Hippo Signaling Pathway in Cancer Biology

The Hippo signalling pathway is an evolutionarily conserved network of kinases and adaptors that governs organ size, tissue homeostasis and cell fate. At its core, the sterile 20-like kinases MST1/2 phosphorylate and activate the large tumour suppressors LATS1/2, which in turn phosphorylate the transcriptional co-activators YAP and TAZ. Phosphorylated YAP/TAZ are sequestered in the cytoplasm or targeted for degradation, preventing their association with TEAD transcription factors in the nucleus. Proper activation of Hippo restricts cell proliferation, promotes apoptosis and maintains contact inhibition. Conversely, pathway inactivation—through loss of MST1/2 or LATS1/2 function, deregulation of upstream regulators such as the NF2 (Merlin) tumour suppressor, or altered cell polarity and mechanical cues—permits nuclear accumulation of YAP/TAZ. There they drive expression of genes that foster proliferation, epithelial-mesenchymal transition, stem-like traits, invasion and resistance to therapy. Cross-talk with signalling cascades including Wnt, TGF-β and Bcl-2 family members further amplifies oncogenic programmes. Aberrant Hippo signalling is implicated in a broad spectrum of malignancies, from hepatocellular carcinoma to gastric, breast and lung tumours. Therapeutic strategies are now emerging to restore pathway integrity or to block YAP/TAZ–TEAD interactions, heralding precision approaches to curb tumour growth and metastasis.

Research from Nature Portfolio

Recent mechanistic studies have refined our understanding of kinase redundancy within the core Hippo cascade. A seminal analysis revealed that members of the MAP4K family act in parallel to MST1/2 as direct activators of LATS1/2, thereby ensuring robust phosphorylation of YAP/TAZ across diverse stimuli and uncovering a previously underappreciated layer of pathway resilience. In addition, contemporary investigations into cell competition have demonstrated that activation of YAP1 in young glial progenitor cells endows them with a MYC/E2F-driven “winner” phenotype capable of displacing diseased or aged neighbours. Although conducted in a neurobiological context, these findings illuminate general principles by which YAP1-mediated transcriptional programmes may sculpt tumour-niche interactions and influence clonal dominance within malignancies.

Hippo Signaling Pathway in Cancer Biology publication trend

The graph below shows the total number of articles in hippo signaling pathway in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

MST1/2: Mammalian sterile 20-like kinases that initiate the Hippo kinase cascade through phosphorylation of downstream effectors.

LATS1/2: Large tumour suppressor kinases activated by MST1/2 (and MAP4Ks) that phosphorylate YAP/TAZ to inhibit their transcriptional activity.

YAP/TAZ: Transcriptional co-activators regulated by Hippo phosphorylation; unphosphorylated forms translocate to the nucleus to drive proliferative and anti-apoptotic gene expression.

TEAD: A family of DNA-binding transcription factors that partner with YAP/TAZ to regulate expression of genes governing cell proliferation, survival and migration.

NF2 (Merlin): An upstream tumour suppressor that links cell–cell junctions and membrane–cytoskeleton interactions to activation of the Hippo kinase cascade.

References

1. Young glial progenitor cells competitively replace aged and diseased human glia in the adult chimeric mouse brain. Nature Biotechnology (2023).
2. Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency. Molecular Cancer (2023).
3. Mst1 and Mst2 Maintain Hepatocyte Quiescence and Suppress Hepatocellular Carcinoma Development through Inactivation of the Yap1 Oncogene. Cancer Cell (2009).
4. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nature Communications (2015).