MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway

Zhipeng Meng; Toshiro Moroishi; Violaine Mottier-Pavie; Steven W. Plouffe; Carsten G. Hansen; Audrey W. Hong; Hyun Woo Park; Jung Soon Mo; Wenqi Lu; Shicong Lu; Fabian Flores; Fa Xing Yu; Georg Halder; Kun Liang Guan

doi:10.1038/ncomms9357

MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway

Zhipeng Meng, Toshiro Moroishi, Violaine Mottier-Pavie, Steven W. Plouffe, Carsten G. Hansen, Audrey W. Hong, Hyun Woo Park, Jung Soon Mo, Wenqi Lu, Shicong Lu, Fabian Flores, Fa Xing Yu, Georg Halder, Kun Liang Guan

Research output: Contribution to journal › Article › peer-review

299 Citations (Scopus)

Abstract

The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members-Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway.

Original language	English
Article number	8357
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9357
Publication status	Published - 2015 Oct 5

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (CA132809, EY022611, DEO15964, CA23100 and CA196878, K.-L.G.). T.M. is supported by the Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowships for Research Abroad and by a grant from the Yasuda Medical Foundation. C.G.H. is supported by a Postdoctoral Fellowship from the Danish Council for Independent Research | Nature Sciences. S.W.P. and A.W.H. were supported in part by a University of California, San Diego (UCSD) Graduate Training Programme in Cellular and Molecular Pharmacology training grant (T32 GM007752).

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms9357

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title = "MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway",

abstract = "The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members-Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway.",

author = "Zhipeng Meng and Toshiro Moroishi and Violaine Mottier-Pavie and Plouffe, {Steven W.} and Hansen, {Carsten G.} and Hong, {Audrey W.} and Park, {Hyun Woo} and Mo, {Jung Soon} and Wenqi Lu and Shicong Lu and Fabian Flores and Yu, {Fa Xing} and Georg Halder and Guan, {Kun Liang}",

note = "Funding Information: This work was supported by grants from the National Institutes of Health (CA132809, EY022611, DEO15964, CA23100 and CA196878, K.-L.G.). T.M. is supported by the Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowships for Research Abroad and by a grant from the Yasuda Medical Foundation. C.G.H. is supported by a Postdoctoral Fellowship from the Danish Council for Independent Research | Nature Sciences. S.W.P. and A.W.H. were supported in part by a University of California, San Diego (UCSD) Graduate Training Programme in Cellular and Molecular Pharmacology training grant (T32 GM007752). Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

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doi = "10.1038/ncomms9357",

language = "English",

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T1 - MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway

AU - Meng, Zhipeng

AU - Moroishi, Toshiro

AU - Mottier-Pavie, Violaine

AU - Plouffe, Steven W.

AU - Hansen, Carsten G.

AU - Hong, Audrey W.

AU - Park, Hyun Woo

AU - Mo, Jung Soon

AU - Lu, Wenqi

AU - Lu, Shicong

AU - Flores, Fabian

AU - Yu, Fa Xing

AU - Halder, Georg

AU - Guan, Kun Liang

N1 - Funding Information: This work was supported by grants from the National Institutes of Health (CA132809, EY022611, DEO15964, CA23100 and CA196878, K.-L.G.). T.M. is supported by the Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowships for Research Abroad and by a grant from the Yasuda Medical Foundation. C.G.H. is supported by a Postdoctoral Fellowship from the Danish Council for Independent Research | Nature Sciences. S.W.P. and A.W.H. were supported in part by a University of California, San Diego (UCSD) Graduate Training Programme in Cellular and Molecular Pharmacology training grant (T32 GM007752). Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/10/5

Y1 - 2015/10/5

N2 - The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members-Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway.

AB - The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members-Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway.

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MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway

Abstract

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