RGD Reference Report - Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling. - Rat Genome Database

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Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling.

Authors: Matsushima, Shouji  Kuroda, Junya  Zhai, Peiyong  Liu, Tong  Ikeda, Shohei  Nagarajan, Narayani  Oka, Shin-Ichi  Yokota, Takashi  Kinugawa, Shintaro  Hsu, Chiao-Po  Li, Hong  Tsutsui, Hiroyuki  Sadoshima, Junichi 
Citation: Matsushima S, etal., J Clin Invest. 2016 Sep 1;126(9):3403-16. doi: 10.1172/JCI85624. Epub 2016 Aug 15.
RGD ID: 13601987
Pubmed: PMID:27525436   (View Abstract at PubMed)
PMCID: PMC5004961   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI85624   (Journal Full-text)

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 O2- 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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
mitochondrion located_inIDA 13601987; 13601987PMID:27525436ARUK-UCL 
nucleus located_inIDA 13601987; 13601987PMID:27525436ARUK-UCL 
perinuclear endoplasmic reticulum located_inIDA 13601987; 13601987PMID:27525436ARUK-UCL 
perinuclear region of cytoplasm located_inIDA 13601987; 13601987PMID:27525436ARUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Fyn  (FYN proto-oncogene, Src family tyrosine kinase)
Nox4  (NADPH oxidase 4)

Additional Information