2. Academic Validation
  3. TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization

TspanC8 tetraspanins differentially regulate the cleavage of ADAM10 substrates, Notch activation and ADAM10 membrane compartmentalization

  • Cell Mol Life Sci. 2016 May;73(9):1895-915. doi: 10.1007/s00018-015-2111-z.
Stéphanie Jouannet 1 2,  Julien Saint-Pol 1 2,  Laurent Fernandez 3 4,  Viet Nguyen 2,  Stéphanie Charrin 1 2,  Claude Boucheix 1 2,  Christel Brou 5,  Pierre-Emmanuel Milhiet 3 4,  Eric Rubinstein 6 7
Affiliations

Affiliations

  • 1 Inserm, U935, 94807, Villejuif, France.
  • 2 Université Paris-Sud, Institut André Lwoff, 94807, Villejuif, France.
  • 3 Inserm, U1054, 34090, Montpellier, France.
  • 4 Université de Montpellier, CNRS, UMR5048, Centre de Biochimie Structurale, Montpellier, France.
  • 5 Institut Pasteur, Laboratoire "Signalisation et Pathogenèse", 75015, Paris, France.
  • 6 Inserm, U935, 94807, Villejuif, France. eric.rubinstein@inserm.fr.
  • 7 Université Paris-Sud, Institut André Lwoff, 94807, Villejuif, France. eric.rubinstein@inserm.fr.
PMID: 26686862 DOI: 10.1007/s00018-015-2111-z
Abstract

The metalloprotease ADAM10 mediates the shedding of the ectodomain of various cell membrane proteins, including APP, the precursor of the amyloid peptide Aβ, 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.

Keywords

ADAM10; Ectodomain shedding; Membrane compartmentalization; Microdomain; Notch; Tetraspanin.

Figures