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First published online September 17, 2008
doi: 10.1242/10.1242/jcs.017996

Journal of Cell Science 121, 3121-3132 (2008)
Published by The Company of Biologists 2008
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Integrin-linked kinase – essential roles in physiology and cancer biology

Paul C. McDonald1, Andrew B. Fielding1 and Shoukat Dedhar1,2,*

1 British Columbia Cancer Agency, BC Cancer Research Centre, Department of Cancer Genetics, Vancouver BC, Canada
2 University of British Columbia, Department of Biochemistry and Molecular Biology, Vancouver BC, Canada


Figure 1
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  		Fig. 1. The ILK interactome. ILK is localized in FAs, where it forms multiprotein complexes with several proteins that are involved in cytoskeletal dynamics and cell-signaling cascades. The N-terminal ankyrin repeats of ILK interact directly with several key proteins, including PINCH, ILKAP, SPARC and T-cadherin. PINCH also couples ILK to T 4, Rsu1 and NCK2. NCK2 associates with growth factor receptors, which potentially links ILK to growth-factor signaling. The central PH-like domain of ILK binds to PtdIns(3,4,5)P3 and is required for PI3K-dependent activation of ILK. The C-terminal kinase domain of ILK interacts with 1 and 3 integrin, as well as with several actin-binding adaptor proteins, including -parvin, -parvin, paxillin, Mig-2 and Wech. Key binding partners that are involved in cell signaling also bind the ILK kinase domain, including PDK1, Akt, Rictor and Src. In particular, a direct interaction between Rictor and ILK is important for phosphorylation of Akt at Ser473. Rsu1, Ras suppressor 1; T 4, thymosin 4; RTK, receptor tyrosine kinase; GF, growth factor; SPARC, secreted protein acidic and rich in cysteine; PIP3, PtdIns(3,4,5)P3; PDK1, protein-dependent kinase 1; N, N terminal; C, C terminal; P, phosphorylation site; ECM, extracellular matrix; SH3, Src homology 3; CH2, calponin homology 2; ANK, ankyrin repeat; Mig-2, mitogen-induced gene 2 (also known as fermitin family homolog 2); PHI-1, phosphatase holoenzyme inhibitor 1.

 

Figure 2
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  		Fig. 2. Overview of the intracellular signaling pathways regulated by ILK. ILK is a central component of signaling cascades that control an array of biological processes that are crucial both to normal tissue homeostasis and to the progression of malignant disease. Activation of ILK by integrins and soluble mediators results in the regulation of downstream effectors that, in turn, modulate processes such as motility and contractility, survival, EMT, invasion, proliferation, and angiogenesis. ILK activity is antagonized by ILKAP and PTEN. Ang2, angiopoietin 2; GF, growth factor; SPARC, secreted protein acidic and rich in cysteine; PIP3, PtdIns(3,4,5)P3; PDK1, protein-dependent kinase 1; P, phosphorylation site; SMOC2, secreted modular calcium-binding protein 2; ET-1, endothelin 1; NAC, nascent polypeptide-associated complex and coactivator; -parv, -parvin; HIF1, hypoxia-inducible factor 1.

 

Figure 3
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  		Fig. 3. ILK also localizes to the centrosome. Data from a SILAC-based unbiased proteomic screen place ILK in the centrosome, and indicate that it interacts with tubulin and tubulin-binding proteins to aid in the organization of the mitotic spindle. Binding partners of ILK include -tubulin, -tubulin, RUVBL1 and RUVBL2. The inhibition of ILK activity or expression inhibits Aurora-A–TACC3–ch-TOG interactions, which indicates that ILK might be important in mitotic-spindle assembly.

 

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