Oncogenic mutations reduce the stability of Src kinase

The oncogenic potential of the viral tyrosine kinase v-Src is due to its constitutive activity. Unlike the highly homologous cellular c-Src kinase, a C-terminal deletion of the regulatory tail and numerous point mutations make the viral kinase uncontrollable. To determine the basis of these differences, we analysed the structure and stability of v-Src and c-Src in vitro. We show that the stability of v-Src against unfolding and irreversible aggregation is significantly lower than that of c-Src. Furthermore, in v-Src hydrophobic residues are more exposed already in the native state. In consequence, v-Src was found to be inactive close to physiological temperatures. We thus suggest that the ensemble of mutations that transform c-Src into the oncogenic variant cause a concomitant destabilisation of the kinase. (C) 2004 Elsevier Ltd. All rights reserved.