期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-00795-y
关键词
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资金
- NIH [2P40OD010949-10A1]
- Wellcome Trust [090090/Z/09/Z]
- BBSRC [BB/I021248/1]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- UCL Cancer Research UK Centre
- Ministry of National Education (The Republic of Turkey)
- National Natural Science Foundation of China [31470223, 31670106]
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning
- Francis Crick Institute - Cancer Research UK [FC001175]
- Francis Crick Institute - UK Medical Research Council [FC001175]
- Francis Crick Institute - Wellcome Trust [FC001175]
- European Research Council [311331]
- European Research Council (ERC) [311331] Funding Source: European Research Council (ERC)
- Biotechnology and Biological Sciences Research Council [BB/I021248/1] Funding Source: researchfish
- Cancer Research UK [17064] Funding Source: researchfish
- The Francis Crick Institute [10176, 10436, 10487, 201358/Z/16/Z, 10175] Funding Source: researchfish
- Wellcome Trust [201358/Z/16/Z] Funding Source: Wellcome Trust
- BBSRC [BB/I021248/1] Funding Source: UKRI
The Hippo tumor suppressor pathway is essential for development and tissue growth control, encompassing a core cassette consisting of the Hippo (MST1/2), Warts (LATS1/2), and Tricornered (NDR1/2) kinases together with MOB1 as an important signaling adaptor. However, it remains unclear which regulatory interactions between MOB1 and the different Hippo core kinases coordinate development, tissue growth, and tumor suppression. Here, we report the crystal structure of the MOB1/NDR2 complex and define key MOB1 residues mediating MOB1's differential binding to Hippo core kinases, thereby establishing MOB1 variants with selective loss-of-interaction. By studying these variants in human cancer cells and Drosophila, we uncovered that MOB1/Warts binding is essential for tumor suppression, tissue growth control, and development, while stable MOB1/Hippo binding is dispensable and MOB1/Trc binding alone is insufficient. Collectively, we decrypt molecularly, cell biologically, and genetically the importance of the diverse interactions of Hippo core kinases with the pivotal MOB1 signal transducer.
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