Abstract |
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.
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Authors | Ali R Keramati, Rajvir Singh, Aiping Lin, Saeed Faramarzi, Zhi-jia Ye, Shrikant Mane, George Tellides, Richard P Lifton, Arya Mani |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 108
Issue 5
Pg. 1914-8
(Feb 01 2011)
ISSN: 1091-6490 [Electronic] United States |
PMID | 21245321
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- LDL-Receptor Related Proteins
- LRP6 protein, human
- Low Density Lipoprotein Receptor-Related Protein-6
- Platelet-Derived Growth Factor
- RNA, Messenger
- Cyclin D1
- Receptor, Platelet-Derived Growth Factor beta
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Topics |
- Atherosclerosis
(pathology, physiopathology)
- Cell Proliferation
- Cyclin D1
(metabolism)
- Humans
- Immunohistochemistry
- LDL-Receptor Related Proteins
(physiology)
- Low Density Lipoprotein Receptor-Related Protein-6
- Muscle, Smooth, Vascular
(cytology)
- Platelet-Derived Growth Factor
(physiology)
- RNA, Messenger
(genetics)
- Receptor, Platelet-Derived Growth Factor beta
(genetics)
- Signal Transduction
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