ADAM10

ADAM10 is a membrane-bound ectodomain sheddase that cleaves cell-surface proteins and regulates signaling, adhesion, and proteolytic release of soluble ectodomains^[1]. Mechanistically, ADAM10 drives ligand-dependent Notch activation, and Adam10-deficient mice show embryonic defects resembling impaired Notch signaling^[2]. In primary neurons, ADAM10 acts as the physiologically relevant constitutive α-secretase for amyloid precursor protein, linking its activity to non-amyloidogenic APP processing^[3]. In disease models, ADAM10 substrates connect the enzyme to neurodegeneration, inflammation, autoimmunity, and cancer biology^[1][4]. Compared with ADAM17, ADAM10 shows distinct substrate use: ligand-induced Notch1 cleavage depends on ADAM10, whereas EDTA-induced ligand-independent Notch1 processing depends on ADAM17^[5]. This isoform distinction supports experimental designs that combine genetic loss-of-function with selective inhibitors to separate ADAM10-mediated shedding from overlapping ADAM17 activity^[4][6]. For pharmacological studies, GI254023X preferentially inhibits ADAM10 over ADAM17 and blocks ADAM10-mediated shedding of substrates including CX3CL1, CXCL16, IL-6R, and Notch^[4][6]. Newer exosite inhibitors such as CID 3117694 provide substrate-selective ADAM10 inhibition without zinc binding, offering tools to dissect ADAM10 biology beyond broad active-site blockade^[7].