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      A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions

      review-article
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      Toxins
      MDPI
      ADAM, disintegrin, SVMP

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          Abstract

          Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs’ function that have underscored the importance of these proteins in physiological and pathological processes over the years.

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          Most cited references102

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          Nuclear signalling by tumour-associated antigen EpCAM.

          EpCAM was found to be overexpressed on epithelial progenitors, carcinomas and cancer-initiating cells. The role of EpCAM in proliferation, and its association with cancer is poorly explained by proposed cell adhesion functions. Here we show that regulated intramembrane proteolysis activates EpCAM as a mitogenic signal transducer in vitro and in vivo. This involves shedding of its ectodomain EpEX and nuclear translocation of its intracellular domain EpICD. Cleavage of EpCAM is sequentially catalysed by TACE and presenilin-2. Pharmacological inhibition or genetic silencing of either protease impairs growth-promoting signalling by EpCAM, which is compensated for by EpICD. Released EpICD associates with FHL2, beta-catenin and Lef-1 to form a nuclear complex that contacts DNA at Lef-1 consensus sites, induces gene transcription and is oncogenic in immunodeficient mice. In patients, EpICD was found in nuclei of colon carcinoma but not of normal tissue. Nuclear signalling of EpCAM explains how EpCAM functions in cell proliferation.
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            The ADAMs family of metalloproteases: multidomain proteins with multiple functions.

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              EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF.

              Cross-communication between different signalling systems allows the integration of the great diversity of stimuli that a cell receives under varying physiological situations. The transactivation of epidermal growth factor receptor (EGFR)-dependent signalling pathways upon stimulation of G-protein-coupled receptors (GPCRs), which are critical for the mitogenic activity of ligands such as lysophosphatidic acid, endothelin, thrombin, bombesin and carbachol, provides evidence for such an interconnected communication network. Here we show that EGFR transactivation upon GPCR stimulation involves proHB-EGF and a metalloproteinase activity that is rapidly induced upon GPCR-ligand interaction. We show that inhibition of proHB-EGF processing blocks GPCR-induced EGFR transactivation and downstream signals. The pathophysiological significance of this mechanism is demonstrated by inhibition of constitutive EGFR activity upon treatment of PC3 prostate carcinoma cells with the metalloproteinase inhibitor batimastat. Together, our results establish a new mechanistic concept for cross-communication among different signalling systems.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                23 April 2016
                April 2016
                : 8
                : 4
                : 122
                Affiliations
                Department of Dermatology and Venerology, University of Cologne, Cologne 50937, Germany; nives.giebeler@ 123456uk-koeln.de
                Author notes
                [* ]Correspondence: paola.zigrino@ 123456uni-koeln.de ; Tel.: +49-221-478-97443
                Article
                toxins-08-00122
                10.3390/toxins8040122
                4848645
                27120619
                a00ab5d2-b0a7-4024-8f5a-062af1e063cf
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 March 2016
                : 19 April 2016
                Categories
                Review

                Molecular medicine
                adam,disintegrin,svmp
                Molecular medicine
                adam, disintegrin, svmp

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