Cell contact-dependent regulation of epithelial-myofibroblast transition via the Rho-Rho kinase-phospho-myosin pathway

Lingzhi Fan, Attila Sebe, Zalán Péterfi, András Masszi, Ana C.P. Thirone, Ori D. Rotstein, Hiroyasu Nakano, Christopher A. McCulloch, Katalin Szászi, István Mucsi, András Kapus

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133 Citations (Scopus)

Abstract

Epithelial-mesenchymal-myofibroblast transition (EMT), a key feature in organ fibrosis, is regulated by the state of intercellular contacts. Our recent studies have shown that an initial injury of cell-cell junctions is a prerequisite for transforming growth factor-β1 (TGF-β1)-induced transdifferentiation of kidney tubular cells into α-smooth muscle actin (SMA)-expressing myofibroblasts. Here we analyzed the underlying contact-dependent mechanisms. Ca2+ removal-induced disruption of intercellular junctions provoked Rho/Rho ldnase (ROK)-mediated myosin light chain (MLC) phosphorylation and Rho/ROK-dependent SMA promoter activation. Importantly, myosin-based contractility itself played a causal role, because the myosin ATPase inhibitor blebbistatin or a nonphosphorylatable, dominant negative MLC (DN-MLC) abolished the contact disruption-triggered SMA promoter activation, eliminated the synergy between contact injury and TGF-β1, and suppressed SMA expression. To explore the responsible mechanisms, we investigated the localization of the main SMA-inducing transcription factors, serum response factor (SRF), and its coactivator myocardin-related transcription factor (MRTF). Contact injury enhanced nuclear accumulation of SRF and MRTF. These processes were inhibited by DN-Rho or DN-MLC. TGf-β1 strongly facilitated nuclear accumulation of MRTF in cells with reduced contacts but not in intact epithelia. DN-myocardin abrogated the Ca2+-removal- ± TGF-β1-induced promoter activation. These studies define a new mechanism whereby cell contacts regulate epithelial-myofibroblast transition via Rho-ROK-phospho-MLC-dependent nuclear accumulation of MRTF.

Original languageEnglish
Pages (from-to)1083-1097
Number of pages15
JournalMolecular Biology of the Cell
Volume18
Issue number3
DOIs
Publication statusPublished - Mar 1 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Fan, L., Sebe, A., Péterfi, Z., Masszi, A., Thirone, A. C. P., Rotstein, O. D., Nakano, H., McCulloch, C. A., Szászi, K., Mucsi, I., & Kapus, A. (2007). Cell contact-dependent regulation of epithelial-myofibroblast transition via the Rho-Rho kinase-phospho-myosin pathway. Molecular Biology of the Cell, 18(3), 1083-1097. https://doi.org/10.1091/mbc.E06-07-0602