期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 73, 期 9, 页码 1895-1915出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-015-2111-z
关键词
Membrane compartmentalization; Notch; ADAM10; Tetraspanin; Ectodomain shedding; Microdomain
资金
- INSERM
- CNRS
- Association pour la Recherche sur le Cancer
- NRB-Vaincre le Cancer
- Institut du Cancer et d'Immunogenetique
- Institut National du Cancer
- French Ministry of Research
The metalloprotease ADAM10 mediates the shedding of the ectodomain of various cell membrane proteins, including APP, the precursor of the amyloid peptide A beta, and Notch receptors following ligand binding. ADAM10 associates with the members of an evolutionary conserved subgroup of tetraspanins, referred to as TspanC8, which regulate its exit from the endoplasmic reticulum. Here we show that 4 of these TspanC8 (Tspan5, Tspan14, Tspan15 and Tspan33) which positively regulate ADAM10 surface expression levels differentially impact ADAM10-dependent Notch activation and the cleavage of several ADAM10 substrates, including APP, N-cadherin and CD44. Sucrose gradient fractionation, single molecule tracking and quantitative mass-spectrometry analysis of the repertoire of molecules co-immunoprecipitated with Tspan5, Tspan15 and ADAM10 show that these two tetraspanins differentially regulate ADAM10 membrane compartmentalization. These data represent a unique example where several tetraspanins differentially regulate the function of a common partner protein through a distinct membrane compartmentalization.
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