Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion.
Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion.
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DOI：
10.1038/ncomms14646
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发表时间：
2017-03-15
影响因子：
16.6
通讯作者：
Norman JC
中科院分区：
文献类型：
--
作者：
Gundry C;Marco S;Rainero E;Miller B;Dornier E;Mitchell L;Caswell PT;Campbell AD;Hogeweg A;Sansom OJ;Morton JP;Norman JC
已知Rab GT3效应物Rab偶联蛋白（RCP）通过控制整合素和受体酪氨酸激酶（RTK）运输促进体外侵袭行为，但RCP如何影响体内转移尚不清楚。在这里，我们确定了RTK的Eph家族，EphA 2，是一个货物的RCP调节的内吞途径，控制细胞：细胞排斥和体内转移。通过狐猴酪氨酸激酶-3（LMTK 3）在Ser 435处的RCP和通过Akt在Ser 897处的EphA 2的磷酸化都是促进EphA 2的Rab 14依赖性（和Rab 11独立性）运输所必需的，其产生驱使肿瘤细胞分开的细胞：细胞排斥事件。RCP或EphA 2的遗传破坏在胰腺腺癌的本地小鼠模型中对抗细胞：细胞排斥和转移，而另一种RCP货物α5整联蛋白的条件性敲除不抑制胰腺癌转移，这表明Eph受体的RCP依赖性运输在体内驱动肿瘤扩散的作用。肝配蛋白受体介导的接触抑制，但在这一过程中他们的细胞内运输是未知的。在这里，作者表明EphA 2受体运输受Rab GT3效应器Rab偶联蛋白的调节，Rab GT3效应器Rab偶联蛋白在LMTK 3介导的磷酸化后与Rab 14内体缔合。
The Rab GTPase effector, Rab-coupling protein (RCP) is known to promote invasive behaviour in vitro by controlling integrin and receptor tyrosine kinase (RTK) trafficking, but how RCP influences metastasis in vivo is unclear. Here we identify an RTK of the Eph family, EphA2, to be a cargo of an RCP-regulated endocytic pathway which controls cell:cell repulsion and metastasis in vivo. Phosphorylation of RCP at Ser435 by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser897 by Akt are both necessary to promote Rab14-dependent (and Rab11-independent) trafficking of EphA2 which generates cell:cell repulsion events that drive tumour cells apart. Genetic disruption of RCP or EphA2 opposes cell:cell repulsion and metastasis in an autochthonous mouse model of pancreatic adenocarcinoma—whereas conditional knockout of another RCP cargo, α5 integrin, does not suppress pancreatic cancer metastasis—indicating a role for RCP-dependent trafficking of an Eph receptor to drive tumour dissemination in vivo. Ephrin receptors mediate contact inhibition, but their intracellular trafficking during this process is unknown. Here the authors show that EphA2 receptor trafficking is regulated by the Rab GTPase effector Rab-coupling protein, which associates with Rab14-endosomes upon LMTK3-mediated phosphorylation.