ArticleJournal of thrombosis and haemostasis : JTH2021
Paxillin binding to the PH domain of kindlin-3 in platelets is required to support integrin αIIbβ3 outside-in signaling.
Article in Journal of thrombosis and haemostasis : JTH, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Structural basis of kindlin-3 in leukocyte adhesion deficiency III.Journal of thrombosis and haemostasis : JTH · 2026Article
- TRAF2 and NCK interacting kinase: a novel regulator of integrin αResearch and practice in thrombosis and haemostasis · 2025Article
- Paxillin and Kindlin: Research Progress and Biological Functions.Biomolecules · 2025Review
- Regulation of platelet activation and thrombus formation in acute non-ST segment elevation myocardial infarction: Role of Beclin1.Clinical and translational science · 2024Article
- Structure, signal transduction, activation, and inhibition of integrin αIIbβ3.Thrombosis journal · 2023Review
- Immunothrombosis and the Role of Platelets in Venous Thromboembolic Diseases.International journal of molecular sciences · 2022Review
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Authors and funding
7 authors.
Funding
Abstract
backgroundKindlin-3 is essential for supporting the bidirectional signaling of integrin αIIbβ3 in platelets by bridging the crosstalk between integrin αIIbβ3 and the cytoplasmic signaling adaptors.
objectiveIn this study, we identified a previously unrecognized paxillin binding site in the pleckstrin homology (PH) domain of kindlin-3 and verified its functional significance.
methodsStructure-based approaches were employed to identify the paxillin binding site in the PH domain of kindlin-3. In addition, the bidirectional signaling of integrin αIIbβ3 were evaluated in both human and mouse platelets.
resultsIn brief, we found that a β1-β2 loop in the PH domain of kindlin-3, an important part of the canonical membrane phospholipid binding pocket, was also involved in mediating paxillin interaction. Interestingly, the binding sites of paxillin and membrane phospholipids in the PH domain of kindlin-3 were mutually exclusive. Specific disruption of paxillin binding to the PH domain by point mutations inhibited platelet spreading on immobilized fibrinogen while having no inhibition on soluble fibrinogen binding to stimulated platelets. In addition, a membrane-permeable peptide derived from the β1-β2 loop in the PH domain of kindlin-3 was capable of inhibiting platelet spreading and clot retraction, but it had no effect on soluble fibrinogen binding to platelets and platelet aggregation. Treatment with this peptide significantly reduced thrombus formation in mice.
conclusionTaken together, these findings suggest that interaction between paxillin and the PH domain of kindlin-3 plays an important role in supporting integrin αIIbβ3 outside-in signaling in platelets, thus providing a novel antithrombotic target.
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