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

Isabel Serrano1, Paul C McDonald1, Frances Lock1

  • 1Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada V5Z 1L3.

Nature Communications
|December 21, 2013
PubMed

Insights

Integrin-linked kinase (ILK) suppresses the Hippo tumor suppressor pathway by inhibiting Merlin. ILK inhibition reactivates the Hippo pathway, offering a potential cancer therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Cancer is characterized by the silencing of tumor suppressor genes and pathways.
  • The Hippo tumor suppressor pathway is frequently inactivated in various cancers, promoting tumor progression and metastasis.
  • Mechanisms underlying Hippo pathway inactivation in tumors are not fully understood.

Purpose of the Study:

  • To elucidate the role of integrin-linked kinase (ILK) in the regulation of the Hippo tumor suppressor pathway.
  • To investigate ILK as a potential therapeutic target for cancer treatment.

Main Methods:

  • Investigated ILK's mechanism in Hippo pathway suppression using molecular biology techniques.
  • Examined the effects of ILK inhibition on Hippo pathway components (MST1, LATS1, YAP/TAZ, TEAD) in cancer cell lines.
  • Utilized genetic deletion and pharmacological inhibition of ILK in preclinical cancer models.

Main Results:

  • Demonstrated that ILK suppresses the Hippo pathway through phospho-inhibition of MYPT1-PP1, leading to Merlin inactivation.
  • ILK inhibition activated MST1 and LATS1, concurrently inactivating YAP/TAZ and TEAD-mediated transcription in breast, prostate, and colon cancer cells.
  • Genetic ILK deletion inhibited ErbB2-driven YAP/TAZ activation in mammary tumors.
  • Pharmacological ILK inhibition suppressed YAP activation and tumor growth in vivo.

Conclusions:

  • Identified ILK as a critical regulator upstream of the Hippo tumor suppressor pathway.
  • Established ILK as a novel cancer therapeutic target due to its role in Hippo pathway inactivation and tumor growth.

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