The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1.
Although plasminogen activator inhibitor-1 (PAI-1) is known to stimulate cell migration, little is known about underlying mechanisms. We show that both active and inactive (e.g. cleaved) PAI-1 can activate the Jak/Stat signaling system and stimulate cell migration in chemotaxis, haptotaxis, chemokinesis, and wound healing assays. Moreover, antibodies to the LDL receptor-related protein (LRP) and an LRP antagonist (RAP) blocked these motogenic effects of PAI-1, while a PAI-1 mutant that did not bind to LRP failed to activate the Jak/Stat signaling pathway or to stimulate cell migration. PAI-1 had no chemotactic effect on LRP-deficient cells. These results indicate that LRP is a signaling molecule, that it mediates the migration-promoting activity of PAI-1, and that this activity does not require intact, biologically active PAI-1. Activation of this LRP-dependent signaling pathway by PAI-1 may begin to explain how the inhibitor stimulates cell migration in a variety of normal and pathological processes.
Department of Cell Biology, The Scripps Research Institute, VB-3, La Jolla, California 92037, USA.
Bernard
B
Degryse
Jaap G
JG
Neels
Ralf-Peter
RP
Czekay
Kathleen
K
Aertgeerts
Yu-Ichi
Y
Kamikubo
David J
DJ
Loskutoff
D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D003599:Cytoskeleton / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000502:physiology*; D008856:Microscopy, Fluorescence; D009154:Mutation; D019000:Phosphotyrosine / Q000737:chemistry; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry; D014945:Wound Healing
D000199:Actins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D017395:Plasminogen Activator Inhibitor 1; D019000:Phosphotyrosine; D014443:Tyrosine