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The Role of integrin-linked kinase (ILK) in cellular signalling

University of British Columbia

Integrins are a family of heterodimeric transmembrane receptors that link the cytoskeleton to the extracellular matrix, and mediate cell adhesion and bidirectional signalling. The Integrin-linked kinase (ILK) was identified as a protein capable of interacting with pi and P3 integrin subunits. ILK behaves as a potent oncogene, and is capable of transforming normal epithelial cells and forming tumours in nude mice. ILK is a serine/threonine kinase which phophorylates and activates PKB/Akt at serine-473, and phosphorylates and inhibits GSK-3cc/p at serine 21/9. When normal epithelial cells detach from the extracellular matrix, they undergo suspension-induced apoptosis, or anoikis. Because ILK links integrins to the anti-apoptotic PKB/Akt pathway, we investigated whether ILK elicits its oncogenic effects by inhibiting anoikis. Here, we show that ILK inhibits anoikis in a PKB/Akt-dependent manner. Furthermore, inhibition of ILK activity in cancer cell lines induced anoikis. In prostate cancer cells which are lacking expression of the upstream regulator of ILK, PTEN, inhibition of ILK activity, as well as re-introduction of PTEN induces cell cycle arrest and apoptosis. We also examined the role of ILK, and its interacting partners CH-ILKBP and paxillin, in focal adhesion formation and inside out signalling. We found that proper recruitment of and activation of ILK is crucial for P integrin activation, cell attachment, and migration, as well as the recruitment of its binding partners to focal adhesion complexes. The data presented here underscores the importance of ILK as a central regulator of the PKB/Akt pathway and anoikis, as well as integrin-mediated functions and focal adhesion formation. They also identify ILK as a potential novel target in tumour therapy.

Thesis/Dissertation

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2009-11-27

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http://hdl.handle.net/2429/15829

Genetics

University of British Columbia

UBCV

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