한빛사 논문
Eunah Kima,b, Jeong Gu Kangc, Min Jueng Kangd, Jae Hyung Parke, Yeon Jung Kima,b, Tae Hyun Kweona,b, Han-Woong Leee, Eek‐hoon Jhoa,f, Yong-ho Leea,g, Seung-Il Kimh, Eugene C. Yia,d, Hyun Woo Parke, Won Ho Yanga,i, and Jin Won Choa,b,i,1
aGlycosylation Network Research Center, Yonsei University, 03722 Seoul, Republic of Korea; bInterdisciplinary Program of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, 03722 Seoul, Republic of Korea; cGenome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea; dDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, 03080 Seoul, Republic of Korea; eDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 03722 Seoul, Republic of Korea; fDepartment of Life Science, University of Seoul, 02504 Seoul, Republic of Korea; gDepartment of Internal Medicine, Yonsei University College of Medicine, 03722 Seoul, Republic of Korea; hCollege of Medicine, Yonsei University, 03722 Seoul, Republic of Korea; and iDepartment of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 03722 Seoul, Republic of Korea
1To whom correspondence may be addressed.
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.
Hippo pathway, LATS2, MOB1, O-GlcNAcylation, cancer
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