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 language | English |
|---|---|
| Pages (from-to) | 481-493 |
| Number of pages | 13 |
| Journal | EMBO Journal |
| Volume | 31 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 18-01-2012 |
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All Science Journal Classification (ASJC) codes
- Neuroscience(all)
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
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MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis. / Hosono, Yasuyuki; Yamaguchi, Tomoya; Mizutani, Eri; Yanagisawa, Kiyoshi; Arima, Chinatsu; Tomida, Shuta; Shimada, Yukako; Hiraoka, Michiyo; Kato, Seiichi; Yokoi, Kohei; Suzuki, Motoshi; Takahashi, Takashi.
In: EMBO Journal, Vol. 31, No. 2, 18.01.2012, p. 481-493.Research output: Contribution to journal › Article
TY - JOUR
T1 - MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis
AU - Hosono, Yasuyuki
AU - Yamaguchi, Tomoya
AU - Mizutani, Eri
AU - Yanagisawa, Kiyoshi
AU - Arima, Chinatsu
AU - Tomida, Shuta
AU - Shimada, Yukako
AU - Hiraoka, Michiyo
AU - Kato, Seiichi
AU - Yokoi, Kohei
AU - Suzuki, Motoshi
AU - Takahashi, Takashi
PY - 2012/1/18
Y1 - 2012/1/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84857189404&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857189404&partnerID=8YFLogxK
U2 - 10.1038/emboj.2011.416
DO - 10.1038/emboj.2011.416
M3 - Article
C2 - 22085929
AN - SCOPUS:84857189404
VL - 31
SP - 481
EP - 493
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 2
ER -