Peer-Reviewed Journal Details
Mandatory Fields
Seipold, L;Damme, M;Prox, J;Rabe, B;Kasparek, P;Sedlacek, R;Altmeppen, H;Willem, M;Boland, B;Glatzel, M;Saftig, P
2017
January
Biochimica Et Biophysica Acta-Molecular Cell Research
Tetraspanin 3: A central endocytic membrane component regulating the expression of ADAM10, presenilin and the amyloid precursor protein
Validated
Optional Fields
DISINTEGRIN/METALLOPROTEINASE ADAM10 ALZHEIMERS-DISEASE FRAGMENTS BRAIN ALPHA CELLS MICRODOMAINS TRAFFICKING SECRETASE PROTEASES
1864
217
230
Despite existing knowledge about the role of the A Disintegrin and Metalloproteinase 10 (ADAM10) as the alpha-secretase involved in the non-amyloidogenic processing of the amyloid precursor protein (APP) and Notch signalling we have only limited information about its regulation. In this study, we have identified ADAM10 interactors using a split ubiquitin yeast two hybrid approach. Tetraspanin 3 (Tspan3), which is highly expressed in the murine brain and elevated in brains of Alzheimer's disease (AD) patients, was identified and confirmed to bind ADAM10 by co-immunoprecipitation experiments in mammalian cells in complex with APP and the gamma-secretase protease presenilin. Tspan3 expression increased the cell surface levels of its interacting partners and was mainly localized in early and late endosomes. In contrast to the previously described ADAM10-binding tetraspanins, Tspan3 did not affect the endoplasmic reticulum to plasma membrane transport of ADAM10. Heterologous Tspan3 expression significantly increased the appearance of carboxy-terminal cleavage products of ADAM10 and APP, whereas N-cadherin ectodomain shedding appeared unaffected. Inhibiting the endocytosis of Tspan3 by mutating a critical cytoplasmic tyrosine-based internalization motif led to increased surface expression of APP and ADAM10. After its downregulation in neuroblastoma cells and in brains of Tspan3-deficient mice, ADAM10 and APP levels appeared unaltered possibly due to a compensatory increase in the expression of Tspans 5 and 7, respectively. In conclusion, our data suggest that Tspan3 acts in concert with other tetraspanins as a stabilizing factor of active ADAM10, APP and the gamma-secretase complex at the plasma membrane and within the endocytic pathway. (C) 2016 Elsevier B.V. All rights reserved.
AMSTERDAM
0167-4889
10.1016/j.bbamcr.2016.11.003
Grant Details