Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration

A. Wayne Orr, Carrie A. Elzie, Dennis F. Kucik, Joanne E. Murphy-Ullrich

Research output: Contribution to journalReview articlepeer-review

138 Scopus citations

Abstract

The matricellular extracellular matrix protein thrombospondin-1 (TSP1) stimulates focal adhesion disassembly through a sequence (known as the hep I peptide) in its heparin-binding domain. This mediates signaling through a receptor co-complex involving calreticulin and low-density lipoprotein (LDL) receptor-related protein (LRP). We postulate that this transition to an intermediate adhesive state enhances cellular responses to dynamic environmental conditions. Since cell adhesion dynamics affect cell motility, we asked whether TSP1/hep I-induced intermediate adhesion alters cell migration. Using both transwell and Dunn chamber assays, we demonstrate that TSP1 and hep I gradients stimulate endothelial cell chemotaxis. Treatment with focal adhesion-labilizing concentrations of TSP1/hep I in the absence of a gradient enhances endothelial cell random migration, or chemokinesis, associated with an increase in cells migrating, migration speed, and total cellular displacement. Calreticulin-null and LRP-null fibroblasts do not migrate in response to TSP1/hep I, nor do endothelial cells treated with the LRP inhibitor receptor-associated protein (RAP). Furthermore, TSP1/hep I-induced focal adhesion disassembly is associated with reduced chemotaxis to basic fibroblast growth factor (bFGF) but enhanced chemotaxis to acidic (a)FGF, suggesting differential modulation of growth factor-induced migration. Thus, TSP1/hep I stimulation of intermediate adhesion regulates the migratory phenotype of endothelial cells and fibroblasts, suggesting a role for TSP1 in remodeling responses.

Original languageEnglish (US)
Pages (from-to)2917-2927
Number of pages11
JournalJournal of cell science
Volume116
Issue number14
DOIs
StatePublished - Jul 15 2003

Keywords

  • Calreticulin
  • Cell migration
  • Focal adhesion
  • LDL receptor-related protein
  • Thrombospondin-1

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration'. Together they form a unique fingerprint.

Cite this