Internalization but not binding of thrombospondin-1 to low density lipoprotein receptor-related protein-1 requires heparan sulfate proteoglycans

Shuxia Wang, Mary E. Herndon, Sripriya Ranganathan, Svetlana Godyna, Jack Lawler, W. Scott Argraves, Gene Liau

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

The amino-terminal domain of the extracellular matrix (ECM) protein thrombospondin-1 (TSP-1) mediates binding to cell surface heparan sulfate proteoglycans (HSPG) as well as binding to the endocytic receptor, low density lipoprotein-related protein (LRP-1). We previously found that recombinant TSP-1 containing the amino-terminal residues 1-214, retained both of these interactions (Mikhailenko et al. [1997]: J Biol Chem 272:6784-6791). Here, we examined the activity of a recombinant protein containing amino-terminal residues 1-90 of TSP-1 and found that this domain did not retain high-affinity heparin-binding. The loss of heparin-binding correlated with decreased binding to the fibroblast cell surface. However, both ligand blotting and solid phase binding studies indicate that this truncated fragment of TSP-1 retained high-affinity binding to LRP-1. Consistent with this, it also retained the ability to block the uptake and degradation of 125I-TSP-1. However, TSP-11-90 itself was poorly endocytosed and this truncated amino-terminal domain was considerably more effective than the full-length heparin-binding domain (HBD) of TSP-1 in blocking the catabolism of endogenously expressed TSP-1. These results indicate that TSP-1 binding to LRP-1 does not require prior or concomitant interaction with cell surface HSPG but suggest subsequent endocytosis requires high-affinity heparin-binding.

Original languageEnglish
Pages (from-to)766-776
Number of pages11
JournalJournal of Cellular Biochemistry
Volume91
Issue number4
DOIs
StatePublished - 2004

Keywords

  • Endocytosis
  • Heparan sulfate proteoglycan
  • Heparin-binding domain
  • Low density lipoprotein-related protein
  • Thrombospondin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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