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National Institute of Environmental Health Sciences

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Publication Detail

Title: MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression.

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

Published In Nat Commun, (2019 04 03)

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.

PubMed ID: 30944303 Exiting the NIEHS site

MeSH Terms: Animals; Carcinoma, Renal Cell/metabolism; Carcinoma, Renal Cell/pathology; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism*; Cell Line, Tumor; Cell Proliferation/physiology; Female; HEK293 Cells; HeLa Cells; Heterografts; Humans; Kidney Neoplasms/metabolism; Kidney Neoplasms/pathology; Mice; Mice, Nude; Mutation; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/metabolism; Proto-Oncogene Proteins c-akt/metabolism*; Signal Transduction; c-Mer Tyrosine Kinase/metabolism*

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