TACE Activation by MAPK-Mediated Regulation of Cell Surface Dimerization and TIMP3 Association

A metalloproteinase implicated in inflammation and cancer is inactive as dimers and active as monomers. Falling Apart for Activation The ADAM metalloproteinase TACE [tumor necrosis factor–α (TNF-α)–converting enzyme] mediates the cleavage of several signaling molecules, including TNF-α and transforming growth factor–α (TGF-α), to generate soluble forms. Xu et al. sought to understand the mechanisms by which the MAPKs p38 and ERK activate TACE. Under basal conditions, inactive TACE was present at the cell surface in dimers that interacted preferentially with the metalloproteinase inhibitor TIMP3. Stimulation of p38 or ERK activity resulted in higher relative amounts of TACE monomers at the cell surface, decreased association of TACE with TIMP3, and increased TACE activity. This mechanism of activation may also apply to related ADAM metalloproteinase. 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, and cancer progression. TACE-mediated ectodomain cleavage is activated by signaling of the mitogen-activated protein kinases (MAPKs) p38 and ERK (extracellular signal–regulated kinase). Here, we found that under basal conditions, TACE was predominantly present as dimers at the cell surface, which required its cytoplasmic domain and enabled efficient association with tissue inhibitor of metalloproteinase-3 (TIMP3) and silencing of TACE activity. Upon activation of the ERK or p38 MAPK pathway, the balance shifted from TACE dimers to monomers, and this shift was associated with increased cell surface presentation of TACE and decreased TIMP3 association, which relieved the inhibition of TACE by TIMP3 and increased TACE-mediated proteolysis of transforming growth factor–α. Thus, cell signaling altered the dimer-monomer equilibrium and inhibitor association to promote activation of TACE-mediated ectodomain shedding, a regulatory mechanism that may extend to other ADAM proteases.

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