title: Context-dependent switch in chemo/mechanotransduction via multilevel crosstalk among cytoskeleton-regulated MRTF and TAZ and TGFβ-regulated Smad3.
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.
authors.affiliation: Keenan Research Centre for Biomedical Science of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1T8.
authors.forename: Pam
authors.initials: P
authors.lastname: Speight
authors.affiliation: Keenan Research Centre for Biomedical Science of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1T8.
authors.forename: Michael
authors.initials: M
authors.lastname: Kofler
authors.affiliation: Keenan Research Centre for Biomedical Science of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1T8.|Department Surgery, University of Toronto, Toronto, Ontario, Canada M5P 1T5.
authors.forename: Katalin
authors.initials: K
authors.lastname: Szászi
authors.affiliation: Keenan Research Centre for Biomedical Science of St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1T8.|Department Surgery, University of Toronto, Toronto, Ontario, Canada M5P 1T5.|Department Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: András
authors.initials: A
authors.lastname: Kapus
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018374:LLC-PK1 Cells; D040542:Mechanotransduction, Cellular; D020239:Receptor Cross-Talk; D051900:Smad3 Protein / Q000378:metabolism*; D013552:Swine; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000199:Actins; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta