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.