The Hippo effector YAP1/TEAD1 regulates EPHA3 expression to control cell contact and motility

Marwah M Al-Mathkour,Esma Alp,Ava M Boston,Bekir Cinar,Abdulrahman M Dwead

doi:10.1038/s41598-022-07790-4

Marwah M Al-Mathkour, Esma Alp + Show 3 more

Open Access

https://doi.org/10.1038/s41598-022-07790-4

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Abstract

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.

Highlights

The ephrin type-A receptor 3 (EPHA3) protein tyrosine kinase, a member of the ephrin receptor family, regulates cell fate, cell motility, and cell–cell interaction
The results showed that LNCaP, C4-2, 22Rv1, and PC3 cell differentially expressed Ephrin A (EphA) and Ephrin B (EphB) receptors and their ligands, as demonstrated by reverse transcriptase (RT)-polymerase chain reaction (PCR) (Fig. 1a–c; Figure S1 and S2)
We have identified the STK4/MST1-YAP1-TEAD1 axis as a crucial transcriptional regulator of EPHA3 expression and functions

Summary

Introduction

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. EPHA3 knockout by CRISPR/Cas[9] 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. Increasing evidence suggests that dysregulated EPHA3 signaling is implicated in multiple malignancies with poorer p rognosis[45–48] Despite these observations, little is known about the mechanism contributing to the transcriptional regulation of EPHA3

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