RRC ID 18552
著者 Hosono Y, Yamaguchi T, Mizutani E, Yanagisawa K, Arima C, Tomida S, Shimada Y, Hiraoka M, Kato S, Yokoi K, Suzuki M, Takahashi T.
タイトル MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis.
ジャーナル EMBO J
Abstract 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.
巻・号 31(2)
ページ 481-93
公開日 2012-1-18
DOI 10.1038/emboj.2011.416
PII emboj2011416
PMID 22085929
PMC PMC3261566
MeSH Actomyosin / metabolism Adenocarcinoma / pathology Animals Cell Line Cell Line, Tumor Cell Movement / physiology Cell Shape CpG Islands / genetics Cytoskeletal Proteins / physiology* DNA Methylation DNA-Binding Proteins / antagonists & inhibitors DNA-Binding Proteins / physiology* Dogs Gene Expression Regulation, Neoplastic* Humans Kidney Lung Neoplasms / pathology Myosin Light Chains / metabolism Neoplasm Invasiveness Neoplasm Metastasis / physiopathology* Phosphorylation Promoter Regions, Genetic / genetics Protein Processing, Post-Translational Transcription Factors Transcriptional Activation* rho-Associated Kinases / antagonists & inhibitors* rho-Associated Kinases / physiology
IF 9.889
引用数 59
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
リソース情報
ヒト・動物細胞 MDCK(RCB0995)