Tetraspanin12 regulates ADAM10‐dependent cleavage of amyloid precursor protein
- 8 July 2009
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 23 (11), 3674-3681
- https://doi.org/10.1096/fj.09-133462
Abstract
Using mass spectrometry, we identified ADAM10 (a membrane-associated metalloproteinase) as a partner for TSPAN12, a tetraspanin protein. TSPAN12-ADAM10 interaction was confirmed by reciprocal coimmunoprecipitation in multiple tumor cell lines. TSPAN12, to a greater extent than other tetraspanins (CD81, CD151, CD9, and CD82), associated with ADAM10 but not with ADAM17. Overexpression of TSPAN12 enhanced ADAM10-dependent shedding of amyloid precursor protein (APP) in MCF7 (breast cancer) and SH-SY5Y (neuroblastoma) cell lines. Conversely, siRNA ablation of endogenous TSPAN12 markedly diminished APP proteolysis in both cell lines. Furthermore, TSPAN12 overexpression enhanced ADAM10 prodomain maturation, whereas TSPAN12 ablation diminished ADAM10 maturation. A palmitoylation-deficient TSPAN12 mutant failed to associate with ADAM10, inhibited ADAM10-dependent proteolysis of APP, and inhibited ADAM10 maturation, most likely by interfering with endogenous wild-type TSPAN12. In conclusion, TSPAN12 serves as a novel and robust partner for ADAM10 and promotes ADAM10 maturation, thereby facilitating ADAM10-dependent proteolysis of APP. This novel mode of regulating APP cleavage is of relevance to Alzheimer's disease therapy.Keywords
Funding Information
- National Institutes of Health (GM38903, CA102034)
This publication has 50 references indexed in Scilit:
- Tetraspanin Proteins Regulate Membrane Type-1 Matrix Metalloproteinase-dependent Pericellular ProteolysisMolecular Biology of the Cell, 2009
- ADAMs 10 and 17 Represent Differentially Regulated Components of a General Shedding Machinery for Membrane Proteins Such as Transforming Growth Factor α, L-Selectin, and Tumor Necrosis Factor αMolecular Biology of the Cell, 2009
- Receptor for Advanced Glycation End Products Is Subjected to Protein Ectodomain Shedding by MetalloproteinasesJournal of Biological Chemistry, 2008
- Structural basis for tetraspanin functions as revealed by the cryo-EM structure of uroplakin complexes at 6-Å resolutionThe Journal of cell biology, 2006
- The molecular players of sperm–egg fusion in mammalsSeminars in Cell & Developmental Biology, 2006
- Metabolic Activation-related CD147-CD98 ComplexMolecular & Cellular Proteomics, 2005
- Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linkingBiochemical Journal, 2004
- EWI-2 regulates α3β1 integrin–dependent cell functions on laminin-5The Journal of cell biology, 2003
- The association of the tetraspanin D6.1A with the α6β4 integrin supports cell motility and liver metastasis formationJournal of Cell Science, 2003
- FPRP, a Major, Highly Stoichiometric, Highly Specific CD81- and CD9-associated ProteinJournal of Biological Chemistry, 2001