TY - JOUR
T1 - BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways
AU - De Jesus Perez, Vinicio A.
AU - Ali, Ziad
AU - Alastalo, Tero Pekka
AU - Ikeno, Fumiaki
AU - Sawada, Hirofumi
AU - Lai, Ying Ju
AU - Kleisli, Thomas
AU - Spiekerkoetter, Edda
AU - Qu, Xiumei
AU - Rubinos, Laura H.
AU - Ashley, Euan
AU - Amieva, Manuel
AU - Dedhar, Shoukat
AU - Rabinovitch, Marlene
PY - 2011/1/10
Y1 - 2011/1/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78651341882&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78651341882&partnerID=8YFLogxK
U2 - 10.1083/jcb.201008060
DO - 10.1083/jcb.201008060
M3 - Article
C2 - 21220513
AN - SCOPUS:78651341882
SN - 0021-9525
VL - 192
SP - 171
EP - 188
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 1
ER -