TY - JOUR
T1 - MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression
AU - Jiang, Yao
AU - Zhang, Yanqiong
AU - Leung, Janet Y.
AU - Fan, Cheng
AU - Popov, Konstantin I.
AU - Su, Siyuan
AU - Qian, Jiayi
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
N1 - Funding Information:
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.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
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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U2 - 10.1038/s41467-019-09233-7
DO - 10.1038/s41467-019-09233-7
M3 - Article
C2 - 30944303
AN - SCOPUS:85063951366
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1515
ER -