Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly.
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 Galphai2 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 Galphai2 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.
Orr
Anthony Wayne
AW
Department of Pathology, Division of Molecular and Cellular Pathology and The Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, VH 668 1530, 3rd Ave. South, Birmingham, AL 35294-0019, USA.
Pedraza
Claudio E
CE
Pallero
Manuel Antonio
MA
Elzie
Carrie A
CA
Goicoechea
Silvia
S
Strickland
Dudley K
DK
Murphy-Ullrich
Joanne E
JE
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D037282:Calreticulin / Q000378:metabolism*; D002417:Cattle; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D005057:Eukaryotic Cells / Q000378:metabolism*; D022001:Focal Adhesions / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000502:physiology; D019699:Thrombospondins / Q000378:metabolism*
D000906:Antibodies; D037282:Calreticulin; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011993:Recombinant Fusion Proteins; D019699:Thrombospondins; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases