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

The oncogenes yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are potent liver oncogenes. Because gene mutations cannot fully explain their nuclear enrichment, we aim to understand which mechanisms cause YAP/TAZ activation in liver cancer cells. The combinat...

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Main Authors: Tóth, Marcell (Author) , Wan, Shan (Author) , Schmitt, Jennifer (Author) , Birner, Patrizia (Author) , Wei, Teng (Author) , Bubnoff, Fabian von (Author) , Torre, Carolina de la (Author) , Thomann, Stefan (Author) , Pinna, Federico (Author) , Schirmacher, Peter (Author) , Weiler, Sofia Maria Elisabeth (Author) , Breuhahn, Kai (Author)
Format: Article (Journal)
Language:English
Published: 14 January 2025
In: International journal of molecular sciences
Year: 2025, Volume: 26, Issue: 2, Pages: 1-17
ISSN:1422-0067
DOI:10.3390/ijms26020660
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.3390/ijms26020660
Verlag, kostenfrei, Volltext: https://www.mdpi.com/1422-0067/26/2/660
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Author Notes:Marcell Tóth, Shan Wan, Jennifer Schmitt, Patrizia Birner, Teng Wei, Fabian von Bubnoff, Carolina de la Torre, Stefan Thomann, Federico Pinna, Peter Schirmacher, Sofia Maria Elisabeth Weiler and Kai Breuhahn
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Summary:The oncogenes yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are potent liver oncogenes. Because gene mutations cannot fully explain their nuclear enrichment, we aim to understand which mechanisms cause YAP/TAZ activation in liver cancer cells. The combination of proteomics and functional screening identified numerous apical cell polarity complex proteins interacting with YAP and TAZ. Co-immunoprecipitation (Co-IP) experiments confirmed that membrane protein palmitoylated 5 (MPP5; synonym: PALS1) physically interacts with YAP and TAZ. After removing different MPP5 protein domains, Co-IP analyses revealed that the PDZ domain plays a crucial role in YAP binding. The interaction between YAP and MPP5 in the cytoplasm of cancer cells was demonstrated by proximity ligation assays (PLAs). In human hepatocellular carcinoma (HCC) tissues, a reduction in apical MPP5 expression was observed, 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. Low MPP5 levels define an HCC patient group with a poor clinical outcome. In summary, MPP5 facilitates the nuclear exclusion of YAP and TAZ in liver cancer. This qualifies MPP5 as a potential tumor-suppressor gene and explains how changes in cell polarity can foster tumorigenesis.
Item Description:Gesehen am 07.08.2025
Physical Description:Online Resource
ISSN:1422-0067
DOI:10.3390/ijms26020660

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