Elevated transforming growth factor β signaling activation in β-actin-knockout mouse embryonic fibroblasts enhances myofibroblast features

Research output: Contribution to journalArticle

Abstract

Signaling by the transforming growth factor-β (TGF-β) is an essential pathway regulating a variety of cellular events. TGF-β is produced as a latent protein complex and is required to be activated before activating the receptor. The mechanical force at the cell surface is believed to be a mechanism for latent TGF-β activation. Using β-actin null mouse embryonic fibroblasts as a model, in which actin cytoskeleton and cell-surface biophysical features are dramatically altered, we reveal increased TGF-β1 activation and the upregulation of TGF-β target genes. In β-actin null cells, we show evidence that the enhanced TGF-β signaling relies on the active utilization of latent TGF-β1 in the cell culture medium. TGF-β signaling activation contributes to the elevated reactive oxygen species production, which is likely mediated by the upregulation of Nox4. The previously observed myofibroblast phenotype of β-actin null cells is inhibited by TGF-β signaling inhibition, while the expression of actin cytoskeleton genes and angiogenic phenotype are not affected. Together, our study shows a scenario that the alteration of the actin cytoskeleton and the consequent changes in cellular biophysical features lead to changes in cell signaling process such as TGF-β activation, which in turn contributes to the enhanced myofibroblast phenotype.

Original languageEnglish (US)
Pages (from-to)8884-8895
Number of pages12
JournalJournal of Cellular Physiology
Volume233
Issue number11
DOIs
StatePublished - Nov 2018

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Keywords

  • NADPH oxidase 4 (Nox4)
  • TGF-β
  • mouse embryonic fibroblast (MEF)
  • myofibroblast
  • reactive oxygen species (ROS)
  • β-actin

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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