| Summary: | 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. === Medicine, Faculty of === Medical Genetics, Department of === Graduate
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