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Integrin-linked kinase: a cancer therapeutic target unique among its ILK

Key Points

  • Integrin-linked kinase (ILK) is a β1-integrin cytoplasmic domain interacting protein, and functions as a scaffold in forming multiprotein complexes connecting integrins to the actin cytoskeleton and signalling pathways.

  • ILK is essential for embryonic development.

  • ILK activity is stimulated by adhesion to the extracellular matrix and by growth factors in a phosphatidylinositol 3-kinase (PI3K)-dependent manner.

  • Overexpression of ILK in epithelial cells induces epithelial–mesenchymal transition (EMT) by inhibiting E-cadherin expression, activates nuclear β-catenin and induces a transformed, tumorigenic phenotype.

  • Mammary epithelial cell specific expression of ILK in transgenic mice induces hyperplasia and tumour formation.

  • Overexpression or constitutive activation of ILK promotes cell survival by stimulating the phosphorylation of AKT on Ser473, and inhibiting ILK in cancer cells inhibits AKT phosphorylation and cell survival.

  • ILK activity is constitutively activated in PTEN-negative tumours, and inhibiting ILK induces apoptosis and cell-cycle arrest

  • ILK regulates tumour angiogenesis. ILK activation promotes vascular endothelial growth factor (VEGF) expression in tumour cells, and ILK has an essential role in VEGF-mediated endothelial activation and angiogenesis.

  • ILK expression and activity are increased in many types of cancer, such as prostate, colon, gastric and ovarian cancers, and malignant melanomas.

  • Small-molecule inhibitors of ILK have been identified and shown to inhibit cancer-cell growth, survival and invasion in vitro, and tumour growth and angiogenesis in vivo.

Abstract

Cancer development requires the acquisition of several capabilities that include increased replicative potential, anchorage and growth-factor independence, evasion of apoptosis, angiogenesis, invasion of surrounding tissues and metastasis. One protein that has emerged as promoting many of these phenotypes when dysregulated is integrin-linked kinase (ILK), a unique intracellular adaptor and kinase that links the cell-adhesion receptors, integrins and growth factors to the actin cytoskeleton and to a range of signalling pathways. The recent findings of increased levels of ILK in various cancers, and that inhibition of ILK expression and activity is antitumorigenic, makes ILK an attractive target for cancer therapeutics.

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Figure 1: Schematic of ILK primary structure and identification of amino acids required for ILK activity.
Figure 2: Multiprotein ILK complex in focal adhesions.
Figure 3: Signalling pathways activated by ILK.

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Acknowledgements

The authors acknowledge support from the National Cancer Institute of Canada from funds raised by the Canadian Cancer Society and the Terry Fox Foundation to S.D., and the Canadian Institutes for Health Research to S.D and G.H.

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Correspondence to Shoukat Dedhar.

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Competing interests

Shoukat Dedhar is a scientific consultant for QLT Inc., which has the license to develop ILK modulators. Greg Hannigan and Shoukat Dedhar are holders of patents relating to ILK and its uses.

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DATABASES

Entrez Gene

AKT

APC

ATM

ATR

CDK4

cyclin D1

DAB2

E-cadherin

GSK3β

ILKAP

MMP9

paxillin

PDGF

PINCH1

PINCH2

PTEN

STK11

TGFβ

VEGF

α-parvin

β-parvin

β-catenin

National Cancer Institute

brain cancer

breast cancer

colorectal cancer

melanoma

ovarian cancer

prostate cancer

Glossary

FOCAL-ADHESION PLAQUES

Points of cell adhesion where integrins connect to the actin cytoskeleton. These structures are readily visible by immunofluorescence microscopy.

EPITHELIAL–MESENCHYMAL TRANSITION

Conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

ANKYRIN REPEAT

A repeating sequence of 30–33 amino acids that was found in the ankyrin protein. Ankyrin repeats facilitate protein–protein interactions and are found in a wide range of proteins.

LIM

LIM domains were originally identified as a cysteine-rich repeat (CRR) in Lin-11, (C. elegans) ISl-1 (mouse) and Mec3 (yeast) proteins.

RNA INTERFERENCE

A technique to specifically silence the expression of a gene at the mRNA and protein level. Introduction of small double-stranded RNA (22 mer) into cells results in binding to target mRNA and induces its degradation.

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Hannigan, G., Troussard, A. & Dedhar, S. Integrin-linked kinase: a cancer therapeutic target unique among its ILK. Nat Rev Cancer 5, 51–63 (2005). https://doi.org/10.1038/nrc1524

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