Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly

Anthony Wayne Orr, Claudio E. Pedraza, Manuel Antonio Pallero, Carrie A. Elzie, Silvia Goicoechea, Dudley K. Strickland, Joanne E. Murphy-Ullrich

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

Thrombospondin (TSP) signals focal adhesion disassembly (the intermediate adhesive state) through interactions with cell surface calreticulin (CRT). TSP or a peptide (hep I) of the active site induces focal adhesion disassembly through binding to CRT, which activates phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinase (ERK) through Gαi2 proteins. Because CRT is not a transmembrane protein, it is likely that CRT signals as part of a coreceptor complex. We now show that low density lipoprotein receptor-related protein (LRP) mediates focal adhesion disassembly initiated by TSP binding to CRT. LRP antagonists (antibodies, receptor-associated protein) block hep I/TSP-induced focal adhesion disassembly. LRP is necessary for TSP/hep I signaling because TSP/hep I is unable to stimulate focal adhesion disassembly or ERK or PI3K signaling in fibroblasts deficient in LRP. LRP is important in TSP-CRT signaling, as shown by the ability of hep I to stimulate association of Gαi2 with LRP. The isolated proteins LRP and CRT interact, and LRP and CRT are associated with hep I in molecular complexes extracted from cells. These data establish a mechanism of cell surface CRT signaling through its coreceptor, LRP, and suggest a novel function for LRP in regulating cell adhesion.

Original languageEnglish (US)
Pages (from-to)1179-1189
Number of pages11
JournalJournal of Cell Biology
Volume161
Issue number6
DOIs
StatePublished - Jun 23 2003

Keywords

  • Cell adhesion
  • ERK
  • Focal adhesions
  • G proteins
  • Thrombospondin

ASJC Scopus subject areas

  • Cell Biology

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