Proteolytic cleavage represents a unique and irreversible posttranslational event regulating the function and half-life of many intracellular and extracellular proteins. The metalloproteinase ADAM10 has raised attention since it cleaves an increasing number of protein substrates close to the extracellular membrane leaflet. This "ectodomain shedding" regulates the turnover of a number of transmembrane proteins involved in cell adhesion and receptor signaling. It can initiate intramembrane proteolysis followed by nuclear transport and signaling of the cytoplasmic domain. ADAM10 has also been implicated in human disorders ranging from neurodegeneration to dysfunction of the immune system and cancer. Targeting proteases for therapeutic purposes remains a challenge since these enzymes including ADAM10 have a wide range of substrates. Accelerating or inhibiting a specific protease activity is in most cases associated with unwanted side effects and a therapeutic useful window of application has to be carefully defined. A better understanding of the regulatory mechanisms controlling the expression, subcellular localization and activity of ADAM10 will likely uncover suitable drug targets which will allow a more specific and fine-tuned modulation of its proteolytic activity.
