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Receptor Protein Tyrosine Phosphatase-Receptor Tyrosine Kinase Substrate Screen Identifies EphA2 as a Target for LAR in Cell Migration

机译:受体蛋白酪氨酸磷酸酶-受体酪氨酸激酶底物筛选确定EphA2作为细胞迁移中LAR的靶标

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Receptor tyrosine kinases (RTKs) exist in equilibrium between tyrosyl-phosphorylated and dephosphorylated states. Despite a detailed understanding of how RTKs become tyrosyl phosphorylated, much less is known about RTK tyrosyl dephosphorylation. Receptor protein tyrosine phosphatases (RPTPs) can play essential roles in the dephosphorylation of RTKs. However, a complete understanding of the involvement of the RPTP subfamily in RTK tyrosyl dephosphorylation has not been established. In this study, we have employed a small interfering RNA (siRNA) screen to identify RPTPs in the human genome that serve as RTK phosphatases. We observed that each RPTP induced a unique fingerprint of tyrosyl phosphorylation among 42 RTKs. We identified EphA2 as a novel LAR substrate. LAR dephosphorylated EphA2 at phosphotyrosyl 930, uncoupling Nck1 from EphA2 and thereby attenuating EphA2-mediated cell migration. These results demonstrate that each RPTP exerts a unique regulatory fingerprint of RTK tyrosyl dephosphorylation and suggest a complex signaling interplay between RTKs and RPTPs. Furthermore, we observed that LAR modulates cell migration through EphA2 site-specific dephosphorylation.
机译:受体酪氨酸激酶(RTKs)在酪氨酰磷酸化和去磷酸化状态之间处于平衡状态。尽管对RTK如何变成酪氨酰磷酸化有了详细的了解,但对RTK酪氨酰去磷酸化的了解却很少。受体蛋白酪氨酸磷酸酶(RPTP)可以在RTK的去磷酸化中发挥重要作用。但是,尚未完全了解RPTP亚家族参与RTK酪氨酰去磷酸化。在这项研究中,我们采用了一个小的干扰RNA(siRNA)筛选来鉴定人类基因组中充当RTK磷酸酶的RPTP。我们观察到,每个RPTP诱导42个RTK之间的酪氨酰磷酸化的唯一指纹。我们确定EphA2为新型LAR底物。 LAR在磷酸酪氨酰930处使EphA2去磷酸化,将Nck1与EphA2解偶联,从而减弱EphA2介导的细胞迁移。这些结果表明,每个RPTP均具有RTK酪氨酰去磷酸化的独特调控指纹,并暗示RTK和RPTP之间存在复杂的信号相互作用。此外,我们观察到LAR通过EphA2位点特异性去磷酸化调节细胞迁移。

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