Zhou Yue, Yamada Naoki, Tanaka Tomohiro, Hori Takashi, Yokoyama Satoru, Hayakawa Yoshihiro, Yano Seiji, Fukuoka Junya, Koizumi Keiichi, Saiki Ikuo, Sakurai Hiroaki
Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Department of Diagnostic Pathology, Toyama University Hospital, Toyama 930-0194, Japan.
Nat Commun. 2015 Jul 9;6:7679. doi: 10.1038/ncomms8679.
Crosstalk between inflammatory signalling pathways and receptor tyrosine kinases has been revealed as an indicator of cancer malignant progression. In the present study, we focus on EphA2 receptor tyrosine kinase, which is overexpressed in many human cancers. It has been reported that ligand-independent phosphorylation of EphA2 at Ser-897 is induced by Akt. We show that inflammatory cytokines promote RSK-, not Akt-, dependent phosphorylation of EphA2 at Ser-897. In addition, the RSK-EphA2 signalling pathway controls cell migration and invasion of metastatic breast cancer cells. Moreover, Ser-897-phosphorylated EphA2 co-localizes with phosphorylated active form of RSK in various human tumour specimens, and this double positivity is related to poor survival in lung cancer patients, especially those with a smoking history. Taken together, these results indicate that the phosphorylation of EphA2 at Ser-897 is controlled by RSK and the RSK-EphA2 axis might contribute to cell motility and promote tumour malignant progression.
炎症信号通路与受体酪氨酸激酶之间的串扰已被揭示为癌症恶性进展的一个指标。在本研究中，我们聚焦于EphA2受体酪氨酸激酶，它在许多人类癌症中过表达。据报道，Akt可诱导EphA2在Ser-897位点发生非配体依赖性磷酸化。我们发现，炎症细胞因子可促进RSK而非Akt依赖性的EphA2在Ser-897位点的磷酸化。此外，RSK-EphA2信号通路控制转移性乳腺癌细胞的迁移和侵袭。而且，Ser-897磷酸化的EphA2与RSK的磷酸化活性形式在各种人类肿瘤标本中共定位，这种双阳性与肺癌患者尤其是有吸烟史患者的不良生存相关。综上所述，这些结果表明EphA2在Ser-897位点的磷酸化受RSK调控，且RSK-EphA2轴可能有助于细胞运动并促进肿瘤恶性进展。
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