The cell polarity protein MPP5/PALS1 controls the subcellular localization of the oncogenes YAP and TAZ in hepatocellular carcinoma

The oncogenes yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are potent oncogenes in the liver. Mutations in upstream regulators cannot explain the nuclear enrichment of both proteins, illustrating that other mechanisms might affect their subcellular localization and activity. In this project, we aim to understand which mechanisms support the activation of YAP/TAZ in liver cancer.

Through proteomics, we identified numerous apical cell polarity complex proteins that interact with YAP and TAZ. A subsequent functional screen revealed that the loss of MPP5 (synonym: PALS1) in liver cancer cells led to the nuclear enrichment of YAP/TAZ. Co-immunoprecipitation (co-IP) experiments showed that MPP5 physically interacts with YAP and TAZ. Subsequent co-IP analyses, after removing four distinct MPP5 protein domains, revealed that the PDZ and Gukc domains play a crucial role in YAP binding. The interaction between YAP/TAZ and MPP5 in the cytoplasm of liver cancer cells was confirmed by proximity ligation assays (PLAs). In human hepatocellular carcinoma (HCC) tissues, a reduction of apical MPP5 was observed, positively correlating with the nuclear accumulation of YAP and TAZ. Expression data analysis illustrated that MPP5 is inversely associated with YAP/TAZ target gene signatures in human HCCs. Lastly, low MPP5 levels define an HCC patient group with poor clinical outcome.

The loss or improper localization of MPP5 facilitates the nuclear accumulation of the oncogenes YAP and TAZ in HCC cells. This qualifies MPP5 as a tumor-suppressor gene in hepatocarcinogenesis and explains how the loss of cell polarity can foster tumorigenesis.

Publication History

Article published online:
20 January 2025