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Integrins are transmembrane proteins that transmit bi‐directional signals across the cell membrane through global structural rearrangement among three different conformational states: bent, extended‐ closed, and extended‐open conformations. However, the β8 integrin is distinctive and may adopt only one conformation, that is, extended‐closed conformation, with high affinity for ligands under physiological conditions, and may not transmit bi‐directional signals like other integrin members. It is unclear how different β8 domains affect its unique conformation and signaling. We swapped different domains of integrin β3 with those of β8 and investigated how they affected integrin ligand binding, global conformation, and outside‐in signaling. We found that the β8 epidermal growth factor (EGF) domains increased integrin ligand binding ability and contributed to its extended conformation. By comparison, the β8 transmembrane and cytoplasmic domains had little effect on ligand binding or global conformation. The β8 EGF and transmembrane domains did not affect integrin‐mediated cell adhesion, cell spreading, focal adhesion formation, or colocalization of integrin with other proteins, but the cytoplasmic domain had a defective effect on outside‐in signaling. Our results showed that different domains of β8 play various roles on its unique conformation, ligand binding, and signaling, which are considered atypical among integrin members. [ABSTRACT FROM AUTHOR]

• EBV can upregulate the PI3K/AKT pathway through its encoded EBER1 and LMP2A, thereby promoting the expression of YAP1 in EBVaGC cells. • YAP1 enhances the proliferation, migration, autophagy, S-phase accumulation, and anti-apoptotic ability of EBVaGC cells, which may play carcinogenic role in EBVaGC progression. • YAP1 also enhances EBV replication, and TPA and NaB induced EBV lytic reactivation, forming a bidirectional regulatory mechanism with EBV, further promoting the development of EBVaGC. This study aims to explore the role and regulatory mechanism of Yes-associated protein 1 (YAP1) in the development of Epstein-Barr virus-associated gastric cancer (EBVaGC). Here we showed that EBV can upregulate the expression and activity of YAP1 protein through its encoded latent products EBV-encoded small RNA 1 (EBER1) and latent membrane protein 2A (LMP2A), enhancing the malignant characteristics of EBVaGC cells. In addition, we also showed that overexpression of YAP1 induced the expression of EBV encoding latent and lytic phase genes and proteins in the epithelial cell line AGS-EBV infected with EBV, and increased the copy number of the EBV genome, while loss of YAP1 expression reduced the aforementioned indicators. Moreover, we found that YAP1 enhanced EBV lytic reactivation induced by two known activators, 12-O-tetradecanoylhorbol-13-acetate (TPA) and sodium butyrate (NaB). These results indicated a bidirectional regulatory mechanism between EBV and YAP1 proteins, providing new experimental evidence for further understanding the regulation of EBV infection patterns and carcinogenic mechanisms in gastric cancer. [ABSTRACT FROM AUTHOR]