Activation of tumor necrosis factor-alpha-converting enzyme-mediated ectodomain shedding by nitric oxide

Ectodomain shedding of cell surface proteins is an important process in a w ide variety of physiological and developmental events. Recently, tumor necr osis factor-alpha-converting enzyme (TACE) has been found to play an essent ial role in the shedding of several critical surface proteins, which is evi denced by multiple developmental defects exhibited by TACE knockout mice. H owever, little is known about the physiological activation of TACE, Here, w e show that nitric oxide (NO) activates TACE-mediated ectodomain shedding. Using an in vitro model of TACE activation, we show that NO activates TACE by nitrosation of the inhibitory motif of the TACE prodomain. Thus, NO prod uction activates the release of cytokines, cytokine receptors, and adhesion molecules, and NO may be involved in other ectodomain shedding processes.