Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1864, Issue 11, Pages 2071-2081Publisher
ELSEVIER
DOI: 10.1016/j.bbamcr.2017.06.005
Keywords
ADAM10; Ectodomain shedding; Regulation; Disease; Therapy; Drugs
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB877]
- VERUM foundation
- Alzheimer Research Price of the Breuer Foundation
- Belgian Federal Science Policy Office [IUAP P7/16, IAP VII P7/16]
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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.
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