Mechanisms controlling the shedding of transmembrane molecules.

Abstract

Although the number of cell-surface transmembrane molecules known to release their extracellular domain to the cell media has grown greatly during past years, the protease(s) involved have remained elusive until recently. The analysis of ectodomain shedding of proteins as diverse as membrane-anchored growth factors, such as pro-transforming growth factor a (proTGF-a) and pro-tumour necrosis factor a (proTNF-ol), growth factor receptors, ectoenzymes, cell adhesion molecules and the /j amyloid precursor protein (/jAPP) has revealed several common features. The shedding of most proteins occurs at a fixed distance from the plasma membrane, can be activated via protein kinase C (PKC) and can be prevented by hydroxamic acid-based metalloprotease inhibitors initially developed to block the shedding of proTNF-x [l]. The structural diversity of proteins that undergo protein ectodomain shedding initially suggested the existence of several proteases involved, each endowed with a restricted specificity. However, Chinese hamster ovary (CHO) cell mutants selected for a lack of proTGF-x shedding (M1 and M2 cells) showed a general defect in protein ectodomain shedding, indicating the existence of at least a common component necessary for the shedding of multiple transmembrane proteins [2,3]. The first protease shown to be involved in a shedding event acts on proTNF-z and belongs to the family of metalloprotease disintegrins (also known as the ADAM family), a family of modular transmembrane Znzf-dependent metalloproteases that contain a disintegrin domain. Metalloprotease disintegrins are involved in sperm-egg fusion, muscle fusion in C2C12 myoblasts and the regulation of neural cell fate at different stages of neurogenesis in Ilrosophila (metalloprotease disintegrins are reviewed in [4,5]). The substrates of most members of the metallopro-