Role of the metalloprotease ADAM17 in metabolic regulation

Abstract

"Some signaling molecules and/or their receptors are secreted as membrane- bound proteins. Most of these ligands require the cleavage, also known as “shedding” of their ectodomain by proteases to release their soluble and active forms to mediate autocrine, paracrine, and sometimes endocrine forms of signaling. Shedding ectodomains of transmembrane receptors, dampen signaling or promote non-canonical signaling via the soluble forms of these receptors. An important protease is ADAM17, it belongs to the ADAM family of metalloproteases known earlier for its role in cell adhesion but more recently as the protease important in inflammation via its regulation of the bioavailability of soluble tumor necrosis factor α (TNFα) and its receptors, TNFRI & TNFRII. ADAM17 also sheds the ectodomain of most of the ligands for epidermal growth factor receptor (EGFR), a signaling pathway important in development and growth, and implicated in some cancers. At least 80 other substrates of ADAM17 have been identified. As a result of the plethora of substrates cleaved by ADAM17, it is involved in the regulation of several biological processes in health and disorders such as obesity. Obesity, a state of positive energy balance is associated with chronic inflammation of adipose tissues and ADAM17 is thought to play an important role in this as a result of its role in inflammation. Mice null for ADAM17 are protected from obesity and its associated comorbidities by increasing energy expenditure, a phenotype that cannot be explained only by its role in modulating inflammation. It is therefore important to understand the contribution of ADAM17 within different tissue compartments to the metabolically beneficial phenotypes resulting from ADAM17 inactivation, the substrate(s) of ADAM17 involved, and the mechanism(s) of action. (...)