Nuclear actin regulates cell proliferation and migration via inhibition of SRF and TEAD

Madeleine C McNeill, Jason Wray, Graciela B Sala-Newby, Charles C T Hindmarch, Sarah A Smith, Reza Ebrahimighaei, Andrew C Newby, Mark Bond

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Abstract

Actin dynamics regulate cell behaviour in response to physiological signals. Here we demonstrate a novel role for nuclear actin in inhibiting cell proliferation and migration. We demonstrate that physiological signals that elevate cAMP, which is anti-mitogenic in vascular smooth muscle cells, increases nuclear actin monomer levels. Expression of a nuclear-targeted polymerisation-defective actin mutant (NLS-ActinR62D) inhibited proliferation and migration. Preventing nuclear actin monomer accumulation by enhancing its nuclear export or polymerisation reversed the anti-mitogenic and anti-migratory effects of cAMP. Transcriptomic analysis identified repression of proliferation and migration associated genes regulated by serum response factor (SRF) and TEA Domain (TEAD) transcription factors. Accordingly, NLS-ActinR62D inhibited SRF and TEAD activity and target gene expression, and these effects were reversed by constitutively-active mutants of the TEAD and SRF co-factors YAP, TAZ and MKL1. In summary, intranuclear actin inhibits proliferation and migration by inhibiting YAP-TEAD and MKL-SRF activity. This mechanism explains the anti-mitogenic and anti-migratory properties of physiological signals that elevate cAMP.
Original languageEnglish
Article number118691
Number of pages16
JournalBiochimica et Biophysica Acta (BBA) - Molecular Cell Research
Volume1867
Issue number7
Early online date28 Feb 2020
DOIs
Publication statusPublished - 1 Jul 2020

Keywords

  • Actin
  • nuclear
  • cAMP
  • proliferation
  • migration
  • YAP
  • TEAD
  • SRF

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