[en] By mediating proteolytic shedding on the cell surface the disintegrin and metalloproteinases ADAM10 and ADAM17 function as critical regulators of growth factors, cytokines and adhesion molecules. We here report that stimulation of lung epithelial A549 tumor cells with phorbol-12-myristate-13-acetate (PMA) leads to the downregulation of the surface expressed mature form of ADAM17 without affecting ADAM10 expression. This reduction could not be sufficiently explained by metalloproteinase-mediated degradation, dynamin-mediated internalization or microdomain redistribution of ADAM17. Instead, surface downregulation of ADAM17 was correlated with the presence of its mature form in exosomes. Exosomal ADAM17 release was also observed in monocytic and primary endothelial cells where it could be induced by stimulation with lipopolysaccharide. Antibody-mediated surface labelling of ADAM17 revealed that at least part of exosomal ADAM17 was oriented with the metalloproteinase domain outside and had been expressed on the cell surface. Suppression of iRHOM2-mediated ADAM17 maturation prevented surface expression and exosomal release of ADAM17. Further, deletion of the protease's C-terminus or cell treatment with a calcium chelator diminished exosomal release as well as surface downregulation of ADAM17, underlining that both processes are closely associated. Co-incubation of ADAM17 containing exosomes with cells expressing the ADAM17 substrates TGFalpha or amphiregulin lead to increased shedding of both substrates. This was prevented when exosomes were prepared from cells with shRNA-mediated ADAM17 knockdown. These data indicate that cell stimulation can downregulate expression of mature ADAM17 from the cell surface and induce release of exosomal ADAM17, which can then distribute and contribute to substrate shedding on more distant cells.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Groth, Esther
Pruessmeyer, Jessica
Babendreyer, Aaron
Schumacher, Julian
Pasqualon, Tobias
Dreymueller, Daniela
Higashiyama, Shigeki
Lorenzen, Inken
Grotzinger, Joachim
Cataldo, Didier ; Université de Liège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Ludwig, Andreas
Language :
English
Title :
Stimulated release and functional activity of surface expressed metalloproteinase ADAM17 in exosomes.
Publication date :
2016
Journal title :
Biochimica et Biophysica Acta
ISSN :
0006-3002
eISSN :
1878-2434
Publisher :
Elsevier, Amsterdam, Netherlands
Volume :
1863
Issue :
11
Pages :
2795-2808
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2016 Elsevier B.V. All rights reserved.
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