TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association.

摘要: Ectodomain shedding mediated by tumor necrosis factor-α (TNF-α)-converting enzyme [TACE; also known as ADAM17 (a disintegrin and metalloproteinase 17)] provides an important switch in regulating cell proliferation, inflammation, cancer progression. TACE-mediated ectodomain cleavage is activated signaling of the mitogen-activated protein kinases (MAPKs) p38 ERK (extracellular signal-regulated kinase). Here, we found that under basal conditions, TACE was predominantly present dimers at surface, which required its cytoplasmic domain enabled efficient association with tissue inhibitor metalloproteinase-3 (TIMP3) silencing activity. Upon activation or MAPK pathway, balance shifted from to monomers, this shift associated increased surface presentation decreased TIMP3 association, relieved inhibition proteolysis transforming growth factor-α. Thus, altered dimer-monomer equilibrium promote shedding, a regulatory mechanism may extend other ADAM proteases.