The oncogenic lung cancer fusion kinase CD74-ROS activates a novel invasiveness pathway through E-Syt1 phosphorylation.
The oncogenic lung cancer fusion kinase CD74-ROS activates a novel invasiveness pathway through E-Syt1 phosphorylation.
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DOI：
10.1158/0008-5472.can-11-3990
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发表时间：
2012-08-01
期刊：
影响因子：
11.2
通讯作者：
Charest A
中科院分区：
文献类型：
--
作者：
Jun HJ;Johnson H;Bronson RT;de Feraudy S;White F;Charest A
肺癌患者通常伴有转移性疾病，因此预后非常差。最近在非小细胞肺癌(NSCLC)中发现了几种新的ROS受体酪氨酸激酶分子改变，这为开发新的靶向治疗策略提供了治疗机会。在这里，我们报告了NSCLC来源的融合CD74-ROS，占NSCLC中所有ROS融合蛋白的30%，是一种活性和致癌的酪氨酸酶。我们发现表达CD74-ROS的细胞在体外具有高度侵袭性，在体内具有转移性。药物抑制CD74-ROS激酶活性可通过减弱下游信号网络来逆转其转化能力。利用定量磷酸蛋白质组学，我们揭示了CD74-ROS激活一条驱动细胞侵袭的新途径的机制。CD74-ROS的表达导致延伸的突触素样蛋白E-Syt1的磷酸化。在不改变CD74-ROS的致癌活性的情况下，消除E-Syt1的表达可以显著降低体外和体内的侵袭性。此外，CD74-ROS在非侵袭性NSCLC细胞系中的表达很容易产生侵袭性，这与E-Syt1磷酸化的获得是平行的。综上所述，我们的研究结果表明，E-Syt1是癌细胞侵袭的介质，并从分子上确定了ROS融合蛋白激酶作为治疗NSCLC的靶点。
Patients with lung cancer often present with metastatic disease and therefore have a very poor prognosis. The recent discovery of several novel ROS receptor tyrosine kinase molecular alterations in non-small-cell lung cancer (NSCLC) presents a therapeutic opportunity for the development of new targeted treatment strategies. Here, we report that the NSCLC-derived fusion CD74-ROS, which accounts for 30% of all ROS fusion kinases in NSCLC, is an active and oncogenic tyrosine kinase. We found that CD74-ROS expressing cells were highly invasive in vitro and metastatic in vivo. Pharmacological inhibition of CD74-ROS kinase activity reversed its transforming capacity by attenuating downstrream signaling networks. Using quantitative phosphoproteomics, we uncovered a mechanism by which CD74-ROS activates a novel pathway driving cell invasion. Expression of CD74-ROS resulted in the phosphorylation of the extended synaptotagmin-like protein E-Syt1. Elimination of E-Syt1 expression drastically reduced invasiveness both in vitro and in vivo without modifying the oncogenic activity of CD74-ROS. Furthermore, expression of CD74-ROS in non-invasive NSCLC cell lines readily confered invasive properties that paralleled the acquisition of E-Syt1 phosphorylation. Taken together, our findings indicate that E-Syt1 is a mediator of cancer cell invasion and molecularly define ROS fusion kinases as therapeutic targets in the treatment of NSCLC.