The cytoplasmic tail of the mannose 6-phosphate/insulin-like growth factor-II receptor has two signals for lysosomal enzyme sorting in the Golgi.
The mannose 6-phosphate/insulin-like growth factor-II (Man-6-P/IGF-II) receptor is known to cycle between the Golgi, endosomes, and the plasma membrane. In the Golgi the receptor binds newly synthesized lysosomal enzymes and transports them directly to an endosomal (prelysosomal) compartment without traversing the plasma membrane. Deletion of the carboxyl-terminal Leu-Leu-His-Val residues of the 163 amino acid cytoplasmic tail of the bovine Man-6-P/IGF-II receptor partially impaired this function, resulting in the diversion of a portion of the receptor-ligand complexes to the cell surface, where they were endocytosed. The same phenotype was observed when 134 residues of the cytoplasmic tail were deleted from the carboxyl terminus. Disruption of the Tyr24-Lys-Tyr-Ser-Lys-Val29 plasma membrane internalization signal alone had little effect on Golgi sorting, but when combined with either deletion resulted in a complete loss of this function. The mutant receptors retained the ability to recycle to the Golgi and bind cathepsin D. These results indicate that the cytoplasmic tail of the Man-6-P/IGF-II receptor contains two signals that contribute to Golgi sorting, presumably by interacting with the Golgi clathrin-coated pit adaptor proteins. The Leu-Leu-containing sequence represents a novel motif for mediating interaction with Golgi adaptor proteins.
Johnson
K F
KF
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Kornfeld
S
S
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D002402:Cathepsin D / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D004705:Endocytosis / Q000502:physiology; D006056:Golgi Apparatus / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II; D007739:L Cells; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism*; D008360:Mannosephosphates; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D010766:Phosphorylation; D021382:Protein Sorting Signals / Q000235:genetics / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine
D008024:Ligands; D008360:Mannosephosphates; D021382:Protein Sorting Signals; D017451:Receptors, Somatomedin; C027693:mannose-6-phosphate; D014443:Tyrosine; D007335:Insulin-Like Growth Factor II; D002402:Cathepsin D