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

Author:

Orr Anthony Wayne1,Pedraza Claudio E.1,Pallero Manuel Antonio1,Elzie Carrie A.1,Goicoechea Silvia1,Strickland Dudley K.2,Murphy-Ullrich Joanne E.1

Affiliation:

1. Department of Pathology, Division of Molecular and Cellular Pathology and the Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, Birmingham, AL 35294

2. Department of Vascular Biology, Holland Laboratory, American Red Cross, Rockville, MD 20855

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.

Publisher

Rockefeller University Press

Subject

Cell Biology

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