MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression

Yao Jiang; Yanqiong Zhang; Janet Y. Leung; Cheng Fan; Konstantin I. Popov; Siyuan Su; Jiayi Qian; Xiaodong Wang; Alisha Holtzhausen; Eric Ubil; Yang Xiang; Ian Davis; Nikolay V. Dokholyan; Gang Wu; Charles M. Perou; William Y. Kim; H. Shelton Earp; Pengda Liu

doi:10.1038/s41467-019-09233-7

MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression

Yao Jiang, Yanqiong Zhang, Janet Y. Leung, Cheng Fan, Konstantin I. Popov, Siyuan Su, Jiayi Qian, Xiaodong Wang, Alisha Holtzhausen, Eric Ubil, Yang Xiang, Ian Davis, Nikolay V. Dokholyan, Gang Wu, Charles M. Perou, William Y. Kim, H. Shelton Earp, Pengda Liu

Microbiology, Immunology, and Molecular Genetics

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

33 Scopus citations

Abstract

Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt interactome is less understood. Here, we report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt’s movement to plasma membrane. We further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. We also determine that MERTK phosphorylates Akt1-Y26, releasing SAV1 binding and allowing Akt responsiveness to canonical PI-3K pathway activation. This work provides a mechanism underlying MERTK-mediated Akt activation and survival signaling in kidney cancer. Akt activation drives oncogenesis and therapeutic resistance; this mechanism of Akt regulation by MERTK/SAV1 provides yet another complexity in an extensively studied pathway, and may yield prognostic information and therapeutic targets.

Original language	English
Article number	1515
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09233-7
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

The authors thank Liu, Earp, and Kim lab members for critical reading of the manuscript and helpful discussions. The authors also thank Dr. Qing Zhang (UNC-Chapel Hill) and Zhang lab members for sharing the reagents and suggestions. This work was supported by the NIH grants (P.L. R00CA181342, H.S.E. CA016086, N.V.D. R01GM114015 and R01GM123247), the UNC IBM Junior Faculty Development Award (P.L.), the V Scholar Research Grant (P.L.), and UNC University Cancer Research Fund (P.L.).

Funders	Funder number
UNC IBM
Duke-UNC-Washington University
National Institutes of Health (NIH)	R01GM114015, CA016086, R00CA181342
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R01GM123247

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-09233-7

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Jiang, Y., Zhang, Y., Leung, J. Y., Fan, C., Popov, K. I., Su, S., Qian, J., Wang, X., Holtzhausen, A., Ubil, E., Xiang, Y., Davis, I., Dokholyan, N. V., Wu, G., Perou, C. M., Kim, W. Y., Earp, H. S., & Liu, P. (2019). MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression. Nature Communications, 10(1), Article 1515. https://doi.org/10.1038/s41467-019-09233-7

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title = "MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression",

abstract = "Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt interactome is less understood. Here, we report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt{\textquoteright}s movement to plasma membrane. We further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. We also determine that MERTK phosphorylates Akt1-Y26, releasing SAV1 binding and allowing Akt responsiveness to canonical PI-3K pathway activation. This work provides a mechanism underlying MERTK-mediated Akt activation and survival signaling in kidney cancer. Akt activation drives oncogenesis and therapeutic resistance; this mechanism of Akt regulation by MERTK/SAV1 provides yet another complexity in an extensively studied pathway, and may yield prognostic information and therapeutic targets.",

author = "Yao Jiang and Yanqiong Zhang and Leung, \{Janet Y.\} and Cheng Fan and Popov, \{Konstantin I.\} and Siyuan Su and Jiayi Qian and Xiaodong Wang and Alisha Holtzhausen and Eric Ubil and Yang Xiang and Ian Davis and Dokholyan, \{Nikolay V.\} and Gang Wu and Perou, \{Charles M.\} and Kim, \{William Y.\} and Earp, \{H. Shelton\} and Pengda Liu",

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AU - Su, Siyuan

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AU - Wang, Xiaodong

AU - Holtzhausen, Alisha

AU - Ubil, Eric

AU - Xiang, Yang

AU - Davis, Ian

AU - Dokholyan, Nikolay V.

AU - Wu, Gang

AU - Perou, Charles M.

AU - Kim, William Y.

AU - Earp, H. Shelton

AU - Liu, Pengda

PY - 2019/12/1

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N2 - Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt interactome is less understood. Here, we report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt’s movement to plasma membrane. We further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. We also determine that MERTK phosphorylates Akt1-Y26, releasing SAV1 binding and allowing Akt responsiveness to canonical PI-3K pathway activation. This work provides a mechanism underlying MERTK-mediated Akt activation and survival signaling in kidney cancer. Akt activation drives oncogenesis and therapeutic resistance; this mechanism of Akt regulation by MERTK/SAV1 provides yet another complexity in an extensively studied pathway, and may yield prognostic information and therapeutic targets.

AB - Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt interactome is less understood. Here, we report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt’s movement to plasma membrane. We further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. We also determine that MERTK phosphorylates Akt1-Y26, releasing SAV1 binding and allowing Akt responsiveness to canonical PI-3K pathway activation. This work provides a mechanism underlying MERTK-mediated Akt activation and survival signaling in kidney cancer. Akt activation drives oncogenesis and therapeutic resistance; this mechanism of Akt regulation by MERTK/SAV1 provides yet another complexity in an extensively studied pathway, and may yield prognostic information and therapeutic targets.

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MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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