MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression

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

doi:10.1038/s41467-019-09233-7

Cited by 30 publications

(35 citation statements)

References 54 publications

(67 reference statements)

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“…The MERTK receptor tyrosine kinase phosphorylates Akt1-Y26, mediating Akt activation and survival signaling, which in turn drives oncogenesis and therapeutic resistance. 70 Thus, cisplatin damages on MERTK gene may be implicated in mechanism of action of the drug. This result also support that MERTK is a potential therapeutic target.…”

Section: Bioinformatics Analysismentioning

confidence: 99%

“…This result also support that MERTK is a potential therapeutic target. 70,71 In addition to the phosphorylation-related genes mentioned above, another phosphorylation-related gene, AKT3, has also been identified as cisplatin gene target with an EG g of 57 ( Figure 4G). The protein encoded by this gene is a member of the AKT (or PKB) serine/threonine protein kinase family.…”

Section: Bioinformatics Analysismentioning

confidence: 99%

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Genome-Wide Mapping of Cisplatin Damaged Gene Loci

Luo

et al. 2020

Preprint

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Cisplatin is a DNA targeting anticancer drug, yet its damaged gene loci have remained unclear. In the present work, combining affinity isolation and high throughput sequencing, we genome-widely mapped 17729 gene loci containing platination lesions, which mainly function as enzymes, transcription regulators, transporters and kinases, and of which 445 genes account for 71% of potential gene targets for cancer therapy reported in the literature. The most related core signaling pathway, disease and tissue toxicity of 7578 genes with an enrichment fold (EFG) of >12, where EFG refers to the ratio of total read counts of a gene detected in cells with and without cisplatin treatment, are sperm motility, cancer and hepatotoxicity with association P values of < 1×10−22. Among 616 kinase genes damaged by cisplatin, 427 are protein kinases which account for 82% of putative protein kinases, suggesting that cisplatin may act as broad-spectrum protein kinase inhibitor. Western Blot assays verified that expression of 8 important protein kinase genes was significantly reduced due to cisplatin damage. SPAG9 is closely related to 147 of 361 cancer diseases which the cisplatin damaged genes are associated with and was severely damaged by cisplatin. Given SPAG9 abundantly expresses JIP-4, a upstream mediator of protein kinase signaling, in testis, it may be responsible for the high sensitivity of testicular cancer to cisplatin, thus being a potential therapeutic target for precise treatment of testicular cancer. These findings provide novel insights into better understanding in molecular mechanism of anticancer activity and toxicity of cisplatin, more importantly inspire further studies in prioritizing gene targets for precise treatment of cancers.

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Section: Bioinformatics Analysismentioning

confidence: 99%

Section: Bioinformatics Analysismentioning

confidence: 99%

Genome-Wide Mapping of Cisplatin Damaged Gene Loci

Luo

et al. 2020

Preprint

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“…In combination with the abundant presence of apoptotic PtdSer [11], cancer cells are capable of TAM receptor auto-signaling. This subsequently results in the activation of various downstream pathways, including ERK, MAPK, AKT and others [12,13]. Interestingly, TAM receptors have been implicated in therapy resistance to MAPK, PI3 K and EGFR inhibitors [13].…”

Section: Tam Receptors In the Tumor Microenvironmentmentioning

confidence: 99%

TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

Peeters

Rahbech

Straten

2019

Cancer Immunol Immunother

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The TAM receptors—TYRO3, AXL, MERTK—are pleiotropically expressed receptors in both healthy and diseased tissue. A complex of the ligands Protein S (PROS1) or Growth Arrest-Specific 6 (GAS6) with apoptotic phosphatidylserine activates the TAM receptors. Hence, this receptor family is essential for the efferocytosis of apoptotic material by antigen-presenting cells. In addition, TAM receptors are expressed by virtually all cells of the tumor microenvironment. They are also potent oncogenes, frequently overexpressed in cancer and involved in survival and therapy resistance. Due to their pro-oncogenic and immune-inhibitory traits, TAM receptors have emerged as promising targets for cancer therapy. Recently, TAM receptors have been described to function as costimulatory molecules on human T cells. TAM receptors’ ambivalent functions on many different cell types therefore make therapeutic targeting not straight-forward. In this review we summarize our current knowledge of the function of TAM receptors in the tumor microenvironment. We place particular focus on TAM receptors and the recently unraveled role of MERTK in activated T cells and potential consequences for anti-tumor immunity.

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“…We examined Hippo pathway constituents discovering that one Hippo signaling component, SAV1 (protein salvador 1), binds and suppresses AKT activation in RCC. 3 Specifically, the WW domain of SAV1 binds a proline motif in the PH (pleckstrin homology) domain of AKT and suppresses AKT activation, an action independent of SAV1's function in Hippo signaling. Our results demonstrate that SAV1 binding to AKT-PH domain impedes the plasma membrane attachment as well as AKT binding to its upstream activating kinases such as PDK1 and mTORC2 (mechanistic target of rapamycin complex 2).…”

mentioning

confidence: 99%

“…When we engineered these cancer-relevant mutated SAV1 molecules, they were deficient in binding AKT, and led to AKT hyperactivation facilitating RCC growth. 3 Another SAV1 linkage was shown in that SAV1 can bind directly to the protein phosphatase PP2A (protein phosphatase 2A) suppressing its phosphatase activity. SAV1 is also co-purified with the protein phosphatase PP1A and both of these phosphatases are linked with AKT dephosphorylation through direct or indirect mechanisms 4 Thus, SAV1 binding may bring PP1A/PP2A to dephosphorylate AKT-pT308 and pS473, which warrants further investigations.…”

mentioning

confidence: 99%

Beyond growth signaling: apoptotic sensor MERTK activates AKT by a novel mechanism

Zhang

Earp

Liu

2019

Molecular & Cellular Oncology

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Canonically the oncogenic kinase AKT is activated by growth signals. Our work suggests apoptotic materials, abundant in tumors, also contribute to AKT activation by stimulating MERTK that in turn phosphorylates Y26 in the AKT PH domain. pY26 reverses binding of an AKT endogenous, WW-domain containing inhibitor, SAV1, allowing AKT responsiveness to classic growth signals. This novel mechanism may contribute to drug resistance.

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MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression

Cited by 30 publications

References 54 publications

Genome-Wide Mapping of Cisplatin Damaged Gene Loci

Genome-Wide Mapping of Cisplatin Damaged Gene Loci

TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

Beyond growth signaling: apoptotic sensor MERTK activates AKT by a novel mechanism

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