期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 14, 期 5, 页码 1082-1094出版社
WILEY
DOI: 10.1111/jth.13281
关键词
blood platelets; retinoic acid receptors; actin-related protein 2-3 complex; actin; protein interaction domains and motifs
资金
- Canadian Institutes of Health Research (CIHR) [MOP-81208, MOP-259952]
- American Heart Association Western States Affiliate [0625098Y, 09BG1A 2250381]
- Volkswagen Foundation
- [HL066277]
- [HL112311]
- [HL044525]
- [AG040631]
- [HL126547]
- [HL092161]
- [GM103806]
- [HL075507]
Background: Platelets utilize proteins and pathways classically reserved for the nuclear niche. Methods: We determined whether human platelets express retinoic-acid-receptor family members, traditionally thought of as nuclear transcription factors, and deciphered the function of RAR alpha. Results: We found that RAR alpha is robustly expressed in human platelets and megakaryocytes and interacts directly with actin-related protein-2/3 complex (Arp2/3) subunit 5 (Arp2/3s5). Arp2/3s5 co-localized with RAR alpha in situ and regulated platelet cytoskeletal processes. The RAR alpha ligand all-trans retinoic acid (atRA) disrupted RAR alpha. Arp2/3 interactions. When isolated human platelets were treated with atRA, rapid cytoskeletal events (e.g. platelet spreading) were inhibited. In addition, when platelets were cultured for 18 h in the presence of atRA, actin-dependent morphological changes (e.g. extended cell body formation) were similarly inhibited. Using in vitro actin branching assays, RAR alpha and Arp2/3-regulated complex actin branch formation was demonstrated. Consistent with inhibition of cytoskeletal processes in platelets, atRA, when added to this branching assay, resulted in dysregulated actin branching. Conclusion: Our findings identify a previously unknown mechanism by which RAR alpha regulates Arp2/3-mediated actin cytoskeletal dynamics through a non-genomic signaling pathway. These findings have broad implications in both nucleated and anucleate cells, where actin cytoskeletal events regulate cell morphology, movement and division.
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