Cellular uptake of saposin (SAP) precursor and lysosomal delivery by the low density lipoprotein receptor-related protein (LRP)

Sphingolipid activator proteins SAP‐A, ‐B, ‐C and ‐D (also called saposins) are generated by proteolytic processing from a 73 kDa precursor and function as obligatory activators of lysosomal enzymes involved in glycosphingolipid metabolism. Although the SAP precursor can be recognized by the mannose...

Full description

Saved in:
Bibliographic Details
Published in:The EMBO journal 1998-08, Vol.17 (16), p.4617-4625
Main Authors: Hiesberger, Thomas, Hüttler, Silke, Rohlmann, Astrid, Schneider, Wolfgang, Sandhoff, Konrad, Herz, Joachim
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell Line
DNA Primers
Endocytosis
Glycoproteins - metabolism
Humans
lipoprotein receptor-related protein
Low Density Lipoprotein Receptor-Related Protein-1
Lysosomes - metabolism
mannose-6-phosphate
Mice
Protein Precursors - genetics
Protein Precursors - metabolism
Receptors, Cell Surface - metabolism
Receptors, Immunologic - metabolism
Receptors, LDL - metabolism
saposin
Signal Transduction
sphingolipid
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Sphingolipid activator proteins SAP‐A, ‐B, ‐C and ‐D (also called saposins) are generated by proteolytic processing from a 73 kDa precursor and function as obligatory activators of lysosomal enzymes involved in glycosphingolipid metabolism. Although the SAP precursor can be recognized by the mannose‐6‐phosphate (M‐6‐P) receptor and shuttled directly from the secretory pathway to the lysosome, a substantial fraction of newly synthesized precursor is secreted from the cell where it may participate in sphingolipid transport and signaling events. Re‐uptake of the secreted precursor is mediated by high‐affinity cell surface receptors that are apparently distinct from the M‐6‐P receptor. We found that the low density lipoprotein receptor‐related protein (LRP), a multifunctional endocytic receptor that is expressed on most cells, can mediate cellular uptake and lysosomal delivery of SAP precursor. Additional in vivo experiments in mice revealed that the mannose receptor system on macrophages also participates in precursor internalization. We conclude that SAP precursor gains entry into cells by at least three independent receptor mechanisms including the M‐6‐P receptor, the mannose receptor and LRP.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/17.16.4617