EphA2 signaling following endocytosis: role of Tiam1.
EphA2 signaling following endocytosis: role of Tiam1.
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DOI：
10.1111/tra.12123
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Huynh-Do U
中科院分区：
文献类型：
--
作者：
Boissier P;Chen J;Huynh-Do U
Eph受体及其膜结合配体ephrin代表受体酪氨酸激酶（RTK）的复杂亚家族。Eph/ephrin结合可导致各种相反的细胞行为，例如粘附与排斥，或细胞迁移与细胞粘附。最近，Eph内吞作用已被确定为负责这种多样性的关键步骤之一。Eph受体与许多RTK一样，在配体介导的活化后被快速内吞，并在降解前通过内吞区室运输。然而，越来越明显的是，内吞作用以许多不同的方式控制信号传导。在这里，我们表明活化的EphA 2在溶酶体中降解，并且约35%的内化受体再循环回到质膜。我们的研究也是第一个证明EphA 2保留了在内体中发出信号的能力。特别是，激活的EphA 2与Rho家族GEF Tiam 1在内体中相互作用。这种关联导致Tiam 1激活，这反过来又增加了Rac 1活性，并促进Eph/ephrin内吞作用。用RNA干扰破坏Tiam 1功能损害了ephrinA 1依赖的Rac 1激活和ephrinA 1诱导的EphA 2内吞作用。总之，我们的研究结果揭示了EphA 2内吞作用，细胞内运输和信号终止的调节，并建立Tiam 1作为EphA 2信号传导的重要调节剂。
Eph receptors and their membrane-bound ligands, the ephrins, represent a complex subfamily of receptor tyrosine kinases (RTKs). Eph/ephrin binding can lead to various and opposite cellular behaviours such as adhesion versus repulsion, or cell migration versus cell adhesion. Recently, Eph endocytosis has been identified as one of the critical steps responsible for such diversity. Eph receptors, as many RTKs, are rapidly endocytosed following ligand-mediated activation and traffic through endocytic compartments prior to degradation. However, it is becoming obvious that endocytosis controls signalling in many different manners. Here we showed that activated EphA2 are degraded in the lysosomes and that about 35% of internalized receptors are recycled back to the plasma membrane. Our study is also the first to demonstrate that EphA2 retains the capacity to signal in endosomes. In particular, activated EphA2 interacted with the Rho family GEF Tiam1 in endosomes. This association led to Tiam1 activation, which in turn increased Rac1 activity and facilitated Eph/ephrin endocytosis. Disrupting Tiam1 function with RNA interference impaired both ephrinA1-dependent Rac1 activation and ephrinA1-induced EphA2 endocytosis. In summary, our findings shed new light on the regulation of EphA2 endocytosis, intracellular trafficking and signal termination and establish Tiam1 as an important modulator of EphA2 signalling.
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