MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis

Yasuyuki Hosono, Tomoya Yamaguchi, Eri Mizutani, Kiyoshi Yanagisawa, Chinatsu Arima, Shuta Tomida, Yukako Shimada, Michiyo Hiraoka, Seiichi Kato, Kohei Yokoi, Motoshi Suzuki, Takashi Takahashi

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)481-493
Number of pages13
JournalEMBO Journal
Volume31
Issue number2
DOIs
Publication statusPublished - Jan 18 2012

Keywords

  • ROCK1
  • actomyosin
  • cytoskeleton
  • lung cancer

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint Dive into the research topics of 'MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis'. Together they form a unique fingerprint.

  • Cite this

    Hosono, Y., Yamaguchi, T., Mizutani, E., Yanagisawa, K., Arima, C., Tomida, S., Shimada, Y., Hiraoka, M., Kato, S., Yokoi, K., Suzuki, M., & Takahashi, T. (2012). MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis. EMBO Journal, 31(2), 481-493. https://doi.org/10.1038/emboj.2011.416