Control of ADAM17 activity by regulation of its cellular localisation

• DOI: 10.1038/srep35067
• Publication Date: 2016-10-12T09:19:11Z
• Authors: Inken Lorenzen; Juliane Lokau; Yvonne Korpys; Mirja Oldefest; Charlotte M. Flynn; Ulrike Künzel; Christoph Garbers; Matthew Freeman; Joachim Grötzinger; Stefan Düsterhöft
• Keywords: Internalization; Proteolysis

Abstract An important, irreversible step in many signalling pathways is the shedding of membrane-anchored proteins. A Disintegrin And Metalloproteinase (ADAM) 17 one major sheddases involved a variety physiological and pathophysiological processes including regeneration, differentiation, cancer progression. This central role implies that ADAM17 activity has to be tightly regulated, at level localisation. Most mature localised intracellularly, with only small amount cell surface. We found constitutively internalised by clathrin-coated pits stimulators such as GPCR ligands induce ADAM17-mediated shedding, but do not alter cell-surface abundance protease. In contrast, PKC-activating phorbol ester PMA, often used strong inducer ADAM17, causes proteolysis also rapid increase protease followed internalisation subsequent degradation Eventually, this leads substantial downregulation ADAM17. Our results therefore imply activation does rely on its relocalisation, PMA-induced PKC drastically dysregulates localisation