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Cited by 434Cell Adhesion Molecules ResearchCellular Mechanics and InteractionsBiochemical and Structural Characterization

The Molecular Basis of Filamin Binding to Integrins and Competition with Talin

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Kiema, Tiila, Lad, Yatish, Jiang, Pengju, Oxley, Camilla L., Baldassarre, Massimiliano, Wegener, Kate L., Campbell, Iain D., Ylänne, Jari +1 more·2006·Molecular Cell
DOI 10.1016/j.molcel.2006.01.011
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Abstract

The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.

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  • Full activation of β1 integrin is induced when Filamin A dissociates and Talin and Kindlin associate upon ligand binding.

    “Full activation of the integrin is induced when Filamin A dissociates and Talin and Kindlin associate upon ligand binding (outside‐in signaling).”

    From The Serine/Threonine Kinase <scp>NDR2</scp> Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the Hippocampus (2025) · cites this paper as Kiema et al. 2006

    The Discussion (page unavailable) says Filamin A competes with talin for integrin β-tail binding and that this competition can affect talin-dependent integrin activation. It does not establish that ligand binding causes Filamin A to dissociate, that talin and Kindlin then associate, or that this sequence induces full activation through outside-in signaling. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Filamin A binding to the T788/789 motif of β1 integrin competes with Talin and Kindlin, maintaining the integrin in an inactivated conformation.

    “A known regulatory mechanism involves Filamin A binding to the T788/789 motif of β1 integrin, where it competes with the activators Talin and Kindlin, maintaining the integrin in an inactivated conformation.”

    From The Serine/Threonine Kinase <scp>NDR2</scp> Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the Hippocampus (2025) · cites this paper as Kiema et al. 2006

    The Results and Discussion (page not provided) show that filamin A binds β1 integrin tails and competes with talin, potentially affecting talin-dependent integrin activation. The copy does not identify β1 T788/789 as the binding motif or describe competition with Kindlin, and it does not establish that filamin maintains an inactive integrin conformation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Phosphorylation of the T788/789 motif promotes β1 integrin activation.

    “This activation is further promoted by the phosphorylation of the T788/789 motif (inside‐out signaling) (Kiema et al. 2006).”

    From The Serine/Threonine Kinase <scp>NDR2</scp> Regulates Integrin Signaling, Synapse Formation, and Synaptic Plasticity in the Hippocampus (2025) · cites this paper as Kiema et al. 2006

    The Results section shows that phospho-mimicking mutations in β7 threonines reduce filamin binding without impairing talin binding. The Discussion only speculates that phosphorylation might thereby modulate integrin activation; it does not show that phosphorylation of the β1 T788/789 motif promotes β1 activation. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 40

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Cited by

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Authors
Kiema, T., Lad, Y., Jiang, P., Oxley, C. L., Baldassarre, M., Wegener, K. L., Campbell, I. D., Ylänne, J., & Calderwood, D. A.
Affiliations
  • University of Oulu (FI)
  • Yale University (US)
  • University of Oxford (GB)
  • University of Jyväskylä (FI)
Corresponding author
  • Ylänne, Jari
  • Calderwood, David A.
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2006-02
Volume
21
Issue
3
Pages
337-347
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2006.01.011
OpenAlex
W2101346022
Cited by
434
References
0
Citations by year
2026: 2 · 2025: 16 · 2024: 8 · 2023: 16 · 2022: 24 · 2021: 22 · 2020: 11 · 2019: 17 · 2018: 11 · 2017: 20 · 2016: 17 · 2015: 23 · 2014: 24 · 2013: 31 · 2012: 32
FWCI
20.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM068600)
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
Keywords
filamin A, integrins, talin, immunoglobulin-like domains, actin cytoskeleton, integrin activation, protein-protein interaction, phosphothreonine, kinase regulation, cell adhesion
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Calpain, Contractile Proteins, Microfilament Proteins, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Conformation, Recombinant Fusion Proteins, Reproducibility of Results, Talin, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Crystallography, X-Ray, Nuclear Magnetic Resonance, Biomolecular, Integrin beta Chains, NIH 3T3 Cells, Mice, Filamins

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