Abstract
Dynamic communication between integrin-containing complexes (focal adhesions, FAs) and actin filaments is critical for regulating cell adhesion. Pseudokinase ILK plays a key role in this process but the underlying mechanism remains highly elusive. Here we show that by recruiting FA adaptors PINCH and Parvin into a heterotrimeric complex (IPP), ILK triggers F-actin filament bundling – a process known to generate force/mechanical signal to promote cytoskeleton reassembly and dynamic cell adhesion. Structural, biochemical, and functional analyses revealed that the F-actin bundling is orchestrated by two previously unrecognized WASP-Homology-2 actin binding motifs within IPP, one from PINCH and the other from Parvin. Strikingly, this process is also sensitized to Mg-ATP bound to the pseudoactive site of ILK and its dysregulation severely impairs stress fibers formation, cell spreading, and migration. These data identify a crucial mechanism for ILK, highlighting its uniqueness as a pseudokinase to transduce non-catalytic signal and regulate cell adhesion.
Highlights
Dynamic communication between integrin-containing complexes and actin filaments is critical for regulating cell adhesion
Our results reveal that by recruiting focal adhesions (FAs) adaptors PINCH and Parvin into a heterotrimeric complex (IPP), Integrin-linked kinase (ILK) is able to trigger F-actin filament bundling via two WASPHomology-2 actin-binding motifs, one from PINCH and the other from Parvin
In this study, we have attempted to resolve a mechanistic puzzle in cell adhesion: How does ILK transduce signal between integrin-containing FAs and F-actin filaments? We asked the specific question of why ILK evolved to function as a pseudokinase but still bound to Mg-ATP—the cofactor essential for conventional kinase catalysis? Through a comprehensive set of biochemical, structural, microscopic, and cell biological experiments, we believe we have obtained important clues for addressing these fundamentally important questions
Summary
Dynamic communication between integrin-containing complexes (focal adhesions, FAs) and actin filaments is critical for regulating cell adhesion. Structural, biochemical, and functional analyses revealed that the F-actin bundling is orchestrated by two previously unrecognized WASP-Homology-2 actin binding motifs within IPP, one from PINCH and the other from Parvin This process is sensitized to Mg-ATP bound to the pseudoactive site of ILK and its dysregulation severely impairs stress fibers formation, cell spreading, and migration. These data identify a crucial mechanism for ILK, highlighting its uniqueness as a pseudokinase to transduce non-catalytic signal and regulate cell adhesion. Our data identify a crucial mechanism for ILK, highlighting its uniqueness as a pseudokinase to transduce noncatalytic signal and regulate cell adhesion
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