Abstract
For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.
Highlights
The proteolytic release of transmembrane proteins, the so-called ectodomain shedding, is a crucial step in a wide variety of cellular and biological processes necessary for many fundamental physiological functions, while dysregulated shedding results in detrimental effects on cell behaviour and is linked to severe diseases [1,2]
We undertook this review to reassess the current knowledge on the roles of ADAM17 in the regulation of epithelial-to-mesenchymal transition (EMT) and, in the following paragraphs, we report the recent insights into potential molecular mechanisms underlying ADAM17-dependent regulation of the EMT process and their relevance to inflammatory, fibrotic and cancer diseases are discussed
ADAM17 regulates TGF-β-induced Ribosomal S6 kinase-1 (RSK1) phosphorylation; overall, these results suggest that the ERK/ADAM17/RSK1 signalling pathway activation was required for TGF-β enhanced connective tissue growth factor (CTGF) expression in the lung [110]
Summary
The proteolytic release of transmembrane proteins, the so-called ectodomain shedding, is a crucial step in a wide variety of cellular and biological processes necessary for many fundamental physiological functions, while dysregulated shedding results in detrimental effects on cell behaviour and is linked to severe diseases [1,2]. The Disintegrin and Metalloproteinase 17 (ADAM17) holds in the plasmatic membrane of several cell types and is able to cleave multiple varieties of cell surface proteins [3]. It is somatically expressed in mammalian organisms and represents an indispensable regulator of numerous signalling pathways controlling physiological and pathophysiological processes such as development, regeneration, immunity, chronic inflammation and carcinogenesis [4,5]. ADAM17 might represent a master-switch during several fibrotic pathologies and has a central role in the regulation of the epithelial-to-mesenchymal transition (EMT), a critical cellular process in cancer metastasis and pathological fibrosis [5]. Being implicated in essential signalling pathways of the immune system, organ fibrosis and cancer progression makes ADAM17 an attractive therapeutic target
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