Fyn-Dependent Regulation of Energy Expenditure and Body Weight Is Mediated by Tyrosine Phosphorylation of LKB1

Yamada, Eijiro; Pessin, Jeffrey E.; Kurland, Irwin J.; Schwartz, Gary J.; Bastie, Claire C.

doi:10.1016/j.cmet.2009.12.010

Cited by 81 publications

(96 citation statements)

References 54 publications

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“…35 In the current study, we reveal a novel mechanism of Fyn-induced oncogenesis by promoting PIKE-A/AMPK interaction. We show that PIKE-A phosphorylation by Fyn is necessary for its interaction with AMPK ( Figure 3).…”

Section: Discussionmentioning

confidence: 96%

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

Zhang

Chan

et al. 2015

Cell Death Differ

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The AMP-activated protein kinase, a key regulator of energy homeostasis, has a critical role in metabolic disorders and cancers. AMPK is mainly regulated by cellular AMP and phosphorylation by upstream kinases. Here, we show that PIKE-A binds to AMPK and blocks its tumor suppressive actions, which are mediated by tyrosine kinase Fyn. PIKE-A directly interacts with AMPK catalytic alpha subunit and impairs T172 phosphorylation, leading to repression of its kinase activity on the downstream targets. Mutation of Fyn phosphorylation sites on PIKE-A, depletion of Fyn, or pharmacological inhibition of Fyn blunts the association between PIKE-A and AMPK, resulting in loss of its inhibitory effect on AMPK. Cell proliferation and oncogenic assays demonstrate that PIKE-A antagonizes tumor suppressive actions of AMPK. In human glioblastoma samples, PIKE-A expression inversely correlates with the p-AMPK levels, supporting that PIKE-A negatively regulates AMPK activity in cancers. Thus, our findings provide additional layer of molecular regulation of the AMPK signaling pathway in cancer progression.

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Section: Discussionmentioning

confidence: 96%

“…Previous study reveals that Fyn inhibits AMPK signaling through phosphorylating LKB1, leading to its nuclear translocation. 35 To test the biological …”

Section: Resultsmentioning

confidence: 99%

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

Zhang

Chan

et al. 2015

Cell Death Differ

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“…31 But whether altered methyaltion of the CpGs studied here are causally involved in the development of obesity or simply markers of the disease state is unknown. Interestingly, 35 and insulin signaling. 36 FYN knockout mice displayed increased glucose clearance and whole body insulin sensitivity associated with decreased adiposity resulting from increased fatty acid use and energy expenditure, 37 and preferentially laid down adipose tissue in the subcutaneous, rather than the visceral, compartment and showed reduced inflammatory cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

Genome wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood

Huang

Davis

Garratt

et al. 2014

Obesity Research & Clinical Practice

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“…FYN is a member of the Src family of nonreceptor tyrosine kinases, which is associated with molecular signaling in the immune system (23), neural system (24), energy metabolism (25), and cancer (26). FYN prevents apoptosis and promotes cell survival through phosphorylation of phosphatidylinositol 3-kinase enhancer-activating Akt (27).…”

Section: Fyn Interacts With Nox4 In Cmsmentioning

confidence: 99%

Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

Matsushima

Kuroda

Zhai

et al. 2016

Journal of Clinical Investigation

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NADPH oxidases (Noxes) produce ROS that regulate cell growth and death. NOX4 expression in cardiomyocytes (CMs) plays an important role in cardiac remodeling and injury, but the posttranslational mechanisms that modulate this enzyme are poorly understood. Here, we determined that FYN, a Src family tyrosine kinase, interacts with the C-terminal domain of NOX4. FYN and NOX4 colocalized in perinuclear mitochondria, ER, and nuclear fractions in CMs, and FYN expression negatively regulated NOX4-induced O 2 -production and apoptosis in CMs. Mechanistically, we found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. Transverse aortic constriction activated FYN in the left ventricle (LV), and FYN-deficient mice displayed exacerbated cardiac hypertrophy and dysfunction and increased ROS production and apoptosis. Deletion of Nox4 rescued the exaggerated LV remodeling in FYN-deficient mice. Furthermore, FYN expression was markedly decreased in failing human hearts, corroborating its role as a regulator of cardiac cell death and ROS production. In conclusion, FYN is activated by oxidative stress and serves as a negative feedback regulator of NOX4 in CMs during cardiac remodeling.

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Fyn-Dependent Regulation of Energy Expenditure and Body Weight Is Mediated by Tyrosine Phosphorylation of LKB1

Cited by 81 publications

References 54 publications

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

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

Genome wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood

Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

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