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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Actin Cytoskeleton / metabolism*
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Catalytic Domain / genetics
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Cell Adhesion / physiology*
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Cell Line, Tumor
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Cell Movement
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Cytoskeleton / metabolism
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Focal Adhesions / metabolism*
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Humans
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LIM Domain Proteins / chemistry
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LIM Domain Proteins / genetics
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LIM Domain Proteins / metabolism
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Microfilament Proteins / chemistry
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism
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Mutation
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Protein Binding
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Protein Interaction Domains and Motifs / genetics
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction* / genetics
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Stress Fibers / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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LIM Domain Proteins
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LIMS1 protein, human
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Membrane Proteins
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Microfilament Proteins
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PARVA protein, human
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integrin-linked kinase
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Protein Serine-Threonine Kinases