Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity

Zhang, S; Qi, Quan; Chan, Chi Bun; Zhou, Wei; Chen, J; Luo, Hongbo; Appin, Christina L.; Brat, Daniel J.; Ye, K

doi:10.1038/cdd.2015.66

Cited by 30 publications

(26 citation statements)

References 44 publications

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“…Consequently, ablation of PIKE in the muscle protects the animals from developing excess weight gain, ectopic lipid accumulation, and diabetes development. Combining our recent discoveries that PIKE-A prevents AMPK phosphorylation by liver kinase B1 or Ca 2+ /calmodulin-dependent protein kinase kinase β (42) and the findings reported in this study, we propose a model that obesity development causes an elevation of circulating TNF-α, which triggers the formation of PIKE-A/AMPK complex in the skeletal muscle. Binding of PIKE-A to AMPK shields the T172 site from being phosphorylated by the upstream kinases.…”

Section: Discussionsupporting

confidence: 71%

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

et al. 2017

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Tumor necrosis factor-α (TNF-α) is an inflammatory cytokine that plays a central role in obesity-induced insulin resistance. It also controls cellular lipid metabolism, but the underlining mechanism is poorly understood. We report in this study that phosphoinositide 3-kinase enhancer A (PIKE-A) is a novel effector of TNF-α to facilitate its metabolic modulation in the skeletal muscle. Depletion of PIKE-A in C2C12 myotubes diminished the inhibitory activities of TNF-α on mitochondrial respiration and lipid oxidation, whereas PIKE-A overexpression exacerbated these cellular responses. We also found that TNF-α promoted the interaction between PIKE-A and AMP-activated protein kinase (AMPK) to suppress its kinase activity in vitro and in vivo. As a result, animals with PIKE ablation in the skeletal muscle per se display an upregulation of AMPK phosphorylation and a higher preference to use lipid as the energy production substrate under high-fat diet feeding, which mitigates the development of diet-induced hyperlipidemia, ectopic lipid accumulation, and muscle insulin resistance. Hence, our data reveal PIKE-A as a new signaling factor that is important for TNF-α–initiated metabolic changes in skeletal muscle.

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Section: Discussionsupporting

confidence: 71%

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

et al. 2017

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“…As Saracatinib and Dasatinib are non-specific inhibitors of individual SFK member 26 , the genetic inhibition of FYN remains the best option to study its functions in glioma biology. Indeed, genetic downregulation of FYN expression inhibited glioma cells migration and proliferation in vitro 3,8,9,27 , yet failed to affect glioma progression in vivo immune suppressive mice 8 .…”

Section: Discussionmentioning

confidence: 99%

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

Comba

Dunn

Argento

et al. 2019

Preprint

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BackgroundHigh grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYN’s role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion.MethodsWe evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME.ResultsWe demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8−/− and CD4−/− immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME.ConclusionsGliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies.Key pointsInhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity.Importance of the StudyFYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its role in vivo remains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.

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“…Accumulating evidence demonstrated that Fyn is a novel potential target in antitumor drug treatment [20]; for example, Fyn is a key molecule in mediating breast cancer epithelial-mesenchymal transition regulation through FOXO1, which is mediated by FGF2 induced the activation of PI3K/AKT and ERK/MAPK pathways [21]. Fyn was reported to mediate the phosphorylation of PIKE-A at site T172 that inhibits AMPK signaling pathway, and results in blocking glioblastoma cell suppression activity [22].…”

Section: Discussionmentioning

confidence: 99%

A Novel Chalcone derivative suppresses Melanoma cell growth through targeting Fyn/Stat3 pathway

Tang

Long

et al. 2020

Preprint

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Background: Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma.Methods: We investigated the impacts of Fyn and its inhibitors Lj-1-60 on melanoma by way of bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro phosphorylation assay to further demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR to confirm the potential mechanisms of Lj-1-60 in melanoma.Results: Our findings showed that Fyn is overexpressed in melanoma cells and knock down of Fyn suppresses the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 11277 chemicals was conducted to vitro screening, among those compounds, eighty-three inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly associates with Fyn and inhibits the Fyn kinase activity with Stat3 as substrate. What’s more, Lj-1-60 suppresses the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocking down cells.Conclusion: Our study revealed a novel Fyn inhibitor could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.

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Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity

Cited by 30 publications

References 44 publications

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses

A Novel Chalcone derivative suppresses Melanoma cell growth through targeting Fyn/Stat3 pathway

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