ADAM10 is Expressed by Ameloblasts, Cleaves the RELT TNF Receptor Extracellular Domain and Facilitates Enamel Development

Abstract

MMP20 cleaves cadherins and may facilitate cell movement, however MMP20 is not known to cleave tight junction or desmosome proteins. Ameloblasts had not previously been screened for membrane anchored proteases that could contribute to cell movement. Here we performed a PCR screen for proteolyticlly active A Disintegrin And Metalloproteinase (ADAM) family members. These proteinases are termed sheddases because they have a transmembrane domain and their catalytic domain on the cell surface can function to release anchored proteins. Significantly, ADAMs can be targeted to specific substrates on the cell membrane through their interaction with tetraspanins. Six ADAMs (ADAM8, 9, 10, 15, 17, 19) were expressed in mouse enamel organs. We show that Adam10 expression begins in the apical loop, continues through the secretory stage and abruptly ends at the transition stage when ameloblast migration ceases. ADAM10 cleaves cadherins and tight junction plus desmosome proteins and is well characterized for its role in cell movement. ADAM10 facilitated LS8 cell migration/invasion through a Matrigel coated membrane and we demonstrate that ADAM10, but not ADAM17 cleaves the RELT extracellular domain. This striking result is significant because RELT mutations cause amelogenesis imperfecta (AI) and this directly links ADAM10 to an important role in enamel development.

The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10

“…The sTNF-α forms homotrimers to recognize TNFR to regulate immune response [ 59 , 60 ]. TNFR has also been identified as a substrate for ADAM10 [ 54 ], and the current study shows that ADAM17 cleaved TNFR-1 as well of microglial cells. IL-6 binds to IL-6R to trigger an immune response, and during this process IL-6 signaling needs the involvement of membrane-bound IL-6R to form the IL-6/IL-6R/gp130 complex [ 61 ].…”

“…These results indicate that p CS might negatively affect the innate immune response of BV2 microglia through inhibiting ADAM17, and possibly through ADAM10. Given that ADAM10 and ADAM17 cleave TNF-α and other cytokine-related substrates, such as IL-6 receptor (IL-6R) and Tumor necrosis factor receptor 1 (TNFR-1) [ 52 , 53 , 54 ], we further investigated the potential role of ADAM10 and ADAM17 in innate immune and phagocytotic responses of BV2 microglial cells constitutively and after LPS stimulation.…”

New missense variants in RELT causing hypomineralised amelogenesis imperfecta

“…These similarities of expression staging and phenotype could suggest a possible common mechanism for these different forms of AI. Of note is the recent report that ADAM10, a protein known to release anchored proteins, is expressed during the secretory phase of amelogenesis (but not thereafter) and that ADAM 10 cleaves the extracellular domain of RELT . Lamellal structures were not present in murine Relt −/− enamel, although there was an absence of the poorly mineralised spaces that would normally be expected at the dentino‐enamel junction.…”

Adam10-dependent Notch signaling establishes dental epithelial cell boundaries required for enamel formation

“…Conversely, it was recently shown that Notch1 -expressing cells in the stratum intermedium represent a reservoir of dental epithelial progenitors that are activated upon tooth injury and contribute to the regeneration of the ameloblast layer ( Sharir et al., 2019 ). Adam10 expression in ameloblasts was recently reported, and in vitro results suggested a role for this molecule in the regulation of enamel secretion ( Ikeda et al., 2019 ).…”