A
disintegrin and
metalloproteinase 10 (ADAM10) is a ubiquitous transmembrane
protein that functions as a "molecular scissor" to cleave the extracellular regions from its transmembrane target
proteins. ADAM10 is well characterized as the
ligand-dependent activator of
Notch proteins, which control cell fate decisions. Indeed, conditional knockouts of ADAM10 in mice reveal impaired B-, T-, and myeloid cell development and/or function. ADAM10 cleaves many other leukocyte-expressed substrates. On B-cells, ADAM10 cleavage of the low-affinity
IgE receptor CD23 promotes
allergy and
asthma, cleavage of ICOS
ligand impairs antibody responses, and cleavage of the BAFF-APRIL receptor transmembrane activator and CAML interactor, and
BAFF receptor, reduce B-cell survival. On microglia, increased ADAM10 cleavage of a rare variant of the
scavenger receptor triggering receptor expressed on myeloid cells 2 may increase susceptibility to
Alzheimer's disease. We and others recently showed that ADAM10 interacts with one of six different regulatory
tetraspanin membrane proteins, which we termed the TspanC8 subgroup, comprising Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33. The TspanC8s are required for ADAM10 exit from the endoplasmic reticulum, and emerging evidence suggests that they dictate ADAM10 subcellular localization and substrate specificity. Therefore, we propose that ADAM10 should not be regarded as a single scissor, but as six different scissors with distinct substrate specificities, depending on the associated TspanC8. In this review, we collate recent transcriptomic data to present the TspanC8 repertoires of leukocytes, and we discuss the potential role of the six TspanC8/ADAM10 scissors in leukocyte development and function.