trans-Golgi retention of a plasma membrane protein: mutations in the cytoplasmic domain of the asialoglycoprotein receptor subunit H1 result in trans-Golgi retention

The ASGP receptor is an endocytic transport receptor responsible for the rapid clearance of glycoproteins with exposed galactoses from the circulation into hepatocytes (for review see Spiess, 1990) . Ligand ASGPs are bound at the cell surface, internalized via clathrin-coated vesicles, and released in the acidic environment of endosomes for subsequent degradation in lysosomes. The ASGP receptor cycles constitutively between the cell surface and early endosomes. The human receptor is at least a trimer composed of two homologous subunits, H1 and H2, which both are required for high affinity ligand binding. The subunits are single-spanning type II membrane proteins with amino-terminal cytoplasmic domains of 40 and 58 residues, respectively. The major subunit H1, which is 2--4 times more abundant than H2, contains all the signals necessary for endocytosis and specific basolateral transport in polarized epithelial cells . A tyrosine-containing signal necessary for efficient endocytosis and basolateral sorting has been identified in the amino-terminal segment of residues 1-11 Geffen et al., 1993) . Mutation of the critical tyrosine at position 5 to alanine or deletion of residues 4-11 result in apolar sorting in transfected MDCK cells and in accumulation of H1 at the plasma membrane in transfected fibroblast and MDCK cells.