Structures of an Eph receptor tyrosine kinase and its potential activation mechanism.
Structures of an Eph receptor tyrosine kinase and its potential activation mechanism.
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DOI：
10.1107/s1399004714021944
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发表时间：
2014-12
期刊：
影响因子：
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通讯作者：
Q. Wei;Jun Liu;Nan Wang;Xiaoying Zhang;Jin Jin-Jin;I. Chin-Sang;Jimin Zheng;Z. Jia
中科院分区：
文献类型：
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作者：
Q. Wei;Jun Liu;Nan Wang;Xiaoying Zhang;Jin Jin-Jin;I. Chin-Sang;Jimin Zheng;Z. Jia
Eph受体酪氨酸激酶（RTKs）及其ephrin配体在包括肿瘤发生在内的生理和病理生理过程中起着至关重要的作用。先前对Eph rtk的研究表明，近膜段（JMS）通过磷酸化JMS内的两个酪氨酸，在激酶激活中起调节作用。在这里，EphA2的结构代表了不同的激活状态。通过确定非磷酸化的非活性结构和磷酸化的活性结构以及另一种构象，揭示了激酶激活过程中的构象变化。研究表明，激活环中酪氨酸残基（Tyr772）的磷酸化，而没有直接参与JMS，足以激活EphA2激酶。这一机制发现与其他Eph rtk（如EphB2）的机制相反，其中两个JMS酪氨酸的磷酸化启动JMS的解离并触发激活环磷酸化以激活激酶。此外，实验表明EphA2底物PTEN，一种与肿瘤抑制有关的磷酸酶，可以调节EphA2的磷酸化状态，这是一个独特的酶-底物互惠系统的例证。基于这些研究，EphA2可能具有不同于其他Eph rtk的替代激活机制。
Eph receptor tyrosine kinases (RTKs) and their ephrin ligands play a crucial role in both physiological and pathophysiological processes, including tumourigenesis. A previous study of Eph RTKs established a regulatory role for the juxtamembrane segment (JMS) in kinase activation through the phosphorylation of two tyrosines within the JMS. Here, structures of EphA2 representing various activation states are presented. By determining the unphosphorylated inactive and phosphorylated active structures as well as an alternative conformation, conformational changes during kinase activation have been revealed. It is shown that phosphorylation of a tyrosine residue (Tyr772) in the activation loop without direct involvement of the JMS is sufficient to activate the EphA2 kinase. This mechanistic finding is in contrast to the mechanism of other Eph RTKs, such as EphB2, in which phosphorylation of the two JMS tyrosines initiates the dissociation of the JMS and triggers activation-loop phosphorylation for kinase activation. Furthermore, experiments demonstrate that the EphA2 substrate PTEN, a phosphatase that has been implicated in tumour suppression, acts to regulate the phosphorylation states of EphA2, exemplifying a unique reciprocal enzyme-substrate system. Based on these studies, it is therefore suggested that EphA2 may possess an alternate activation mechanism distinct from other Eph RTKs.