| RRC ID |
18552
|
| Author |
Hosono Y, Yamaguchi T, Mizutani E, Yanagisawa K, Arima C, Tomida S, Shimada Y, Hiraoka M, Kato S, Yokoi K, Suzuki M, Takahashi T.
|
| Title |
MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis.
|
| Journal |
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.
|
| Volume |
31(2)
|
| Pages |
481-93
|
| Published |
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
|
| Times Cited |
59
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| Resource |
| Human and Animal Cells |
MDCK(RCB0995) |
