New insights into the function and pathophysiology of the ectodomain sheddase A Disintegrin And Metalloproteinase 10 (ADAM10)

Abstract

The 'A Disintegrin And Metalloproteinase 10' (ADAM10) has gained considerable attention due to its discovery as an 'α-secretase' involved in the nonamyloidogenic processing of the amyloid precursor protein, thereby possibly preventing the excessive generation of the amyloid beta peptide, which is associated with the pathogenesis of Alzheimer's disease. ADAM10 was found to exert many additional functions, cleaving about 100 different membrane proteins. ADAM10 is involved in many pathophysiological conditions, ranging from cancer and autoimmune disorders to neurodegeneration and inflammation. ADAM10 cleaves its substrates close to the plasma membrane, a process referred to as ectodomain shedding. This is a central step in the modulation of the functions of cell adhesion proteins and cell surface receptors. ADAM10 activity is controlled by transcriptional and post-translational events. The interaction of ADAM10 with tetraspanins and the way they functionally and structurally depend on each other is another topic of interest. In this review, we will summarize findings on how ADAM10 is regulated and what is known about the biology of the protease. We will focus on novel aspects of the molecular biology and pathophysiology of ADAM10 that were previously poorly covered, such as the role of ADAM10 on extracellular vesicles, its contribution to virus entry, and its involvement in cardiac disease, cancer, inflammation, and immune regulation. ADAM10 has emerged as a regulator controlling cell surface proteins during development and in adult life. Its involvement in disease states suggests that ADAM10 may be exploited as a therapeutic target to treat conditions associated with a dysfunctional proteolytic activity.

Keywords: ADAM10; cancer; ectodomain shedding; immune system; regulation.