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

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Title
O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity
Author(s)
E Kim; Jeong Gu Kang; M J Kang; J H Park; Y J Kim; T H Kweon; H W Lee; E H Jho; Y H Lee; S I Kim; E C Yi; H W Park; W H Yang; J W Cho
Bibliographic Citation
Proceedings of National Academy of Sciences of United States of America, vol. 117, no. 25, pp. 14259-14269
Publication Year
2020
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 MST-LATS 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.
Keyword
Hippo pathwayLATS2MOB1O-GlcNAcylationcancer
ISSN
0027-8424
Publisher
Natl Acad Sciences
DOI
http://dx.doi.org/10.1073/pnas.1913469117
Type
Article
Appears in Collections:
Division of Biomedical Research > Genome Editing Research Center > 1. Journal Articles
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