ADAMmediated

ADAMmediated refers to cellular events driven by members of the ADAM family of proteases, a group of zinc-dependent metalloproteases that are anchored in the plasma membrane and in some cases secreted. The core function of many ADAMs is ectodomain shedding, in which the extracellular domains of membrane proteins are proteolytically cleaved and released as soluble fragments. This shedding can modulate receptor signaling, ligand availability, and cell–cell interactions. The best studied examples involve ADAM10 and ADAM17, although multiple family members contribute in a tissue- and context-specific manner.

Mechanistically, ADAM proteases are synthesized as inactive precursors that are activated by prodomain removal. Once active, they cleave substrates at juxtamembrane sites, producing a soluble ectodomain and a remaining membrane-tethered fragment. In several signaling pathways, such as Notch, ADAM-mediated shedding is the S2 step that precedes intramembrane proteolysis by gamma-secretase and release of intracellular signaling fragments. Notch signaling, as well as shedding of epidermal growth factor (EGF)–family ligands, TNF family cytokines, and various receptors, illustrate the broad impact of ADAM activity.

Substrates span cytokines, growth factors, receptors, and adhesion molecules, influencing processes from development and immune responses to tissue remodeling and cancer progression. Regulation occurs through transcriptional control, propeptide maturation, trafficking to the cell surface, and inhibition by tissue inhibitors of metalloproteinases (TIMPs). Aberrant ADAM activity is linked to inflammatory diseases, cancer, and neurodegenerative conditions, making selective modulation of ADAM-mediated shedding an area of therapeutic interest, albeit challenging due to substrate diversity.