Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation

• Published in: The EMBO journal Vol. 31; no. 1; pp. 29 - 43
• Main Authors: Zhang, Kun, Rodriguez-Aznar, Eva, Yabuta, Norikazu, Owen, Robert J, Mingot, Jose M, Nojima, Hiroshi, Nieto, M Angela, Longmore, Gregory D
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 04.01.2012; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Adhesion; Amino Acid Sequence; Animals; Bioluminescence; breast cancer; Cell Nucleus - metabolism; Cells, Cultured; Dogs; EMBO24; EMBO37; Embryo, Mammalian - metabolism; Embryo, Nonmammalian - metabolism; Embryos; Epithelial-Mesenchymal Transition; HCT116 Cells; HEK293 Cells; Humans; Lats2; Mice; Molecular Sequence Data; Nuclear energy; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; RNA Interference; Snail Family Transcription Factors; Snail1; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Zebrafish; breast cancer; Lats2; Snail1
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.357

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 TGFβ‐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 Lats2 kinase, a Hippo pathway component, is here shown to promote the epithelial–mesenchymal transition by phosphorylating the transcription factor Snail1.