Direct and specific inactivation of protein tyrosine kinases in the Src and FGFR families by reversible cysteine oxidation.
Accumulating evidence suggests that protein tyrosine phosphorylation-based signaling pathways are under the regulation of reactive oxygen species. Although protein tyrosine phosphatases are directly regulated by reversible oxidation, it is not clear whether protein tyrosine kinases (PTKs) are also directly regulated by reduction/oxidation (redox). In this study we report a mechanism of direct oxidative inactivation specific for the PTKs in the Src and fibroblast growth factor receptor (FGFR) families, key enzymes in mammalian signal transduction. Src is fully active when reduced and retains 8-25% of the full activity toward various substrates when oxidized. This inactivation is caused by oxidation of a specific cysteine residue (Cys-277), which results in homodimerization of Src linked by a disulfide bridge. Cys-277 is located in the Gly loop in the catalytic domain. This cysteine residue is conserved only in 8 of the >90 PTKs in the human kinome, including 3 of the 10 Src family kinases and all 4 kinases of the FGFR family. FGFR1 is also reversibly regulated by redox because of this cysteine residue, whereas Csk, a PTK that lacks a cysteine residue at the corresponding position, is not similarly regulated. These results demonstrate a mechanism of direct redox regulation conserved in certain specific PTKs.
Kemble
David J
DJ
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
Sun
Gongqin
G
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D003545:Cysteine / Q000378:metabolism*; D010084:Oxidation-Reduction; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases
D017382:Reactive Oxygen Species; D017468:Receptors, Fibroblast Growth Factor; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D003545:Cysteine