ADAM17 orchestrates Interleukin-6, TNFα and EGF-R signaling in inflammation and cancer

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1869; no. 1; p. 119141
• Main Authors: Schumacher, Neele, Rose-John, Stefan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2022
• Subjects: ADAM17; ADAM17 Protein - antagonists & inhibitors; ADAM17 Protein - genetics; ADAM17 Protein - metabolism; Animals; Anti-Inflammatory Agents - pharmacology; cancer; ErbB Receptors - genetics; ErbB Receptors - metabolism; Humans; Inflammation; Interleukin-17 - genetics; Interleukin-17 - metabolism; Interleukin-6; Neoplasms - metabolism; Protease Inhibitors - pharmacology; Shedding; Signal Transduction; Trans-signaling; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Shedding; Trans-signaling; ADAM17; Inflammation; cancer; Interleukin-6
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2021.119141

It was realized in the 1990s that some membrane proteins such as TNFα, both TNF receptors, ligands of the EGF-R and the Interleukin-6 receptor are proteolytically cleaved and are shed from the cell membrane as soluble proteins. The major responsible protease is a metalloprotease named ADAM17. So far, close to 100 substrates, including cytokines, cytokine receptors, chemokines and adhesion molecules of ADAM17 are known. Therefore, ADAM17 orchestrates many different signaling pathways and is a central signaling hub in inflammation and carcinogenesis. ADAM17 plays an important role in the biology of Interleukin-6 (IL-6) since the generation of the soluble Interleukin-6 receptor (sIL-6R) is needed for trans-signaling, which has been identified as the pro-inflammatory activity of this cytokine. In contrast, Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor is mostly regenerative and protective. Probably due to its broad substrate spectrum, ADAM17 is essential for life and most of the few human individuals identified with ADAM17 gene defects died at young age. Although the potential of ADAM17 as a therapeutic target has been recognized, specific blockade of ADAM17 is not trivial since the metalloprotease domain of ADAM17 shares high structural homology with other proteases, in particular matrix metalloproteases. Here, the critical functions of ADAM17 in IL-6, TNFα and EGF-R pathways and strategies of therapeutic interventions are discussed. •Many transmembrane proteins are shed by limited proteolysis.•Shed soluble proteins constitute a transition from local to systemic responses.•ADAM17 is one of the major shedding proteins.•ADAM17 orchestrates the signaling pathways of IL-6, TNFα and EGF-R.•Therapeutic blockade of ADAM17 could be beneficial in many diseases.