Department of Biology and the Center for Cancer Research and Therapeutic Development, Clark Atlanta University, 223 James P. Brawley Dr, SW, Atlanta, GA, 30314, USA.
Winship Cancer Institute, Emory University, Atlanta, GA, USA.
Sci Rep. 2022 Mar 9;12(1):3840. doi: 10.1038/s41598-022-07790-4.
The EPHA3 protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, cell motility, and cell-cell interaction. These cellular events are critical for tissue development, immunological responses, and the processes of tumorigenesis. Earlier studies revealed that signaling via the STK4-encoded MST1 serine-threonine protein kinase, a core component of the Hippo pathway, attenuated EPHA3 expression. Here, we investigated the mechanism by which MST1 regulates EPHA3. Our findings have revealed that the transcriptional regulators YAP1 and TEAD1 are crucial activators of EPHA3 transcription. Silencing YAP1 and TEAD1 suppressed the EPHA3 protein and mRNA levels. In addition, we identified putative TEAD enhancers in the distal EPHA3 promoter, where YAP1 and TEAD1 bind and promote EPHA3 expression. Furthermore, EPHA3 knockout by CRISPR/Cas9 technology reduced cell-cell interaction and cell motility. These findings demonstrate that EPHA3 is transcriptionally regulated by YAP1/TEAD1 of the Hippo pathway, suggesting that it is sensitive to cell contact-dependent interactions.
Epha3 蛋白酪氨酸激酶是 Ephrin 受体家族的成员，调节细胞命运、细胞迁移和细胞-细胞相互作用。这些细胞事件对于组织发育、免疫反应和肿瘤发生过程至关重要。早期研究表明，通过 STK4 编码的 MST1 丝氨酸-苏氨酸蛋白激酶（Hippo 通路的核心组成部分）进行信号转导，可减弱 EphA3 的表达。在这里，我们研究了 MST1 调节 EphA3 的机制。我们的研究结果表明，转录调节剂 YAP1 和 TEAD1 是 EphA3 转录的关键激活剂。沉默 YAP1 和 TEAD1 可抑制 EphA3 蛋白和 mRNA 水平。此外，我们在远端 EphA3 启动子中鉴定出了推定的 TEAD 增强子，YAP1 和 TEAD1 结合并促进 EphA3 的表达。此外，CRISPR/Cas9 技术敲除 EphA3 可减少细胞-细胞相互作用和细胞迁移。这些发现表明 EphA3 受 Hippo 通路的 YAP1/TEAD1 转录调控，表明其对细胞接触依赖性相互作用敏感。
