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Phosphorylation of PLCγ1 by EphA2 receptor tyrosine kinase promotes tumor growth in lung cancer
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2020-08-04 , DOI: 10.1158/1541-7786.mcr-20-0075
Wenqiang Song 1, 2 , Laura C Kim 3 , Wei Han 4 , Yuan Hou 5 , Deanna N Edwards 1 , Shan Wang 1 , Timothy S Blackwell 2, 4, 6 , Feixiong Cheng 5, 7, 8 , Dana M Brantley-Sieders 1, 9 , Jin Chen 1, 2, 3, 6, 9
Affiliation  

EphA2 receptor tyrosine kinase (RTK) is often expressed at high levels in cancer and has been shown to regulate tumor growth and metastasis across multiple tumor types, including non–small cell lung cancer. A number of signaling pathways downstream of EphA2 RTK have been identified; however, mechanisms of EphA2 proximal downstream signals are less well characterized. In this study, we used a yeast-two-hybrid screen to identify phospholipase C gamma 1 (PLCγ1) as a novel EphA2 interactor. EphA2 interacts with PLCγ1 and the kinase activity of EphA2 was required for phosphorylation of PLCγ1. In human lung cancer cells, genetic or pharmacologic inhibition of EphA2 decreased phosphorylation of PLCγ1 and loss of PLCγ1 inhibited tumor cell growth in vitro. Knockout of PLCγ1 by CRISPR-mediated genome editing also impaired tumor growth in a KrasG12D-p53-Lkb1 murine lung tumor model. Collectively, these data show that the EphA2-PLCγ1 signaling axis promotes tumor growth of lung cancer and provides rationale for disruption of this signaling axis as a potential therapeutic option. Implications: The EphA2-PLCG1 signaling axis promotes tumor growth of non–small cell lung cancer and can potentially be targeted as a therapeutic option.

中文翻译:

EphA2受体酪氨酸激酶磷酸化PLCγ1促进肺癌肿瘤生长

EphA2 受体酪氨酸激酶 (RTK) 通常在癌症中高水平表达,并已被证明可以调节多种肿瘤类型(包括非小细胞肺癌)的肿瘤生长和转移。EphA2 RTK 下游的许多信号通路已被确定;然而,EphA2 近端下游信号的机制尚不清楚。在这项研究中,我们使用酵母双杂交筛选来鉴定磷脂酶 C gamma 1 (PLCγ1) 作为一种新型 EphA2 相互作用蛋白。EphA2 与 PLCγ1 相互作用,EphA2 的激酶活性是 PLCγ1 磷酸化所必需的。在人肺癌细胞中,EphA2 的遗传或药理抑制会降低 PLCγ1 的磷酸化,而 PLCγ1 的缺失会抑制体外肿瘤细胞的生长。通过 CRISPR 介导的基因组编辑敲除 PLCγ1 也会损害 KrasG12D-p53-Lkb1 小鼠肺肿瘤模型中的肿瘤生长。总的来说,这些数据表明 EphA2-PLCγ1 信号轴促进肺癌的肿瘤生长,并为破坏该信号轴作为潜在的治疗选择提供了理论基础。意义:EphA2-PLCG1 信号轴促进非小细胞肺癌的肿瘤生长,并有可能成为一种治疗选择。
更新日期:2020-08-04
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