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Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase

Author

Listed:
  • Isabel Serrano

    (British Columbia Cancer Research Centre)

  • Paul C. McDonald

    (British Columbia Cancer Research Centre)

  • Frances Lock

    (British Columbia Cancer Research Centre)

  • William J. Muller

    (Goodman Cancer Centre, McGill University)

  • Shoukat Dedhar

    (British Columbia Cancer Research Centre)

Abstract

One of the hallmarks of cancers is the silencing of tumour suppressor genes and pathways. The Hippo tumour suppressor pathway is inactivated in many types of cancers, leading to tumour progression and metastasis. However, the mechanisms of pathway inactivation in tumours remain unclear. Here we demonstrate that integrin-linked kinase (ILK) plays a critical role in the suppression of the Hippo pathway via phospho-inhibition of MYPT1-PP1, leading to inactivation of Merlin. Inhibition of ILK in breast, prostate and colon tumour cells results in the activation of the Hippo pathway components MST1 and LATS1 with concomitant inactivation of YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) transcriptional co-activators and TEAD-mediated transcription. Genetic deletion of ILK suppresses ErbB2-driven YAP/TAZ activation in mammary tumours, and its pharmacological inhibition suppresses YAP activation and tumour growth in vivo. Our data demonstrate a role for ILK as a multiple receptor proximal regulator of Hippo tumour suppressor pathway and as a cancer therapeutic target.

Suggested Citation

  • Isabel Serrano & Paul C. McDonald & Frances Lock & William J. Muller & Shoukat Dedhar, 2013. "Inactivation of the Hippo tumour suppressor pathway by integrin-linked kinase," Nature Communications, Nature, vol. 4(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3976
    DOI: 10.1038/ncomms3976
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