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Mol Biol Cell. 2011 Dec;22(23):4472-85. doi: 10.1091/mbc.E11-04-0335. Epub 2011 Sep 30.

β-catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial-myofibroblast transition.

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1
Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada.

Abstract

Injury to the adherens junctions (AJs) synergizes with transforming growth factor-β1 (TGFβ) to activate a myogenic program (α-smooth muscle actin [SMA] expression) in the epithelium during epithelial-myofibroblast transition (EMyT). Although this synergy plays a key role in organ fibrosis, the underlying mechanisms have not been fully defined. Because we recently showed that Smad3 inhibits myocardin-related transcription factor (MRTF), the driver of the SMA promoter and many other CC(A/T)-rich GG element (CArG) box-dependent cytoskeletal genes, we asked whether AJ components might affect SMA expression through interfering with Smad3. We demonstrate that E-cadherin down-regulation potentiates, whereas β-catenin knockdown inhibits, SMA expression. Contact injury and TGFβ enhance the binding of β-catenin to Smad3, and this interaction facilitates MRTF signaling by two novel mechanisms. First, it inhibits the Smad3/MRTF association and thereby allows the binding of MRTF to its myogenic partner, serum response factor (SRF). Accordingly, β-catenin down-regulation disrupts the SRF/MRTF complex. Second, β-catenin maintains the stability of MRTF by suppressing the Smad3-mediated recruitment of glycogen synthase kinase-3β to MRTF, an event that otherwise leads to MRTF ubiquitination and degradation and the consequent loss of SRF/MRTF-dependent proteins. Thus β-catenin controls MRTF-dependent transcription and emerges as a critical regulator of an array of cytoskeletal genes, the "CArGome."

PMID:
21965288
PMCID:
PMC3226468
DOI:
10.1091/mbc.E11-04-0335
[Indexed for MEDLINE]
Free PMC Article
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