O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

Eunah Kima, Eunah Kima, Jeong Gu Kang, Min Jueng Kang, Jae Hyung Park, Yeon Jung Kim, Yeon Jung Kim, Tae Hyun Kweon, Tae Hyun Kweon, Han Woong Lee, Eek Hoon Jho, Eek Hoon Jho, Yong Ho Lee, Yong Ho Lee, Seung Il Kim, Eugene C. Yi, Eugene C. Yi, Hyun Woo Park, Won Ho Yang, Won Ho YangJin Won Cho, Jin Won Cho, Jin Won Cho

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Abstract

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.

Original languageEnglish
Pages (from-to)14259-14269
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number25
DOIs
Publication statusPublished - 2020 Jun 23

All Science Journal Classification (ASJC) codes

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    Kima, E., Kima, E., Kang, J. G., Kang, M. J., Park, J. H., Kim, Y. J., Kim, Y. J., Kweon, T. H., Kweon, T. H., Lee, H. W., Jho, E. H., Jho, E. H., Lee, Y. H., Lee, Y. H., Kim, S. I., Yi, E. C., Yi, E. C., Park, H. W., Yang, W. H., ... Cho, J. W. (2020). O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity. Proceedings of the National Academy of Sciences of the United States of America, 117(25), 14259-14269. https://doi.org/10.1073/pnas.1913469117