EVIDENCE FOR REGULATION OF THE HUMAN ABL TYROSINE KINASE BY A CELLULAR INHIBITOR
EVIDENCE FOR REGULATION OF THE HUMAN ABL TYROSINE KINASE BY A CELLULAR INHIBITOR
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DOI：
10.1073/pnas.88.13.5927
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发表时间：
1991-07-01
影响因子：
11.1
通讯作者：
WITTE, ON
中科院分区：
文献类型：
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作者：
PENDERGAST, AM;MULLER, AJ;WITTE, ON
正常的人ABL蛋白酪氨酸激酶不能检测到磷酸酪氨酸，但激活的人ABL蛋白的致癌形式在体内被酪氨酸磷酸化。ABL的激活可以通过用断点簇区（BCR）序列取代ABL的第一外显子或通过删除非催化SH3 （src同源区3）结构域来实现。ABL激酶激活的另一种模式是高表达，比内源性水平高500倍。这不是高表达ABL分子转磷酸化的结果。体外翻译的ABL蛋白缺乏磷酸酪氨酸，但免疫沉淀和去除裂解物成分后发现酪氨酸激酶活性。磷酸化酪氨酸特异性磷酸酶对ABL和BCR-ABL融合蛋白的去磷酸化速率大致相同。这些综合结果表明，ABL活性的抑制是可逆的，并且表明一种细胞成分与ABL非共价相互作用以抑制其自磷酸化。
Phosphotyrosine cannot be detected on normal human ABL protein-tyrosine kinases, but activated oncogenic forms of the human ABL protein are phosphorylated on tyrosine in vivo. Activation of ABL can occur by substitution of the ABL first exon with breakpoint cluster region (BCR) sequences or by deletion of the noncatalytic SH3 (src homology region 3) domain. An alternative mode for the activation of the ABL kinases is hyperexpression at > 500-fold over endogenous levels. This is not a consequence of transphosphorylation of the hyperexpressed ABL molecules. ABL proteins translated in vitro lack phosphotyrosine, but tyrosine kinase activity is uncovered after immunoprecipitation and removal of lysate components. The rates of dephosphorylation of ABL and BCR-ABL fusion protein by phosphotyrosine-specific phosphatases are approximately the same. These combined results indicate that inhibition of ABL activity is reversible and suggest that a cellular component interacts noncovalently with ABL to inhibit its autophosphorylation.