The Hippo pathway controls organ size and tissue homeostasis by regulating cell proliferation and apoptosis. The LATS-mediated negative feedback loop prevents excessive activation of the effectors YAP/TAZ, maintaining homeostasis of the Hippo pathway. YAP and TAZ are hyperactivated in various cancer cells which lead to tumor growth. Aberrantly increased O-GlcNAcylation has recently emerged as a cause of hyperactivation of YAP in cancer cells. However, the mechanism, which induces hyperactivation of TAZ and blocks LATS-mediated negative feedback, remains to be elucidated in cancer cells. This study found that in breast cancer cells, abnormally increased O-GlcNAcylation hyperactivates YAP/TAZ and inhibits LATS2, a direct negative regulator of YAP/TAZ. LATS2 is one of the newly identified O-GlcNAcylated components in the MSTLATS kinase cascade. Here, we found that O-GlcNAcylation at LATS2 Thr436 interrupted its interaction with the MOB1 adaptor protein, which connects MST to LATS2, leading to activation of YAP/TAZ by suppressing LATS2 kinase activity. LATS2 is a core component in the LATS-mediated negative feedback loop. Thus, this study suggests that LATS2 O-GlcNAcylation is deeply involved in tumor growth by playing a critical role in dysregulation of the Hippo pathway in cancer cells.
|Number of pages||11|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 2020 Jun 23|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank Dr. Dae-Sik Lim and Dr. Wonyul Jang for experimental advice and for providing reagents. This study was supported by National Research Foundation of Korea Grants funded by the Korean Government (The Ministry of Science, ICT and Future Planning) (NRF-2016R1A5A1010764 and NRF-2015M3A9B6073840) to J.W.C.
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