INTRAENDOSOMAL DEGRADATION OF TRANSFORMING GROWTH-FACTOR-ALPHA

Transforming growth factor alpha (TGF alpha) and epidermal growth fact or (EGF) bind to the same receptor, but have different potencies and a ctions. A possible mechanism is that differences in processing may be responsible for their divergent properties. We have examined TGF alpha and EGF processing in isolated rat hepatocytes with and without vario us protease inhibitors and inhibitors of endosomal processing. Our res ults show that EGF undergoes limited degradation in endosomes and is p rimarily degraded in lysosomes. In contrast, TGF alpha is rapidly degr aded in endosomes by insulin-degrading enzyme (EC 3.4.24.56), possibly allowing rapid return of the receptor to the cell surface. Incubation of isolated endosomes preloaded with labeled TGF alpha reveals that d egradation can occur whether the vesicles are acidified or not, as is also the case for insulin. We conclude that TGF alpha is degraded imme diately after internalization, at least partly before acidification ha s occurred, while EGF requires prolonged intracellular residence and l ysosomal degradation. The different degradation pathways may play a ro le in the different activities of the two hormones. (C) 1997 Elsevier Science Inland Ltd.