Tyrosine phosphorylation of p62dok by p210bcr-abl inhibits RasGAP activity
Tyrosine phosphorylation of p62dok by p210bcr-abl inhibits RasGAP activity
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DOI：
10.1073/pnas.040547997
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发表时间：
2000-02-29
影响因子：
11.1
通讯作者：
Kobayashi, R
中科院分区：
文献类型：
--
作者：
Kashige, N;Carpino, N;Kobayashi, R
几乎所有慢性粒细胞白血病患者都存在t(9；22)染色体易位，bcr-abl融合基因表达的融合蛋白p210(bcr-abl)具有较高的酪氨酸激酶活性，慢性粒细胞白血病慢性期分离的造血祖细胞含有结构性酪氨酸磷酸化的p62(Dok)蛋白，p62dok与Ras GTP酶激活蛋白(RasGAP)相关，但仅当p62(Dok)酪氨酸磷酸化时。在这里，我们研究了p62(Dok)与RasGAP之间的相互作用以及p62(Dok)酪氨酸磷酸化对RasGAP活性的影响。我们发现p62(Dok)是被p210(bcr-abl)直接磷酸化的酪氨酸，其磷酸化位点位于p62(Dok)分子的C末端。我们已经鉴定了五个参与RasGAP体外结合的酪氨酸残基，并发现酪氨酸磷酸化的p62(Dok)抑制RasGAP的活性。我们的结果表明，p210(BCR-ABL)可能通过抑制RAS信号的关键下调因子而导致RAS信号通路的激活。
The t(9;22) chromosomal translocation is found in almost all patients with chronic myelogenous leukemia, The resultant Bcr-Abl fusion gene expresses a chimeric fusion protein p210(bcr-abl) with increased tyrosine kinase activity, Hematopoietic progenitors isolated from chronic myelogenous leukemia patients in the chronic phase contain constitutively tyrosine-phosphorylated p62(dok) protein, p62dok associates with the Ras GTPase-activating protein (RasGAP), but only when p62(dok) is tyrosine phosphorylated. Here we have investigated the interaction between p62(dok) and RasGAP and the consequences of p62(dok) tyrosine phosphorylation on the activity of RasGAP. We have found that p62(dok) is directly tyrosine phosphorylated by p210(bcr-abl), and the sites of phosphorylation are located in the C-terminal half of the p62(dok) molecule. We have identified five tyrosine residues that are involved in in vitro RasGAP binding and have found that tyrosine-phosphorylated p62(dok) inhibits RasGAP activity, Our results suggest that p210(bcr-abl) might lead to the activation of the Ras signaling pathway by inhibiting a key down-regulator of Ras signaling.