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ILK: a pseudokinase in the center stage of cell-matrix adhesion and signaling.

ABSTRACT: Integrin-linked kinase (ILK) is a widely expressed and evolutionally conserved component of cell-extracellular matrix (ECM) adhesions. Although initially named as a kinase, ILK contains an unusual pseudoactive site that is incapable of catalyzing phosphorylation. Instead, ILK acts as a central component of a heterotrimer (the PINCH-ILK-parvin complex) at ECM adhesions mediating interactions with a large number of proteins via multiple sites including its pseudoactive site. Through higher level protein-protein interactions, this scaffold links integrins to the actin cytoskeleton and catalytic proteins and thereby regulates focal adhesion assembly, cytoskeleton organization and signaling. This review summarizes recent advances in our understanding of the structure and functions of the PINCH-ILK-parvin complex, and discusses emerging new features of the molecular mechanisms by which it regulates diverse cellular, physiological and pathological processes.

SUBMITTER: Qin J

PROVIDER: S-EPMC3467332 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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ILK: a pseudokinase in the center stage of cell-matrix adhesion and signaling.

Qin Jun J Wu Chuanyue C

Current opinion in cell biology 20120702 5

Integrin-linked kinase (ILK) is a widely expressed and evolutionally conserved component of cell-extracellular matrix (ECM) adhesions. Although initially named as a kinase, ILK contains an unusual pseudoactive site that is incapable of catalyzing phosphorylation. Instead, ILK acts as a central component of a heterotrimer (the PINCH-ILK-parvin complex) at ECM adhesions mediating interactions with a large number of proteins via multiple sites including its pseudoactive site. Through higher level p ...[more]

PMID: 22763012

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Project description:The integrin-associated adaptor proteins integrin-linked kinase (ILK) and kindlin-2 play central roles in integrin signaling and control of cell morphology. A direct ILK-kindlin-2 interaction is conserved across species and involves the F2PH subdomain of kindlin-2 and the pseudokinase domain (pKD) of ILK. However, complete understanding of the ILK-kindlin-2 interaction and its role in integrin-mediated signaling has been impeded by difficulties identifying the binding site for kindlin-2 on ILK. We used conservation-guided mapping to dissect the interaction between ILK and kindlin-2 and identified a previously unknown binding site for kindlin-2 on the C-lobe of the pKD of ILK. Mutations at this site inhibit binding to kindlin-2 while maintaining structural integrity of the pKD. Importantly, kindlin-binding-defective ILK mutants exhibit impaired focal adhesion localization and fail to fully rescue the spreading defects seen in ILK knockdown cells. Furthermore, kindlin-2 mutants with impaired ILK binding are also unable to fully support cell spreading. Thus, the interaction between ILK and kindlin-2 is critical for cell spreading and focal adhesion localization, representing a key signaling axis downstream of integrins.This article has an associated First Person interview with the first author of the paper.

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