The ectodomains of numerous proteins are released from cells by proteolysis to yield soluble intercellular regulators. The responsible protease, tumor necrosis factor-a converting enzyme (TACE), has been identified only in the case when tumor necrosis factor-alpha (TNF alpha) is released. Analyses of cells lacking this metalloproteinase-disintegrin revealed an expanded role for TACE in the processing of other cell surface proteins, including a TNF receptor, the L-selectin adhesion molecule, and transforming growth factor-alpha (TGF alpha). The phenotype of mice Lacking TACE suggests an essential role for soluble TGF alpha in normal development and emphasizes the importance of protein ectodomain shedding in vivo.