Stable MOB1 interaction with Hippo/MST is not essential for development and tissue growth control

Yavuz Kulaberoglu, Kui Lin, Maxine Holder, Zhongchao Gai, Marta Gomez, Belul Assefa Shifa, Merdiye Mavis, Lily Hoa, Ahmad A. D. Sharif, Celia Lujan, Ewan St. John Smith, Ivana Bjedov, Nicolas Tapon, Geng Wu () and Alexander Hergovich ()
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Yavuz Kulaberoglu: University College London
Kui Lin: Shanghai Jiao Tong University
Maxine Holder: Francis Crick Institute
Zhongchao Gai: Shanghai Jiao Tong University
Marta Gomez: University College London
Belul Assefa Shifa: University College London
Merdiye Mavis: University College London
Lily Hoa: University College London
Ahmad A. D. Sharif: University College London
Celia Lujan: University College London
Ewan St. John Smith: University of Cambridge
Ivana Bjedov: University College London
Nicolas Tapon: Francis Crick Institute
Geng Wu: Shanghai Jiao Tong University
Alexander Hergovich: University College London

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00795-y

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