Abstract
We present a novel cell-signaling paradigm in which bone morphogenetic protein 2 (BMP-2) consecutively and interdependently activates the wingless (Wnt)-β-catenin (βC) and Wnt-planar cell polarity (PCP) signaling pathways to facilitate vascular smooth muscle motility while simultaneously suppressing growth. We show that BMP-2, in a phospho-Akt-dependent manner, induces βC transcriptional activity to produce fibronectin, which then activates integrin-linked kinase 1 (ILK-1) via α4-integrins. ILK-1 then induces the Wnt-PCP pathway by binding a proline-rich motif in disheveled (Dvl) and consequently activating RhoA-Rac1-mediated motility. Transfection of a Dvl mutant that binds βC without activating RhoA-Rac1 not only prevents BMP-2-mediated vascular smooth muscle cell motility but promotes proliferation in association with persistent βC activity. Interfering with the Dvl-dependent Wnt-PCP activation in a murine stented aortic graft injury model promotes extensive neointima formation, as shown by optical coherence tomography and histopathology. We speculate that, in response to injury, factors that subvert BMP-2-mediated tandem activation of Wnt-βC and Wnt-PCP pathways contribute to obliterative vascular disease in both the systemic and pulmonary circulations.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Aorta / drug effects
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Aorta / transplantation
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Axin Protein
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Becaplermin
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Bone Morphogenetic Protein 2 / pharmacology*
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Bone Morphogenetic Protein Receptors, Type II / metabolism
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Cell Movement / drug effects*
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Cell Proliferation / drug effects
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Dishevelled Proteins
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Enzyme Activation / drug effects
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Fibronectins / metabolism
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Mice
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Models, Biological
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Mutant Proteins / metabolism
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Myocytes, Smooth Muscle / cytology*
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Myocytes, Smooth Muscle / drug effects*
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Myocytes, Smooth Muscle / enzymology
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Neointima / pathology
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Phosphoproteins / metabolism
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Platelet-Derived Growth Factor / pharmacology
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-sis
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Repressor Proteins / metabolism
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Signal Transduction / drug effects*
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Wnt Proteins / metabolism*
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beta Catenin / metabolism
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rac1 GTP-Binding Protein / metabolism
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rhoA GTP-Binding Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Axin Protein
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Bone Morphogenetic Protein 2
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Dishevelled Proteins
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Fibronectins
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Mutant Proteins
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Phosphoproteins
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Repressor Proteins
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Wnt Proteins
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beta Catenin
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Becaplermin
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integrin-linked kinase
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Glycogen Synthase Kinase 3 beta
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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BMPR2 protein, human
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Bone Morphogenetic Protein Receptors, Type II
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rac1 GTP-Binding Protein
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rhoA GTP-Binding Protein