期刊
EMBO JOURNAL
卷 31, 期 1, 页码 29-43出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2011.357
关键词
breast cancer; Lats2; Snail1
资金
- NIH [P30 DK52574, P30 CA91842, P41 RR00954, UL1 RR024992, P50CA94056, CA85839, GM080673]
- Ministerio de Ciencia e Innovacion [BFU2008-01042, CSD2007-00017, CSD2007-00023]
- Generalitat Valenciana [Prometeo 2008/049]
- Grants-in-Aid for Scientific Research [23370086, 22570185] Funding Source: KAKEN
Snail1 is a central regulator of epithelial cell adhesion and movement in epithelial-to-mesenchymal transitions (EMTs) during embryo development; a process reactivated during cancer metastasis. While induction of Snail1 transcription precedes EMT induction, post-translational regulation of Snail1 is also critical for determining Snail1's protein level, subcellular localization, and capacity to induce EMT. To identify novel post-translational regulators of Snail1, we developed a live cell, bioluminescence-based screen. From a human kinome RNAi screen, we have identified Lats2 kinase as a novel regulator of Snail1 protein level, subcellular localization, and thus, activity. We show that Lats2 interacts with Snail1 and directly phosphorylates Snail1 at residue T203. This occurs in the nucleus and serves to retain Snail1 in the nucleus thereby enhancing its stability. Lats2 was found to positively influence cellular EMT and tumour cell invasion, in a Snail1-dependent manner. Indeed during TGFb-induced EMT Lats2 is activated and Snail1 phosphorylated at T203. Analysis in mouse and zebrafish embryo development confirms that Lats2 acts as a positive modulator of Snail1 protein level and potentiates its in vivo EMT activity. The EMBO Journal (2012) 31, 29-43. doi:10.1038/emboj.2011.357; Published online 27 September 2011
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