Roles of Meltrin β/ADAM19 in the Processing of Neuregulin

Meltrin β/ADAM19 is a member of ADAMs (a disintegrin and metalloproteases), which are a family of membrane-anchored glycoproteins that play important roles in fertilization, myoblast fusion, neurogenesis, and proteolytic processing of several membrane-anchored proteins. The expression pattern of meltrin β during mouse development coincided well with that of neuregulin-1 (NRG), a member of the epidermal growth factor family. Then we examined whether meltrin β participates in the proteolytic processing of membrane-anchored NRGs When NRG-β1 was expressed in mouse L929 cells, its extracellular domain was constitutively processed and released into the culture medium. This basal processing activity was remarkably potentiated by overexpression of wild-type meltrin β, which lead to the significant decrease in the cell surface exposure of extracellular domains of NRG-β1. Furthermore, expression of protease-deficient mutants of meltrin β exerted dominant negative effects on the basal processing of NRG-β1. These results indicate that meltrin β participates in the processing of NRG-β1. Since meltrin β affected the processing of NRG-β4 but not that of NRG-α2, meltrin β was considered to have a preference for β-type NRGs as substrate. Furthermore, the effects of the secretory pathway inhibitors suggested that meltrin β participates in the intracellular processing of NRGs rather than the cleavage on the cell surface.