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Constitutive activation of Src family kinases in mouse embryos that lack Csk
1Laboratory of Molecular Oncology, Institute of Physical and Chemical Research (RIKEN), Ibaraki, Japan.
Abstract:
Csk is a novel cytoplasmic protein-tyrosine kinase that has been shown to inactivate members of the Src family of protein-tyrosine kinases in vitro. To examine the function of Csk in vivo, Csk-deficient mouse embryos were generated by gene targeting in embryonic stem cells. These embryos were developmentally arrested at the 10 to 12 somite stage and exhibited growth retardation and necrosis in the neural tissues. The kinase activity of p60c-src, p59fyn, and p53/56lyn in these embryos was greatly enhanced as an apparent consequence of enhanced specific activity. The increase in kinase activity was associated with an increase in tyrosine phosphorylation of several proteins, especially those around 85 and 120 kd. Thus, these results suggest that Csk indeed acts as an indispensable negative regulator of Src family kinases in vivo.
Insights
Csk deficiency in mice causes developmental arrest and neural tissue damage. This study confirms Csk protein as a vital in vivo regulator of Src family kinases.
Area of Science:
- Cellular Biology
- Molecular Biology
- Developmental Biology
Background:
- Csk (C-terminal Src kinase) is a cytoplasmic protein-tyrosine kinase.
- In vitro studies show Csk inactivates Src family kinases.
- The in vivo function of Csk remained to be elucidated.
Purpose of the Study:
- To investigate the in vivo role of Csk.
- To determine the consequences of Csk deficiency in a whole organism.
Main Methods:
- Gene targeting in embryonic stem cells to create Csk-deficient mouse embryos.
- Analysis of embryonic development, neural tissue, and kinase activity.
- Assessment of protein tyrosine phosphorylation patterns.
Main Results:
- Csk-deficient embryos showed developmental arrest at 10-12 somite stage.
- Growth retardation and neural tissue necrosis were observed.
- Activity of Src family kinases (p60c-src, p59fyn, p53/56lyn) was significantly enhanced.
- Increased tyrosine phosphorylation of specific proteins (85 and 120 kd) occurred.
Conclusions:
- Csk is essential for normal embryonic development in vivo.
- Csk acts as a critical negative regulator of Src family kinase activity.
- Dysregulation of Src family kinases due to Csk deficiency leads to developmental defects.
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