Molecular insights into the multilayered regulation of ADAM17: The role of the extracellular region

In contrast to many other signalling mechanisms shedding of membrane-anchored proteins is an irreversible process. A Disintegrin And Metalloproteinase (ADAM) 17 is one of the major sheddases involved in a variety of physiological and pathophysiological processes including regeneration, differentiation, and cancer progression. Due to its central role in signalling the shedding activity of ADAM17 is tightly regulated, especially on the cell surface, where shedding events take place. The activity of ADAM17 can be subdivided into a catalytic activity and the actual shedding activity. Whereas the catalytic activity is constitutively present, the shedding activity has to be induced and is tightly controlled to prevent pathological situations induced by the release of its substrates. The regulation of the shedding activity of ADAM17 is multilayered and different regions of the protease are involved. Intriguingly, its extracellular domains play crucial roles in different regulatory mechanisms. We will discuss the role of these domains in the control of ADAM17 activity. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.