ADAM10 is a member of the ADAM (a disintegrin and metalloprotease like domain) family. It cleaves the membrane-bound precursor of TNF-alpha at 76-Ala-|-Val-77 to its mature soluble form. It is responsible for the proteolytic release of several cell-surface proteins, including heparin binding epidermal growth-like factor, ephrin-A2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP). It contributes to the normal cleavage of the cellular prion protein and is involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicules, suggesting a vesicle-based protease activity.
Tumor-necrosis factor alpha is a proinflammatory cytokine and contributes to a variety of inflammatory disease responses and programmed cell death. Notch receptor and its ligand participate in cell fate decisions during vertebrate development and are associated with several human disorders, including a T-cell lymphoma. TNA-alpha, notch and its ligand delta are all membrane-bond molecules, which are cleaved by proteases to release mature proteins or functional receptor. ADAM10-, a metalloprotease-disintegrin in the family of mammalian ADAM (for a disintegrin and metalloproteinase domain), was recently identified to cleave TNF-alpha, notch and its ligand delta (1-3). The genes encoding human, mouse, and bovine ADAM10 were recently cloned and designated ADAM10, kuzbanian (KUZ), and MADM, respectively, (1,2,4). ADAM10mRNA is expressed in a variety of human and bovine tissues.