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

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.

• Authors: Yasuyuki Hosono, Tomoya Yamaguchi, Eri Mizutani, Kiyoshi Yanagisawa, Chinatsu Arima, Shuta Tomida, Yukako Shimada, Michiyo Hiraoka, Seiichi Kato, Kohei Yokoi, Motoshi Suzuki, Takashi Takahashi
• Journal: The EMBO journal (EMBO J) Vol. 31 Issue 2 Pg. 481-93 (Jan 18 2012) ISSN: 1460-2075 [Electronic] England
• PMID: 22085929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytoskeletal Proteins
• DNA-Binding Proteins
• MYBPH protein, human
• Myosin Light Chains
• TTF1 protein, human
• Transcription Factors
• Actomyosin
• ROCK1 protein, human
• rho-Associated Kinases

Topics

• 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, 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, physiology)