Hippo途径效应子Yes相关蛋白1(YAP)及其同源物TAZ是转录共激活因子,可通过与TEA结构域(TEAD)家族转录因子结合来控制基因表达。YAP/TAZ-TEAD复合物是癌症特异性转录程序的关键调节因子。促进不同类型癌症的肿瘤进展,包括乳腺癌.尽管付出了巨大的努力,YAP/TAZ-TEAD复合物在很大程度上仍然无法通过药物治疗,原因是对机制的理解不完全.这里,我们报道了核磷酸肌醇作为介导YAP/TAZ与TEAD结合的辅因子。磷酸肌醇激酶PIPKIα和IPMK的酶产物,包括磷脂酰肌醇4,5-二磷酸(PI(4,5)P2)和磷脂酰肌醇3,4,5-三磷酸(P(I3,4,5)P3),桥接YAP/TAZ与TEAD的绑定。抑制这些激酶或YAP/TAZ与PI(4,5)P2和PI(3,4,5)P3的结合减弱了YAP/TAZ与TEAD的相互作用,YAP/TAZ靶基因的表达,和乳腺癌细胞运动。虽然我们不能最终排除IPMK的其他酶产物如肌醇磷酸在机制中发挥作用的可能性,我们的研究结果表明,核磷酸肌醇信号转导在控制YAP/TAZ活性中的作用以前未被认识到,并暗示该通路是YAP/TAZ驱动的乳腺癌的潜在治疗靶点.
The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ-TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ-TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of
phosphoinositide kinases PIPKIα and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear
phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer.