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Cell contact‐dependent regulation of epithelial‐mesenchymal transition in tubular cells
Author(s) -
Kapus Andras,
Fan Lingzhi,
Peterfi Zalan,
Sebe Attila,
Masszi Andras,
Mucsi Istvan
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a201-d
Subject(s) - serum response factor , myocardin , microbiology and biotechnology , transcription factor , myosin , phosphorylation , myofibroblast , actin , biology , chemistry , fibrosis , medicine , biochemistry , gene
Epithelial‐mesenchymal transition (EMT) of tubular cells into α‐smooth muscle actin (SMA)‐expressing myofibroblasts is a key pathologic feature of kidney fibrosis. Our recent studies have shown that an initial injury of intercellular contacts is a prerequisite for the transforming growth factor‐β (TGFβ)‐induced EMT in LLC‐PK1 proximal tubular cells. Here we analyzed the underlying mechanisms. Disruption of cadherin‐based contacts by Ca 2+ ‐removal induced Rho activation and Rho kinase (ROK)‐mediated myosin light chain (MLC) phosphorylation. Concomitantly, the SMA promoter was stimulated in a ROK‐dependent manner. Moreover, myosin‐based contractility per se played a causal role in the process since both the myosin ATPase inhibitor blebbistatin and a non‐phosphorylatable, dominant negative MLC mutant (DN‐MLC) abrogated SMA promoter activation triggered by Ca 2+ ‐removalin the absence or presence of TGFβ. To address the responsible mechanisms, we investigated the localization of the SMA‐inducing transcription factors, serum response factor (SRF) and myocardin‐related transcription factor (MRTF). Contact injury enhanced nuclear translocation of SRF and MRTF‐B. The latter process was prevented by inhibiting endogenous Rho with p190Rho‐GAP. Moreover, DN‐MLC suppressed the nuclear translocation of SRF and decreased the basal nuclear localization/retention of MRTF‐B. These studies define a new mechanism whereby cell contacts may regulate the SMA promoter via Rho‐ROK‐phospho‐MLC‐dependent nuclear translocation of MRTF and SRF. Support: Kidney Foundation of Canada, and Hungarian Science and Technology Foundation CN‐03‐04