Mr 46,000 mannose 6-phosphate specific receptor: its role in targeting of lysosomal enzymes.

Abstract

Antibodies that block the ligand binding site of the cation‐dependent mannose 6‐phosphate specific receptor (Mr 46,000 MPR) were used to probe the function of the receptor in transport of lysosomal enzymes. Addition of the antibodies to the medium of Morris hepatoma 7777 cells, which express only the Mr 46,000 MPR, resulted in a decreased intracellular retention and increased secretion of newly synthesized lysosomal enzymes. In fibroblasts and HepG2 cells that express the cation‐independent mannose 6‐phosphate specific receptor (Mr 215,000 MPR) in addition to the Mr 46,000 MPR, antibodies against the Mr 46,000 MPR inhibited the intracellular retention of newly synthesized lysosomal enzymes only when added to the medium together with antibodies against the Mr 215,000 MPR. Morris hepatoma (M.H.) 7777 did not endocytose lysosomal enzymes, while U937 monocytes, which express both types of MPR, internalized lysosomal enzymes. The uptake was inhibited by antibodies against the Mr 215,000 MPR, but not by antibodies against the Mr 46,000 MPR. These observations suggest that Mr 46,000 MPR mediates transport of endogenous but not endocytosis of exogenous lysosomal enzymes. Internalization of receptor antibodies indicated that the failure to mediate endocytosis of lysosomal enzymes is due to an inability of surface Mr 46,000 MPR to bind ligands rather than its exclusion from the plasma membrane or from internalization.

Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier

“…The M6P͞IGF2R is known to participate in the endocytosis of lysosomal enzymes from the cell surface (30). We speculated that M6P͞IGF2R could be the BBB transporter for P-GUS because M6P͞IGF2R is important in the uptake of P-GUS by peripheral tissues (15) and it had been demonstrated on bovine and rodent brain capillaries (31,32).…”

Substrate autoregulation of glucose transport: hexose 6-phosphate mediates the cellular distribution of glucose transporters

“…For instance, mannose-6-P is a high affinity ligand for the insulin-like growth factor II/mannose-6-P receptor and the cation-dependent mannose-6-P receptor. Both receptors regulate the transport of lysosomal enzymes from the trans-Golgi to a prelysosomal compartment and the cell surface [38][39][40]. Further work will have the challenge of identifying the structures that interact with hexose-6-P and control the cellular location of glucose transporters.…”

Serine phosphorylation site of the 46-kDa mannose 6-phosphate receptor is required for transport to the plasma membrane in Madin-Darby canine kidney and mouse fibroblast cells.

“…Because both the transport kinetics of MPR46 cycling via apical and basolateral membranes and their transcellular transport rates are unknown, it is not possible to conclude from the present data whether the MPR46 is preferentially transported to the basolateral surface. Since MPR46 present at the cell surface is not capable of binding and uptake of lysosomal enzymes (Stein et al, 1987b), its function at the cell surface is still unclear.…”

“…Small fractions of both MPRs are * Corresponding author. transported to the plasma membrane where only the MPR300 mediates the endocytosis of both exogenous lysosomal enzymes and the nonglycosylated insulinlike growth factor II for delivery to lysosomes via the endocytic pathway. The MPR46 does not function in endocytosis of lysosomal enzymes (Stein et al, 1987b), which might be due to the slightly acidic pH required for efficient ligand binding. Both MPRs recycle from the plasma membrane to the TGN and exchange continuously with MPRs in all of the compartments (Braulke, 1996).…”