Hippo/YAP signaling's multifaceted crosstalk in cancer

Abstract

The Hippo/yes-associated protein (YAP) signaling is an evolutionarily conserved regulator in organ size control, which plays pivotal roles in cell proliferation, differentiation, apoptosis, and tissue regeneration. In cancer, dysregulation of Hippo/YAP signaling is typically recognized as one of the crucial drivers in tumorigenesis. However, beyond its canonical transcriptional targets, Hippo/YAP signaling engages in extensive crosstalk with multiple pathways to form an intricate regulatory network, thereby giving rise to its content-dependent influence on tumor initiation, progression and metastasis. This review focuses on the molecular mechanisms underlying the interplay between Hippo/YAP and pivotal signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), wingless-type (Wnt)/β-catenin signaling pathway, transforming growth factor-beta (TGF-β), Hedgehog, Notch and other signaling pathways, as well as their implications in cancer biology. Ultimately, exploiting these mechanisms may represent promising therapeutic strategies for cancer.

Keywords: Hippo/YAP signaling; cancer; crosstalk; signaling pathway; therapeutic target.

FIGURE 1

Canonical regulation of hippo signaling. Under Hippo On conditions (left), phosphorylated upstream kinases MST1/2 form a complex with SAV1 to phosphorylate and activate LATS1/2–MOB1 complex. Activated LATS1/2 phosphorylates the co-activators YAP and TAZ, leading to their cytoplasmic retention via binding to 14-3-3 proteins and subsequent degradation through proteasome, thereby preventing their nuclear translocation and transcriptional activity. The phosphatase PPM1A can counteract this process by dephosphorylating YAP/TAZ. In contrast, under Hippo Off conditions (right), the kinase cascade is inactive, and YAP/TAZ remain unphosphorylated. This allows them to accumulate in the nucleus, where they bind to TEAD transcription factors and promote the expression of genes like CTGF and CYR61, which involved in cell proliferation and survival. This signaling switch integrates inputs from mechanical stress, cell polarity, and oncogenic signals to maintain tissue homeostasis.

FIGURE 2

Mechanistic crosstalk between YAP and other pathways in cancer. In NF-κB pathway, YAP acts as a p65 co-activator or competitor, modulating inflammation and metastasis. In Wnt/β-catenin pathway, YAP forms complex with β-catenin to drive or suppress Wnt target genes, modulating tumor cell proliferation and survival. In TGF-β pathway, YAP binds with Smad2/3, altering transcription or nuclear retention, modulating cell survival and linked with resistance to cancer therapies. In Hedgehog pathway, YAP regulates Gli1 activity and its nuclear localization, inhibiting cell differentiation and modulating tumor cell proliferation. In Notch pathway, YAP modulates Jagged-1, promoting or limiting Notch signaling in a context-dependent manner, regulating cancer stem cell maintenance and tumorigenesis.