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MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis
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MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis
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Journal Article
MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis
2012
Overview
Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of
myosin binding protein H
(
MYBPH
) as a transcriptional target of
TTF‐1
(also known as
NKX2‐1 and TITF1
), a master regulator of lung development that also plays a role as a lineage‐survival oncogene in lung adenocarcinoma development. MYBPH inhibited assembly competence‐conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK), unexpectedly through its direct physical interaction with Rho kinase 1 (ROCK1) rather than with RLC. Consequently, MYBPH inhibited ROCK1 and negatively regulated actomyosin organization, which in turn reduced single cell motility and increased collective cell migration, resulting in decreased cancer invasion and metastasis. Finally, we also show that
MYBPH
is epigenetically inactivated by promoter DNA methylation in a fraction of
TTF‐1
‐positive lung adenocarcinomas, which appears to be in accordance with its deleterious functions in lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of
TTF‐1
expression with favourable prognosis in lung adenocarcinoma patients.
The TTF‐1 transcription factor is upregulated in lung adenocarcinomas, where it apparently suppresses malignant progression. One of its targets, MYBPH, inhibits Rho kinase 1 and hence cell motility and invasion, providing a potential explanation for the protective function of TTF‐1.
Publisher
John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ Animals
/ Cytoskeletal Proteins - physiology
/ DNA
/ DNA-Binding Proteins - antagonists & inhibitors
/ DNA-Binding Proteins - physiology
/ Dogs
/ EMBO05
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Kidney
/ Myosin Light Chains - metabolism
/ Neoplasm Metastasis - physiopathology
/ Promoter Regions, Genetic - genetics
/ Protein Processing, Post-Translational
/ rho-Associated Kinases - antagonists & inhibitors
/ rho-Associated Kinases - physiology
/ ROCK1
