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 Dokholyan, Gang Wu, Charles M. Perou, William Y. Kim, H. Shelton Earp, Pengda Liu

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 languageEnglish (US)
Article number1515
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

phosphorylation
Phosphorylation
Chemical activation
retarding
activation
Post Translational Protein Processing
Phosphatidylinositol 3-Kinases
Proline
Tyrosine
Cell Survival
Carcinogenesis
Cell Proliferation
Cell Membrane
Mutation
Therapeutics
tyrosine
Cell proliferation
releasing
metabolism
Cell membranes

All Science Journal Classification (ASJC) codes

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

Cite this

Jiang, Y., Zhang, Y., Leung, J. Y., Fan, C., Popov, K. I., Su, S., ... Liu, P. (2019). MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression. Nature communications, 10(1), [1515]. https://doi.org/10.1038/s41467-019-09233-7
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 ; Wu, Gang ; Perou, Charles M. ; Kim, William Y. ; Earp, H. Shelton ; Liu, Pengda. / MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.",
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 Nikolay Dokholyan and Gang Wu and Perou, {Charles M.} and Kim, {William Y.} and Earp, {H. Shelton} and Pengda Liu",
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Jiang, Y, Zhang, Y, Leung, JY, Fan, C, Popov, KI, Su, S, Qian, J, Wang, X, Holtzhausen, A, Ubil, E, Xiang, Y, Davis, I, Dokholyan, N, Wu, G, Perou, CM, Kim, WY, Earp, HS & Liu, P 2019, 'MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression', Nature communications, vol. 10, no. 1, 1515. https://doi.org/10.1038/s41467-019-09233-7

MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression. / 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; Wu, Gang; Perou, Charles M.; Kim, William Y.; Earp, H. Shelton; Liu, Pengda.

In: Nature communications, Vol. 10, No. 1, 1515, 01.12.2019.

Research output: Contribution to journalArticle

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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

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.

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