BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways

Vinicio A. De Jesus Perez, Ziad Ali, Tero Pekka Alastalo, Fumiaki Ikeno, Hirofumi Sawada, Ying Ju Lai, Thomas Kleisli, Edda Spiekerkoetter, Xiumei Qu, Laura H. Rubinos, Euan Ashley, Manuel Amieva, Shoukat Dedhar, Marlene Rabinovitch

Research output: Contribution to journalArticle

53 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)171-188
Number of pages18
JournalJournal of Cell Biology
Volume192
Issue number1
DOIs
StatePublished - Jan 10 2011

ASJC Scopus subject areas

  • Cell Biology

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