Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation.
Vascular smooth muscle cell (VSMC) proliferation is an important event in atherosclerosis and other vasculopathies. PDGF signaling is a key mediator of SMC proliferation, but the mechanisms that control its activity remain unclear. We previously identified a mutation in LDL receptor-related protein 6 (LRP6), LRP6(R611C), that causes early atherosclerosis. Examination of human atherosclerotic coronary arteries showed markedly increased expression of LRP6 and colocalization with PDGF receptor β (PDGFR-β). Further investigation showed that wild-type LRP6 inhibits but LRP6(R611C) promotes VSMC proliferation in response to PDGF. We found that wild-type LRP6 forms a complex with PDGFR-β and enhances its lysosomal degradation, functions that are severely impaired in LRP6(R611C). Further, we observed that wild-type and mutant LRP6 regulate cell-cycle activity by triggering differential effects on PDGF-dependent pathways. These findings implicate LRP6 as a critical modulator of PDGF-dependent regulation of cell cycle in smooth muscle and indicate that loss of this function contributes to development of early atherosclerosis in humans.
Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Ali R
AR
Keramati
Rajvir
R
Singh
Aiping
A
Lin
Saeed
S
Faramarzi
Zhi-jia
ZJ
Ye
Shrikant
S
Mane
George
G
Tellides
Richard P
RP
Lifton
Arya
A
Mani
D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D026502:LDL-Receptor Related Proteins / Q000502:physiology*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D015398:Signal Transduction
D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D019938:Cyclin D1; D020797:Receptor, Platelet-Derived Growth Factor beta
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