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 and Pengda Liu ()
Additional contact information
Yao Jiang: Huazhong University of Science and Technology
Yanqiong Zhang: The University of North Carolina at Chapel Hill
Janet Y. Leung: The University of North Carolina at Chapel Hill
Cheng Fan: The University of North Carolina at Chapel Hill
Konstantin I. Popov: The University of North Carolina at Chapel Hill
Siyuan Su: The University of North Carolina at Chapel Hill
Jiayi Qian: The University of North Carolina at Chapel Hill
Xiaodong Wang: The University of North Carolina at Chapel Hill
Alisha Holtzhausen: The University of North Carolina at Chapel Hill
Eric Ubil: The University of North Carolina at Chapel Hill
Yang Xiang: Abclonal Technology
Ian Davis: The University of North Carolina at Chapel Hill
Nikolay V. Dokholyan: The University of North Carolina at Chapel Hill
Gang Wu: Huazhong University of Science and Technology
Charles M. Perou: The University of North Carolina at Chapel Hill
William Y. Kim: The University of North Carolina at Chapel Hill
H. Shelton Earp: The University of North Carolina at Chapel Hill
Pengda Liu: The University of North Carolina at Chapel Hill

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09233-7

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