PDF(Pubmed)
Abstract：
As an output effector of the Hippo signaling pathway, the TEAD transcription factor and co-activator YAP play crucial functions in promoting cell proliferation and organ size. The tumor suppressor NF2 has been shown to activate LATS1/2 kinases and interplay with the Hippo pathway to suppress the YAP-TEAD complex. However, whether and how NF2 could directly regulate TEAD remains unknown. We identified a direct link and physical interaction between NF2 and TEAD4. NF2 interacted with TEAD4 through its FERM domain and C-terminal tail and decreased the protein stability of TEAD4 independently of LATS1/2 and YAP. Furthermore, NF2 inhibited TEAD4 palmitoylation and induced the cytoplasmic translocation of TEAD4, resulting in ubiquitination and dysfunction of TEAD4. Moreover, the interaction with TEAD4 is required for NF2 function to suppress cell proliferation. These findings reveal an unanticipated role of NF2 as a binding partner and inhibitor of the transcription factor TEAD, shedding light on an alternative mechanism of how NF2 functions as a tumor suppressor through the Hippo signaling cascade.
摘要：
作为Hippo信号通路的输出效应子,TEAD转录因子和共激活因子YAP在促进细胞增殖和器官大小方面发挥关键作用。已显示肿瘤抑制因子NF2激活LATS1/2激酶并与Hippo途径相互作用以抑制YAP-TEAD复合物。然而,NF2是否以及如何直接调节TEAD仍然未知。我们确定了NF2和TEAD4之间的直接联系和物理相互作用。NF2通过其FERM结构域和C末端尾部与TEAD4相互作用，并独立于LATS1/2和YAP降低TEAD4的蛋白质稳定性。此外，NF2抑制TEAD4棕榈酰化并诱导TEAD4的细胞质易位，导致TEAD4的泛素化和功能障碍。此外，与TEAD4的相互作用是NF2功能抑制细胞增殖所必需的。这些发现揭示了NF2作为转录因子TEAD的结合伴侣和抑制剂的意想不到的作用，揭示了NF2如何通过Hippo信号级联作为肿瘤抑制因子的替代机制。
