LR11, an LDL receptor gene family member, is a novel regulator of smooth muscle cell migration.
LR11, a member of the LDL receptor family, is highly expressed in vascular smooth muscle cells (SMCs) of the hyperplastic intima, and induces enhanced migration of SMCs in vitro via its upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. In this study, we have delineated the mechanism by which LR11 elevates the expression levels of uPAR in SMCs. Secretion of soluble LR11 is induced in SMCs during the rapidly proliferating phase, and the secreted LR11 induces the migration activities of SMCs. Both the cell-anchored and secreted forms of LR11 have the capacity to bind to and form complexes with uPAR. LR11-overexpressing cells show significantly enhanced uPAR binding, but decreased uPAR internalization. LR11 colocalizes with uPAR on the cell surface and inhibits the LDL receptor-related protein (LRP)-mediated binding and internalization of uPAR. Thus, LR11 mediates the uPAR localization to the plasma membrane. LR11 is highly expressed in the atheromatous plaque areas of apoE knockout mice, particularly in the intimal SMCs at the border between intima and media. The neutralization of LR11 function with anti-LR11 antibody reduced cuff-induced intimal thickness in mice. The novel mechanism of regulation of uPAR localization in SMCs accompanied with enhanced migration activity possibly constitutes an important factor in the process of atherosclerosis and arterial remodeling.
Zhu
Yanjuan
Y
Department of Clinical Cell Biology (F5), Chiba University Graduate School of Medicine,Chiba, Japan.
Bujo
Hideaki
H
Yamazaki
Hiroyuki
H
Ohwaki
Kenji
K
Jiang
Meizi
M
Hirayama
Satoshi
S
Kanaki
Tatsuro
T
Shibasaki
Manabu
M
Takahashi
Kazuo
K
Schneider
Wolfgang J
WJ
Saito
Yasushi
Y
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D019556:COS Cells; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology; D002522:Chlorocebus aethiops; D003094:Collagen; D017077:Culture Media, Conditioned / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004705:Endocytosis; D008024:Ligands; D008565:Membrane Proteins / Q000502:physiology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012995:Solubility; D014162:Transfection
D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D018076:DNA, Complementary; D008024:Ligands; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; C491168:Sorl1 protein, mouse; D003094:Collagen