Extracellular signal-Regulated Kinase 5 (ERK5) is required for the Yes-associated protein (YAP) co-transcriptional activity

Abstract

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.

Bone and Extracellular Signal-Related Kinase 5 (ERK5)

“…Although sparingly discussed [144,145], ERK5 is suggested to facilitate tumor growth in ovarian cancer by upregulating type II collagen expression and enhancing cancer cell proliferation, invasion, and migration [111]. ERK5 plays a role in the pathogenesis and progression of various cancers [84,146]. Charlson et al posited that ERK5 could act as an auxiliary mediator, conveying stimulatory signals from diverse tumor promoters and participating in the regulation of tumor development [147].…”

The Role of Mechanotransduction in Contact Inhibition of Locomotion and Proliferation

“…More specifically, the majority of Yorkie (the Drosophila ortholog of YAP1) dynamically fluctuates between the cytoplasm and nucleus, and a cycle of fast exit of nuclear YAP1 to the cytoplasm followed by fast re-entry to the nucleus ("localizationresets") activates YAP1 target genes [56]. Furthermore, extracellular signal-regulated kinase 5 (ERK5)/mitogen-activated protein kinase 7 (MAPK7) are essential for YAP1/TEAD interaction and YAP1 recruitment on DNA in liver cells [57]. Additionally, Necl-4 and 5 regulate CIP through ERK1/2 (MAPK3/MAPK1) [58] (Figure 2).…”

Role of CELF2 in ferroptosis: Potential targets for cancer therapy (Review)

“…YAP is a co-transcription factor that interacts with DNA-binding transcription factors to regulate diverse cellular behaviours (39). Recent studies have revealed that YAP is located downstream of the MAPK pathway and that ERK1/2/5 (40)(41)(42), p38 (41), mechanistic target of rapamycin (mTOR)C2 (43) and c-Myc (44) can activate YAP in a non-Hippo pathway-dependent manner. Notably, the reciprocal upregulation of c-Myc and YAP has been observed in hepatocellular carcinoma.…”