Pervanadate mediated cysteine oxidation directly activates SRC kinase

Protein tyrosine phosphorylation (pTyr) is regulated by protein tyrosine phosphatases (PTPs) and27 kinases, helping cells detect and react to environmental changes. Pervanadate is commonly used to increase pTyr levels by inhibiting PTPs, leading to the belief that PTPs are the main regulators of pTyr in cell culture. However, we found that pervanadate not only inhibits PTPs but also activates the SRC tyrosine kinase by oxidizing specific cysteine residues and promoting extensive conformational changes. Our study explains how cysteine oxidation activates SRC by overcoming kinase domain autoinhibition and altering phosphopeptide binding by its SH2 domain. We also show that these cysteine residues are essential for SRC to promote cellular overgrowth.