The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology

Figure 3

ADAM17 dependent paracrine and autocrine signaling. A disintegrin and metalloproteinase 17 (ADAM17), also known as a tumor necrosis factor-α converting enzyme (TACE), is involved in the immune defense mechanisms mediated by epithelial cells. ADAM17 releases extracellular domains of transmembrane proteins to produce soluble bioactive signaling proteins taking part in autocrine (activation of receptors within the same epithelial cell layer) and paracrine signaling (activation of cellular receptors on underlying neighboring cells, also termed transactivation). Among the ADAM17 substrates are (1) adhesion proteins (L-selectin, ICAM), (2) transmembrane mucins (MUC-1), (3) membrane-bound cytokines (TNF-α), (4) growth factors (AREG) and other ligands of EGFR (TGF-α, EREG, HB-EGF, and epigen), and (5) cytokine receptors (IL-6R, TNF-R). Ectodomain shedding provides the mechanism for autocrine and paracrine signaling. IL-6R shed from epithelial cells transactivates gp130 on the underlying myofibroblasts, whereas AREG shed from epithelial cells activates EGFR on epithelial cells or on the underlying fibroblasts. The ADAM17 inhibitor TIMP-3 inhibits the ADAM17 proteolytic activity.