consent. The study and the consent form were approved by the local ethical committee of the University of Regensburg (ethics statement 12\u2013101-0048, University of Regensburg, Germany). All experiments involving human tissues and cells have been carried out in accordance to\n                      The Code of Ethics of the World Medical Association\n                      (Declaration of Helsinki).All animal experiments were approved by the institutional committee of Animal Care and Use, University of Regensburg (54\u2009\u00b1\u20092532.1\u20132\/12; Regierung der Oberpfalz, Germany) and conducted in accordance with the German federal law regarding the protection of animals and 'Guide for the Care and Use of Laboratory Animals' (National Institutes of Health publication 8th Edition, 2011).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"214"}}