Research ArticleCell Biology

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

Sci. Signal.  01 May 2012:
Vol. 5, Issue 222, pp. ra34
DOI: 10.1126/scisignal.2002689

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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.