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首页> 外文期刊>Molecular and Cellular Biology >Protein Tyrosine Phosphatase 1B Antagonizes Signalling by Oncoprotein Tyrosine Kinase p210 bcr-abl In Vivo
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Protein Tyrosine Phosphatase 1B Antagonizes Signalling by Oncoprotein Tyrosine Kinase p210 bcr-abl In Vivo

机译：蛋白酪氨酸磷酸酶1B拮抗体内蛋白癌酪氨酸激酶p210 bcr-abl的信号传导。

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The p210 bcr-abl protein tyrosine kinase (PTK) appears to be directly responsible for the initial manifestations of chronic myelogenous leukemia (CML). In contrast to the extensive characterization of the PTK and its effects on cell function, relatively little is known about the nature of the protein tyrosine phosphatases (PTPs) that may modulate p210 bcr-abl-induced signalling. In this study, we have demonstrated that expression of PTP1B is enhanced specifically in various cells expressing p210 bcr-abl, including a cell line derived from a patient with CML. This effect on expression of PTP1B required the kinase activity of p210 bcr-abl and occurred rapidly, concomitant with maximal activation of a temperature-sensitive mutant of the PTK. The effect is apparently specific for PTP1B since, among several PTPs tested, we detected no change in the levels of TCPTP, the closest relative of PTP1B. We have developed a strategy for identification of physiological substrates of individual PTPs which utilizes substrate-trapping mutant forms of the enzymes that retain the ability to bind to substrate but fail to catalyze efficient dephosphorylation. We have observed association between a substrate-trapping mutant of PTP1B (PTP1B-D181A) and p210 bcr-abl, but not v-Abl, in a cellular context. Consistent with the trapping data, we observed dephosphorylation of p210 bcr-abl, but not v-Abl, by PTP1B in vivo. We have demonstrated that PTP1B inhibited binding of the adapter protein Grb2 to p210 bcr-abl and suppressed p210 bcr-abl-induced transcriptional activation that is dependent on Ras. These results illustrate selectivity in the effects of PTPs in a cellular context and suggest that PTP1B may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.
机译：p210 bcr-abl蛋白酪氨酸激酶（PTK）似乎直接导致了慢性粒细胞性白血病（CML）的最初表现。与PTK的广泛表征及其对细胞功能的影响相反，对可调节p210 bcr-abl诱导的信号转导的蛋白酪氨酸磷酸酶（PTP）性质的了解相对较少。在这项研究中，我们已经证明PTP1B的表达在表达p210 bcr-abl的各种细胞中特别是增强，包括来自CML患者的细胞系。对PTP1B表达的这种作用需要p210 bcr-abl的激酶活性，并且迅速发生，并伴随着对PTK温度敏感突变体的最大激活。该效果显然是对PTP1B特有的，因为在几个测试的PTP中，我们未检测到TCPTP（PTP1B的最接近亲戚）的水平发生变化。我们已经开发出一种鉴定单个PTP的生理底物的策略，该策略利用了酶的底物捕获突变体形式，这些形式保留了与底物结合的能力，但未能催化有效的去磷酸化作用。我们已经观察到PTP1B的底物捕获突变体（PTP1B-D181A）和p210 bcr-abl，而不是v-Abl之间的关联，在细胞中。与捕获数据一致，我们在体内观察到p210 bcr-abl（而非v-Abl）被PTP1B脱磷酸。我们已经证明，PTP1B抑制衔接蛋白Grb2与p210 bcr-abl结合，并抑制p210 bcr-abl诱导的依赖Ras的转录激活。这些结果说明了在细胞环境中PTP作用的选择性，并暗示PTP1B可能在体内充当p210 bcr-abl信号传导的特异性负调节剂。

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