title: 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.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Hosono
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Eri
authors.initials: E
authors.lastname: Mizutani
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Arima
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.forename: Yukako
authors.initials: Y
authors.lastname: Shimada
authors.forename: Michiyo
authors.initials: M
authors.lastname: Hiraoka
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kato
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoi
authors.forename: Motoshi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000205:Actomyosin / Q000378:metabolism; D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D048430:Cell Shape; D018899:CpG Islands / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000502:physiology*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004285:Dogs; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney; D008175:Lung Neoplasms / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors; D015533:Transcriptional Activation; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C484119:MYBPH protein, human; D018994:Myosin Light Chains; C504003:TTF1 protein, human; D014157:Transcription Factors; D000205:Actomyosin; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases
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