Physiological functions of endosomal proteolysis.

Endocytosis is a mechanism used by cells for uptake of macromolecules from extracellular fluid. The uptake may take place in specialized regions of the plasma membrane termed clathrincoated pits, but uptake outside these regions has been reported [1]. Macromolecules may be bound to receptors before uptake or may be present in the fluid phase of the forming endocytic vesicle. The proportion of fluid taken up through the two pathways depends on the cell type. In hepatocytes, the bulk of fluid-phase endocytosis seems to take place outside clathrincoated pits [2]. Macrophages and other cells can be stimulated by growth factors to increased fluid-phase endocytosis via so-called macropinosomes [3-5]. After formation of clathrin-coated vesicles, the coat is shed and uncoated 'primary endosomes' are formed [6]. These are small vesicles (100 nm diam.) that transport their cargo to early endosomes (Figure 1). Clathrin-independent endocytosis also leads to formation of primary endosomes that may be even smaller than those resulting from clathrin-dependent endocytosis [7]. Material delivered by one of these pathways may take one of four possible routes once in the early endosomes [6]: (1) the receptor-ligand complex may be directed to lysosomes for degradation; (2) the ligand may dissociate from the receptor and