title: BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways.
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.
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Vinicio A de Jesus
authors.initials: VA
authors.lastname: Perez
authors.forename: Ziad
authors.initials: Z
authors.lastname: Ali
authors.forename: Tero-Pekka
authors.initials: TP
authors.lastname: Alastalo
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ikeno
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Lai
authors.forename: Thomas
authors.initials: T
authors.lastname: Kleisli
authors.forename: Edda
authors.initials: E
authors.lastname: Spiekerkoetter
authors.forename: Xiumei
authors.initials: X
authors.lastname: Qu
authors.forename: Laura H
authors.initials: LH
authors.lastname: Rubinos
authors.forename: Euan
authors.initials: E
authors.lastname: Ashley
authors.forename: Manuel
authors.initials: M
authors.lastname: Amieva
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000637:transplantation; D060466:Axin Protein; D000077214:Becaplermin; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D000072261:Dishevelled Proteins; D004789:Enzyme Activation / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D058426:Neointima / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D000077214:Becaplermin; D055396:Bone Morphogenetic Protein 2; D052006:Bone Morphogenetic Protein Receptors, Type II; D000072261:Dishevelled Proteins; D005353:Fibronectins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D050505:Mutant Proteins; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000099200:Scaffold Protein ILK; C498218:BMPR2 protein, human