Amines inhibit the clustering of alpha2-macroglobulin and EGF on the fibroblast cell surface.
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2-MACROGLOBULIN (2M), insulin and epidermal growth factor (EGF) have a common mechanism for internalisation 1. We have proposed a model for this mechanism1-3 in which the ligands bind to diffusely distributed receptors followed by the collection of the mobile ligand-receptor complexes over coated pits. These coated pits pinch off from the plasma membrane to form endocytic vesicles. The diffuse initial distribution of the 2M receptors has been shown by binding 2M to fixed cells and observing the location of 2M by an electron microscopic immunocytochemical method 2. The mobility of the ligand-receptor complexes has been demonstrated using fluorescence photobleaching recovery4, and the clustering of such complexes has been demonstrated by fluorescence microscopy1,3,5. Electron microscopic immunocytochemical localisation has been used to show that the clustering occurs over coated pits which pinch off to form endocytic vesicles2. The mechanism proposed for the endocytosis of 2M, insulin and EGF is similar to that described for the internalisation of low density lipoprotein (LDL), except that unoccupied LDL receptors may cluster in coated pits before binding LDL 6. It seems likely that many molecules, including other polypeptide hormones and the lysosomal hydrolases7 which bind to specific receptors on the cell surface, are internalised by a similar mechanism. To determine the role of clustering and internalisation in hormone action it would be useful to have an agent that inhibits these processes. It has been found that the internalisation of lysosomal enzymes is noncompetitively inhibited by some amines and ammonia (E. Neufeld, personal communication). It has also been reported that ammonia prevents the internalisation of diptheria toxin by HeLa cells8. In view of these effects, we examined the possibility that amines and ammonia would block the clustering of 2M and EGF, and we report here that these agents are effective in blocking clustering and internalisation. 1979 Nature Publishing Group.
