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稳定的 MOB1 与 Hippo/MST 的相互作用对于发育和组织生长控制并非必需。

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

机构信息

Tumour Suppressor Signalling Network Laboratory, UCL Cancer Institute, University College London, London, WC1E 6BT, UK.

Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK.

出版信息

Nat Commun. 2017 Sep 25;8(1):695. doi: 10.1038/s41467-017-00795-y.

DOI:10.1038/s41467-017-00795-y
PMID:28947795
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5612953/
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.The Hippo tumor suppressor pathway is essential for development and tissue growth control. Here the authors employ a multi-disciplinary approach to characterize the interactions of the three Hippo kinases with the signaling adaptor MOB1 and show how they differently affect development, tissue growth and tumor suppression.

摘要

Hippo 肿瘤抑制途径对于发育和组织生长控制至关重要，它包含一个核心盒，由 Hippo（MST1/2）、Warts（LATS1/2）和 Tricornered（NDR1/2）激酶以及作为重要信号适配器的 MOB1 组成。然而，目前尚不清楚 MOB1 和不同 Hippo 核心激酶之间的哪些调节相互作用协调发育、组织生长和肿瘤抑制。在这里，我们报告了 MOB1/NDR2 复合物的晶体结构，并定义了关键的 MOB1 残基，介导 MOB1 与 Hippo 核心激酶的差异结合，从而建立了具有选择性丧失相互作用的 MOB1 变体。通过在人类癌细胞和果蝇中研究这些变体，我们发现 MOB1/Warts 结合对于肿瘤抑制、组织生长控制和发育至关重要，而稳定的 MOB1/Hippo 结合是可有可无的，并且单独的 MOB1/Trc 结合是不够的。总之，我们从分子、细胞生物学和遗传学上揭示了 Hippo 核心激酶与关键信号转导器 MOB1 的不同相互作用的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/87ec4379e522/41467_2017_795_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/c85bf52c9304/41467_2017_795_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/a5bc7e7be1df/41467_2017_795_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/791cf1dd29c6/41467_2017_795_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/b72eb668c17d/41467_2017_795_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/156473538900/41467_2017_795_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/87ec4379e522/41467_2017_795_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/c85bf52c9304/41467_2017_795_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/a5bc7e7be1df/41467_2017_795_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/791cf1dd29c6/41467_2017_795_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/b72eb668c17d/41467_2017_795_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/156473538900/41467_2017_795_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b898/5612953/87ec4379e522/41467_2017_795_Fig6_HTML.jpg

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