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Nat Commun. 2019 Apr 3;10(1):1515. doi: 10.1038/s41467-019-09233-7.

MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression.

Jiang Y1,2,3, Zhang Y2,3, Leung JY2,4, Fan C2,5,6, Popov KI3, Su S2,3, Qian J2,3, Wang X2,7, Holtzhausen A2,8, Ubil E2,8, Xiang Y9, Davis I2,5,10, Dokholyan NV2,3,11, Wu G1, Perou CM2,5,6, Kim WY2,4,5,8, Earp HS2,8, Liu P12,13.

Author information

1
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
2
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
3
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
4
Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
5
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
6
Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
7
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
8
Department of Medicine and Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
9
Abclonal Technology, 86 Cummings Park Drive, Woburn, MA, 01801, USA.
10
Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
11
Departments of Pharmacology, Biochemistry and Molecular Biology, Pennsylvania State College of Medicine, Hershey, PA, 17033, USA.
12
Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. pengda_liu@med.unc.edu.
13
Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. pengda_liu@med.unc.edu.

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.

PMID:
30944303
PMCID:
PMC6447540
DOI:
10.1038/s41467-019-09233-7
[Indexed for MEDLINE]
Free PMC Article

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