Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids

Abstract

A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are ubiquitous transmembrane “molecular scissors” which proteolytically cleave, or shed, the extracellular regions of other transmembrane proteins. ADAM10 is essential for development because it cleaves Notch proteins to induce Notch signaling and regulate cell fate decisions. ADAM17 is regarded as a first line of defense against injury and infection, by releasing tumor necrosis factor α (TNFα) to promote inflammation and epidermal growth factor (EGF) receptor ligands to maintain epidermal barrier function. However, the regulation of ADAM10 and ADAM17 trafficking and activation are not fully understood. This review will describe how the TspanC8 subgroup of tetraspanins (Tspan5, 10, 14, 15, 17, and 33) and the iRhom subgroup of protease-inactive rhomboids (iRhom1 and 2) have emerged as important regulators of ADAM10 and ADAM17, respectively. In particular, they are required for the enzymatic maturation and trafficking to the cell surface of the ADAMs, and there is evidence that different TspanC8s and iRhoms target the ADAMs to distinct substrates. The TspanC8s and iRhoms have not been studied functionally on platelets. On these cells, ADAM10 is the principal sheddase for the platelet collagen receptor GPVI, and the regulatory TspanC8s are Tspan14, 15, and 33, as determined from proteomic data. Platelet ADAM17 is the sheddase for the von Willebrand factor (vWF) receptor GPIb, and iRhom2 is the only iRhom that is expressed. Induced shedding of either GPVI or GPIb has therapeutic potential, since inhibition of either receptor is regarded as a promising anti-thrombotic therapy. Targeting of Tspan14, 15, or 33 to activate platelet ADAM10, or iRhom2 to activate ADAM17, may enable such an approach to be realized, without the toxic side effects of activating the ADAMs on every cell in the body.

CD9 Regulates Major Histocompatibility Complex Class II Trafficking in Monocyte-Derived Dendritic Cells

“…Several tetraspanins regulate the intracellular trafficking of their molecular partners, controlling expression at the plasma membrane or sorting into intracellular vesicles (76,77). Our results show that CD9 controls different steps of MHC-II intracellular trafficking in MoDCs, regulating egress from MIIC to the surface in immature cells, internalization in immature and mature MoDCs, and recycling in mature cells.…”

Bisphenol-A and Nonylphenol Induce Apoptosis in Reproductive Tract Cancer Cell Lines by the Activation of ADAM17

“…In the same way, BPA and NP stimulate the release of EGFR ligands, such as TGFα or HB-EGF, by activating either ADAM17 or ancillary proteins such as iRhom1 and/or iRhom2 [22,70]. The activation of EGFR by BPA was also observed in LNCaP cells, which leads to the activation of the main cellular regulator p53 [71].…”

Tetraspanin Tspan9 regulates platelet collagen receptor GPVI lateral diffusion and activation

“…Definitive tetraspanin/partner pairs include tetraspanin CD151 with laminin-binding integrins [17], CD81 with the B-cell co-receptor CD19 [49] and the TspanC8 subgroup of tetraspanins with a disintegrin and metalloproteinase 10 (ADAM10) [26]. Their interactions can be detected by co-immunoprecipitation in relatively stringent lysis conditions (e.g.…”