ADAM-17 is activated by the mitogenic protein kinase ERK in a model of kidney fibrosis.
Chronic kidney disease affects 1 of 9 Americans. Recent studies showed increased activation of the metalloenzyme disintegrin ADAM-17 during the development of the disease and that threonine phosphorylation of ADAM-17 may be an important regulator of the enzyme activity. Using kidney mesangial cells we investigated whether profibrotic serotonin (5-HT) induces phosphorylation of ADAM-17 with concomitant increase in the enzyme activity. We found that 5-HT treatment (1 mM for 10 minutes) induced a significant 3-fold increase in ADAM-17 phosphorylation and employing a fluorogenic enzyme activity assay we showed 2.3-fold activation of ADAM-17, both of which was inhibited by PD98059 (1 mM), an inhibitor of extracellular signal regulated kinase (ERK) activation. In coimmunoprecipitation analysis, we observed increased (2.7-fold) binding of activated ERK to ADAM-17 during 5-HT stimulation. We concluded that, during profibrotic stimulus, ERK phosphorylates ADAM-17 in kidney cells which induces concomitant increase in the enzyme activity.
Bell
Hannah L
HL
Medical University of South Carolina, Charleston, 29425, USA.
Gööz
Monika
M
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D005355:Fibrosis / Q000378:metabolism*; D005419:Flavonoids; D005786:Gene Expression Regulation; D007674:Kidney Diseases / Q000378:metabolism*; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology
D005419:Flavonoids; D012701:Serotonin; D020929:Mitogen-Activated Protein Kinase Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one