The importance of shedding of membrane proteins for cytokine biology

Most transmembrane proteins are subjected to limited proteolysis by cellula r proteases. The recent molecular cloning of the TNF-a converting enzyme (T ACE) revealed that this shedding enzyme belongs to a family of metalloprote inases which contain a disintegrin domain (ADAM family). The activity of th ese proteases seems to be tightly regulated. Mice lacking functional TACE a re not viable demonstrating the importance of this enzyme for body homeosta sis. This review describes the current knowledge of shedding enzymes, the A DAM protein family, the mechanism of shedding as well as physiological cons equences of shedding of cytokines and cytokine receptors for cytokine biolo gy.