Abstract
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.
Highlights
The proteolytic cleavage, or “shedding,” of the extracellular region of transmembrane proteins is an important mechanism for the regulation of leukocyte development and function
Leukocyte Regulation by TspanC8/A disintegrin and metalloproteinase 10 (ADAM10) Scissors of the main proteinase families that function as sheddases and can be regarded as “molecular scissors.”
We propose that ADAM10 should be regarded as six different TspanC8/ ADAM10 scissor complexes, rather than a single scissor [37, 38]
Summary
The proteolytic cleavage, or “shedding,” of the extracellular region (ectodomain) of transmembrane proteins is an important mechanism for the regulation of leukocyte development and function. Two publications have shown that ADAM10 is important for normal T-cell development, most likely through regulation of Notch signaling [40, 41]. The embryonic lethality of ADAM10-knockout mice was circumvented by the generation of transgenic mice that express dominant negative ADAM10 under the control of the T-cell-specific Lck promoter [40]. Conditional T-cell-specific ADAM10-knockout mice were generated by crossing ADAM10 floxed mice with mice expressing Cre recombinase driven by the Lck promoter [41].
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