DISRUPTION OF THE CSK GENE, ENCODING A NEGATIVE REGULATOR OF SRC FAMILY TYROSINE KINASES, LEADS TO NEURAL-TUBE DEFECTS AND EMBRYONIC LETHALITY IN MICE
DISRUPTION OF THE CSK GENE, ENCODING A NEGATIVE REGULATOR OF SRC FAMILY TYROSINE KINASES, LEADS TO NEURAL-TUBE DEFECTS AND EMBRYONIC LETHALITY IN MICE
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DOI：
10.1016/0092-8674(93)90641-3
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发表时间：
1993-06-18
期刊：
影响因子：
64.5
通讯作者：
SORIANO, P
中科院分区：
文献类型：
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作者：
IMAMOTO, A;SORIANO, P
所有Src家族非受体酪氨酸激酶都受到羧基末端酪氨酸磷酸化的负调控。为了分析这种调节在发育过程中的意义，我们通过胚胎干细胞中的基因靶向产生了Csk缺陷的小鼠，Csk是一种使酪氨酸磷酸化的激酶。纯合子突变胚胎表现出复杂的表型，包括神经管缺陷，并在妊娠第9天和第10天之间死亡。来源于这些胚胎的细胞表现出Src和相关Fyn激酶活性的数量级增加。Src的羧基端酪氨酸磷酸化减少，但没有消除，并伴随着另一个关键的酪氨酸残基磷酸化增加。这些结果表明，Src家族激酶活性是严重依赖于磷酸化的Csk，并建议激酶活性的调节可能是必不可少的胚胎发生过程中。
All Src family non-receptor tyrosine kinases are negatively regulated by phosphorylation at a carboxy-terminal tyrosine. To analyze the significance of this regulation during development, we have generated mice deficient in Csk, a kinase that phosphorylates this tyrosine, by gene targeting in embryonic stem cells. Homozygous mutant embryos exhibit a complex phenotype that includes defects in the neural tube and die between day 9 and day 10 of gestation. Cells derived from these embryos exhibit an order of magnitude increase in activity of Src and the related Fyn kinase. Phosphorylation at the carboxy-terminal tyrosine of Src was reduced but not eliminated and was accompanied by increased phosphorylation at another key tyrosine residue. These results demonstrate that Src family kinase activity is critically dependent on phosphorylation by Csk and suggest that the regulation of kinase activity may be essential during embryogenesis.