Tetraspanins regulate ADAM10-mediated cleavage of TNF-alpha and epidermal growth factor.
Several cytokines and growth factors are released by proteolytic cleavage of a membrane-anchored precursor, through the action of ADAM (a disintegrin and metalloprotease) metalloproteases. The activity of these proteases is regulated through largely unknown mechanisms. In this study we show that Ab engagement of several tetraspanins (CD9, CD81, CD82) increases epidermal growth factor and/or TNF-alpha secretion through a mechanism dependent on ADAM10. The effect of anti-tetraspanin mAb on TNF-alpha release is rapid, not relayed by intercellular signaling, and depends on an intact MEK/Erk1/2 pathway. It is also associated with a concentration of ADAM10 in tetraspanin-containing patches. We also show that a large fraction of ADAM10 associates with several tetraspanins, indicating that ADAM10 is a component of the "tetraspanin web." These data show that tetraspanins regulate the activity of ADAM10 toward several substrates, and illustrate how membrane compartmentalization by tetraspanins can control the function of cell surface proteins such as ectoproteases.
Arduise
Cécile
C
INSERM U602, Villejuif, France.
Abache
Toufik
T
Li
Lei
L
Billard
Martine
M
Chabanon
Aurélie
A
Ludwig
Andreas
A
Mauduit
Philippe
P
Boucheix
Claude
C
Rubinstein
Eric
E
Le Naour
François
F
D051722:ADAM Proteins / Q000276:immunology / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000276:immunology / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D051861:Kangai-1 Protein / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D034622:RNA Interference; D015398:Signal Transduction / Q000276:immunology; D060225:Tetraspanin 28; D060245:Tetraspanin 29; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C554798:CD81 protein, human; C554869:CD9 protein, human; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D060225:Tetraspanin 28; D060245:Tetraspanin 29; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human