SEARCH

SEARCH BY CITATION

Keywords:

  • ADAM;
  • ectodomain shedding;
  • lipid rafts;
  • neuregulin

Abstract

Meltrin β (Mel β, also called ADAM19) is a member of the ADAM (adisintegrin and metalloprotease) family, which are membrane-anchored glycoproteins that play crucial roles in various biological processes. Many intercellular signaling molecules are membrane-anchored proteins, which are proteolytically processed after becoming membrane-bound, to liberate their extracellular domains (ectodomain shedding). Genetic and biochemical studies have shown that some ADAMs participate in these events. We found previously that Mel β can cleave the extracellular region of the membrane-anchored β-exon-containing Neuregulin-1 (NRG β1) protein, which is one of the main ligands for the neural ErbB receptor. Mel β-deficient mice showed developmental defects in the nervous system. These observations raise the possibility that the NRG ectodomain shedding mediated by Mel β is closely related to the neural development. Here we show that Mel β-mediated ectodomain shedding of NRG β1 takes place in the lipid rafts of neurons. The lipid rafts localization of Mel β requires its membrane-anchoring region, and NRG β1 ectodomain shedding is not enhanced if Mel β cannot reach the lipid rafts. These results indicate that localization of Mel β in lipid rafts is critical for its ectodomain shedding.