CORRESPONDENCE

Many membrane proteins are cleaved at the plasma membrane to release soluble ectodomains, which may exert different biological activities (Murphy, 2008). Membrane-bound growth fac-tors and cytokines become systemically available upon shedding. Soluble receptors for growth fac-tors and cytokines can be antagonists of the cog-nate cytokines, as is the case for IL-1 and TNF (Müllberg et al., 2000). Alternatively, soluble re-ceptors can be agonistic, i.e., together with their respective ligands they stimulate cells, which are otherwise unresponsive to the cytokine, as dem-onstrated for IL-6 trans-signaling (Rose-John et al., 2006). A disintegrin and metalloprotease (ADAM) 17 is an important sheddase involved in the proteolysis of membrane proteins such as TNF, IL-6R, L-selectin, and ligands of the epi-dermal growth factor receptor (EGF-R; Peschon et al., 1998). ADAM17-deficient mice are not vi-able. Interestingly, these mice were reminiscent of mice lacking TGF- (Peschon et al., 1998). Recently, conditional ADAM17 knockout ani-mals have been generated (Horiuchi et al., 2007, 2009). Although these studies confirmed tha