CONSTITUTIVE ACTIVATION OF SRC FAMILY KINASES IN MOUSE EMBRYOS THAT LACK CSK

Csk is a novel cytoplasmic protein-tyrosine kinase that has been shown to inactivate members of the Src family of protein-tyrosine kinases i n vitro. To examine the function of Csk in vivo, Csk-deficient mouse e mbryos were generated by gene targeting in embryonic stem cells. These embryos were developmentally arrested at the 10 to 12 somite stage an d exhibited growth retardation and necrosis in the neural tissues. The kinase activity of p60c-src, p59fyn, and p53/56lyn in these embryos w as greatly enhanced as an apparent consequence of enhanced specific ac tivity. The increase in kinase activity was associated with an increas e in tyrosine phosphorylation of several proteins, especially those ar ound 85 and 120 kd. Thus, these results suggest that Csk indeed acts a s an indispensable negative regulator of Src family kinases in vivo.