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All roads lead to YAP1

Nature Reviews Cancer volume 10, page 6 (2010)Cite this article

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Activation of the hippo pathway inhibits the transcriptional co-activator yes-associated protein 1 (YAP1) through phosphorylation by large tumour suppressor 1 (LATS1) and LATS2. Fernandez-L and colleagues used fluorescence in situ hybridization to analyse a human medulloblastoma tissue microarray of 67 medulloblastoma samples: they found YAP1 amplification in two tumours. Moreover, gene expression analysis of more than 200 human medulloblastoma samples revealed that YAP1 is overexpressed in medulloblastoma subtypes that are dependent on hedgehog or Wnt pathway activation. TEA domain family member 1 (TEAD1), the main transcriptional partner of YAP1, was also overexpressed in these subtypes, indicating that YAP1 might have a role in the aetiology of medulloblastoma.

Primary CGNPs cultured with SHH had increased levels of YAP1 mRNA and protein, and decreased levels of LATS1; further analyses suggested that SHH-dependent signalling stabilizes YAP1 in proliferating cells in vitro and in vivo. Next, the authors found that insulin receptor substrate 1 (IRS1), which is itself induced by the hedgehog pathway, interacts with YAP1 in vitro, and IRS1 expression corresponded with nuclear retention of YAP1 in both primary CGNPs and medulloblastoma cells isolated from Ptch1 +/− Trp53 −/− mice. SHH also induced the accumulation of TEAD1, which interacted with both YAP1 and IRS1 in medulloblastoma cells from Ptch1 +/− Trp53 −/− mice. Ectopic expression of YAP1 was not sufficient to fully recapitulate the mitogenic effects of hedgehog pathway activation in CGNPs but knockdown of YAP1 decreased proliferation. This indicates that the hedgehog pathway probably activates other YAP1 transcriptional partners (such as TEAD1) and that YAP1 is required to maintain proliferation of CGNPs.

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References

ORIGINAL RESEARCH PAPER

  1. Fernandez-L, A. et al. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes & Dev. 1 Dec 2009 (doi:10.1101/gad.1824509)

FURTHER READING

  1. Alarcon, C. et al. Nuclear CDKs drive smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell. 139, 757–769 (2009)

    Article  CAS  Google Scholar 

  2. Hamilton, G. et al. ATM regulates a RASSF1A-dependent DNA damage response. Curr. Biol. 3 Dec 2009 (doi:10.1016/j.cub.2009.10.040)

  3. Zhang, J. et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nature Cell Biol. 22 Nov 2009 (doi:10.1038/ncb1993)

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Authors
  1. Gemma K. Alderton
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Alderton, G. All roads lead to YAP1. Nat Rev Cancer 10, 6 (2010). https://doi.org/10.1038/nrc2779

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  • DOI: https://doi.org/10.1038/nrc2779

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