Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFβ-regulated Smad3

Nat Commun. 2016 May 18;7:11642. doi: 10.1038/ncomms11642.

Abstract

Myocardin-related transcription factor (MRTF) and TAZ are major mechanosensitive transcriptional co-activators that link cytoskeleton organization to gene expression. Despite many similarities in their regulation, their physical and/or functional interactions are unknown. Here we show that MRTF and TAZ associate partly through a WW domain-dependent mechanism, and exhibit multilevel crosstalk affecting each other's expression, transport and transcriptional activity. Specifically, MRTF is essential for TAZ expression; TAZ and MRTF inhibit each other's cytosolic mobility and stimulus-induced nuclear accumulation; they antagonize each other's stimulatory effect on the α-smooth muscle actin (SMA) promoter, which harbours nearby cis-elements for both, but synergize on isolated TEAD-elements. Importantly, TAZ confers Smad3 sensitivity to the SMA promoter. Thus, TAZ is a context-dependent switch during mechanical versus mechano/chemical signalling, which inhibits stretch-induced but is indispensable for stretch+TGFβ-induced SMA expression. Crosstalk between these cytoskeleton-regulated factors seems critical for fine-tuning mechanical and mechanochemical transcriptional programmes underlying myofibroblast transition, wound healing and fibrogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • LLC-PK1 Cells
  • Mechanotransduction, Cellular*
  • Receptor Cross-Talk
  • Smad3 Protein / metabolism*
  • Swine
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • Actins
  • Smad3 Protein
  • Transcription Factors
  • Transforming Growth Factor beta

Grant support