Serine 897 Phosphorylation of EPHA2 Is Involved in Signaling of Oncogenic ERK1/2 Drivers in Thyroid Cancer Cells
Serine 897 Phosphorylation of EPHA2 Is Involved in Signaling of Oncogenic ERK1/2 Drivers in Thyroid Cancer Cells
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DOI：
10.1089/thy.2019.0728
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发表时间：
2020-09-08
期刊：
影响因子：
6.6
通讯作者：
Castellone, Maria Domenica
中科院分区：
文献类型：
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作者：
Allocca, Chiara;Cirafici, Anna Maria;Castellone, Maria Domenica
背景：EPHA 2受体酪氨酸激酶（RTK）丝氨酸897（S897）的胞内结构域磷酸化已被证明介导EPHA 2致癌活性。在这里，我们表明，在甲状腺癌细胞中，携带驱动癌基因，通过细胞外调节激酶（ERK 12）信号传导途径[重排RET RTK（RET/PTC），KRAS（G12 R），或BRAF（V600 E）癌基因]，EPHA 2在S897上强烈磷酸化。EPHA 2 S897嵌入在一个共有序列中，用于被AGC家族激酶磷酸化，包括p90 RSK（核糖体蛋白S6激酶），一种直接ERK 1/2靶标。方法：我们发现重组p90 RSK在体外EPHA 2 S897磷酸化，并且用靶向p90 RSK或ERK 1/2途径的其他组分的化学抑制剂治疗使S897磷酸化钝化。结果：RNA干扰介导的敲低结合拯救实验证明EPHA 2 S897磷酸化介导甲状腺癌细胞增殖和运动。结论：这些发现表明EPHA 2 S897是甲状腺癌中ERK 1/2信号级联致癌活性的关键介质。
Background:Phosphorylation of the intracellular domain of the EPHA2 receptor tyrosine kinase (RTK) on serine 897 (S897) has been demonstrated to mediate EPHA2 oncogenic activity. Here, we show that in thyroid cancer cells harboring driver oncogenes that signal through the extracellular regulated kinase (ERK1/2) signaling pathway [rearranged RET RTK (RET/PTC), KRAS(G12R), or BRAF(V600E)oncogenes], EPHA2 is robustly phosphorylated on S897. EPHA2 S897 is embedded in a consensus sequence for phosphorylation by the AGC family kinases, including p90RSK (ribosomal protein S6 kinase), a direct ERK1/2 target. Methods:We show that recombinant p90RSK phosphorylatesin vitroEPHA2 S897 and that treatment with chemical inhibitors targeting p90RSK or other components of the ERK1/2 pathway blunts S897 phosphorylation. Results:RNA interference-mediated knockdown combined with rescue experiments demonstrated that EPHA2 S897 phosphorylation mediates thyroid cancer cell proliferation and motility. Conclusions:These findings point to EPHA2 S897 as a crucial mediator of the oncogenic activity of the ERK1/2 signaling cascade in thyroid cancer.