Trends in Cell Biology
Volume 9, Issue 8, 1 August 1999, Pages 319-323
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Review
Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling

https://doi.org/10.1016/S0962-8924(99)01612-8Get rights and content

Abstract

Interaction of cells with the extracellular matrix (ECM) results in the regulation of cell growth, differentiation and migration by coordinated signal transduction through integrins and growth-factor receptors. Integrins achieve signalling by interacting with intracellular effectors that couple integrins and growth-factor receptors to downstream components. One well-studied effector is focal-adhesion kinase (FAK), but recently another protein kinase, integrin-linked kinase (ILK), has been identified as a receptor-proximal effector of integrin and growth-factor signalling. ILK appears to interact with and be influenced by a number of different signalling pathways, and this provides new routes for integrin-mediated signalling. This article discusses ILK structure and function and recent genetic and biochemical evidence about the role of ILK in signal transduction.

Section snippets

ILK structure and function

ILK contains three identifiable structural features (Fig. 1). There are four ankyrin repeats in the N-terminus. These are followed by a phosphoinositide-binding motif9 normally present in pleckstrin-homology (PH) domains7. This motif overlaps with the extreme N-terminus of the kinase catalytic domain (Fig. 1). In vitro kinase assays using recombinant ILK, and immunoprecipitation kinase assays in mammalian cell extracts, have revealed that ILK is a functional serine/threonine protein kinase

ILK genetics

ILK is highly evolutionarily conserved: there are ILK homologues in human2, mouse15, Drosophila (D. Brower, pers. commun.) and Caenorhabditis elegans20. The gene encoding human ILK has been localized to human chromosome 11p15.5–p15.4 (Ref. 16). Regional loss of heterozygosity (LOH) indicates that this part of chromosome 11 is strongly associated with tumorigenesis in a manner that might involve genomic imprinting17. Thus, it is possible that dysregulation of ILK function could be a consequence

Mammalian ILK in integrin and growth factor signalling

Two independent strategies have led to insight into the likely physiological role(s) of ILK. These are analysis of alteration in ILK kinase activity upon cell attachment to ECM substrates, and stimulation with growth factors; and gain or loss of function using overexpression by cDNA transfection or mutational analysis, respectively.

Evaluation of the effects of cell adhesion and growth-factor stimulation has shown that the kinase activity of ILK is under stringent control by these stimuli.

Concluding remarks

ILK is an evolutionarily conserved serine/threonine protein kinase containing ankyrin repeats and phosphoinositide phospholipid-binding motifs. ILK is capable of interacting directly with integrin β1, β2 and β3 subunits and might be involved in their phosphorylation. In C. elegans, ILK might function to promote the assembly of focal-adhesion-like muscle attachments, together with integrins and another ILK-interacting protein, PINCH. ILK also appears to be an important effector of integrin and

Note added in proof

It has recently been shown that PDK-1 can, under certain highly artificial and nonphysiological conditions, phosphorylate PKB on Ser473 (Ref. 38). This does not negate the ability of other kinases, such as ILK, also to phosphorylate Ser473 of PKB. In fact, ILK might be a more physiologically relevant PDK-2 as dominant–negative ILK inhibits this phosphorylation in intact cells9.

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