MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis
MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis
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DOI：
10.1038/emboj.2011.416
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发表时间：
2012-01-18
期刊：
影响因子：
11.4
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
--
作者：
Hosono, Yasuyuki;Yamaguchi, Tomoya;Takahashi, Takashi
肌动球蛋白丝组装驱动的细胞迁移是肿瘤侵袭和转移的关键步骤。在此，我们报告了肌球蛋白结合蛋白H（MYBPH）作为TTF-1（也称为NKX 2 -1和TITF 1）的转录靶点的鉴定，TTF-1是肺发育的主要调节因子，在肺腺癌的发展中也起着谱系存活癌基因的作用。MYBPH抑制了肌球蛋白调节轻链（RLC）的组装能力赋予磷酸化以及LIM结构域激酶（LIMK）的激活磷酸化，出乎意料地通过其与Rho激酶1（ROCK 1）而不是与RLC的直接物理相互作用。因此，MYBPH抑制ROCK 1并负调节肌动球蛋白组织，这反过来又降低了单个细胞的运动性并增加了集体细胞迁移，从而降低了癌症的侵袭和转移。最后，我们还表明，MYBPH是表观遗传失活的启动子DNA甲基化的一部分TTF-1阳性肺腺癌，这似乎是根据其有害的功能，肺腺癌的侵袭和转移，以及与矛盾的关联TTF-1表达与肺腺癌患者的良好预后。The EMBO Journal（2012）31，481-493. doi：10.1038/daj.2011.416; 2011年11月15日在线发布
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. The EMBO Journal (2012) 31, 481-493. doi:10.1038/emboj.2011.416; Published online 15 November 2011