1. BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways.
- Author
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Perez VA, Ali Z, Alastalo TP, Ikeno F, Sawada H, Lai YJ, Kleisli T, Spiekerkoetter E, Qu X, Rubinos LH, Ashley E, Amieva M, Dedhar S, and Rabinovitch M
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Animals, Aorta drug effects, Aorta transplantation, Axin Protein, Becaplermin, Bone Morphogenetic Protein Receptors, Type II metabolism, Cell Proliferation drug effects, Dishevelled Proteins, Enzyme Activation drug effects, Fibronectins metabolism, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Humans, Mice, Models, Biological, Mutant Proteins metabolism, Myocytes, Smooth Muscle enzymology, Neointima pathology, Phosphoproteins metabolism, Platelet-Derived Growth Factor pharmacology, Protein Binding drug effects, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-sis, Repressor Proteins metabolism, beta Catenin metabolism, rac1 GTP-Binding Protein metabolism, rhoA GTP-Binding Protein metabolism, Bone Morphogenetic Protein 2 pharmacology, Cell Movement drug effects, Myocytes, Smooth Muscle cytology, Myocytes, Smooth Muscle drug effects, Signal Transduction drug effects, Wnt Proteins metabolism
- 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.
- Published
- 2011
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