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MYBPH, a transcriptional target of TTF‐1, inhibits ROCK1, and reduces cell motility and metastasis
Author(s) -
Hosono Yasuyuki,
Yamaguchi Tomoya,
Mizutani Eri,
Yanagisawa Kiyoshi,
Arima Chinatsu,
Tomida Shuta,
Shimada Yukako,
Hiraoka Michiyo,
Kato Seiichi,
Yokoi Kohei,
Suzuki Motoshi,
Takahashi Takashi
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.416
Subject(s) - biology , rock1 , motility , metastasis , microbiology and biotechnology , cancer research , genetics , kinase , protein kinase a , cancer
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.