Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy.
Cell Death Dis. 2023 Jan 17;14(1):32. doi: 10.1038/s41419-023-05569-7.
YES-associated protein (YAP) is a transcriptional cofactor with a key role in the regulation of several physio-pathological cellular processes, by integrating multiple cell autonomous and microenvironmental cues. YAP is the main downstream effector of the Hippo pathway, a tumor-suppressive signaling able to transduce several extracellular signals. The Hippo pathway acts restraining YAP activity, since its activation induces YAP phosphorylation and cytoplasmic sequestration. However, recent observations indicate that YAP activity can be also modulated by Hippo independent/integrating pathways, still largely unexplored. In this study, we demonstrated the role of the extracellular signal-regulated kinase 5 (ERK5)/mitogen-activated protein kinase in the regulation of YAP activity. By means of ERK5 inhibition/silencing and overexpression experiments, and by using as model liver stem cells, hepatocytes, and hepatocellular carcinoma (HCC) cell lines, we provided evidence that ERK5 is required for YAP-dependent gene expression. Mechanistically, ERK5 controls the recruitment of YAP on promoters of target genes and its physical interaction with the transcriptional partner TEAD; moreover, it mediates the YAP activation occurring in cell adhesion, migration, and TGFβ-induced EMT of liver cells. Furthermore, we demonstrated that ERK5 signaling modulates YAP activity in a LATS1/2-independent manner. Therefore, our observations identify ERK5 as a novel upstream Hippo-independent regulator of YAP activity, thus unveiling a new target for therapeutic approaches aimed at interfering with its function.
Yes 相关蛋白 (YAP) 是一种转录共激活因子，在整合多种细胞自主和微环境信号的情况下，对多种生理病理细胞过程的调节起着关键作用。YAP 是 Hippo 通路的主要下游效应因子，Hippo 通路是一种肿瘤抑制信号，能够转导多种细胞外信号。Hippo 通路通过抑制 YAP 的活性来发挥作用，因为其激活会诱导 YAP 的磷酸化和细胞质隔离。然而，最近的观察表明，YAP 的活性也可以通过 Hippo 非依赖/整合途径来调节，这些途径仍在很大程度上尚未被探索。在这项研究中，我们证明了细胞外信号调节激酶 5 (ERK5)/丝裂原活化蛋白激酶在 YAP 活性调节中的作用。通过 ERK5 抑制/沉默和过表达实验，并使用肝干细胞、肝细胞和肝癌 (HCC) 细胞系作为模型，我们提供了证据表明 ERK5 是 YAP 依赖性基因表达所必需的。从机制上讲，ERK5 控制 YAP 在靶基因启动子上的募集及其与转录伙伴 TEAD 的物理相互作用；此外，它介导了细胞黏附、迁移和 TGFβ 诱导的 EMT 过程中发生的 YAP 激活。此外，我们证明 ERK5 信号以 LATS1/2 非依赖的方式调节 YAP 的活性。因此，我们的观察结果将 ERK5 鉴定为 YAP 活性的一种新型 Hippo 非依赖的上游调节剂，从而为旨在干扰其功能的治疗方法揭示了一个新的靶点。
