title: Non-genomic activities of retinoic acid receptor alpha control actin cytoskeletal events in human platelets.
abstract: Essentials Platelets employ proteins/signaling pathways traditionally thought reserved for nuclear niche. We determined retinoic-acid-receptor alpha (RARα) expression and function in human platelets. RARα/actin-related protein-2/3 complex (Arp2/3) interact via non-genomic signaling in platelets. RARα regulates Arp2/3-mediated actin cytoskeletal dynamics and platelet spreading.
  
  
  
  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 RARα. Results We found that RARα 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 RARα in situ and regulated platelet cytoskeletal processes. The RARα ligand all-trans retinoic acid (atRA) disrupted RARα-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, RARα 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 RARα 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.
authors: Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.|Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.|Department of Internal Medicine, George E. Wahlen Salt Lake City VAMC, Salt Lake City, UT, USA.
authors: M T
authors: MT
authors: Rondina
authors: Department of Immunology and Transfusion Medicine, University of Greifswald, Greifswald, Germany.
authors: M
authors: M
authors: Freitag
authors: Program in Cell Biology, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.
authors: F G
authors: FG
authors: Pluthero
authors: Program in Cell Biology, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.|Departments of Paediatrics and Biochemistry, University of Toronto, Toronto, ON, Canada.
authors: W H A
authors: WH
authors: Kahr
authors: Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.
authors: J W
authors: JW
authors: Rowley
authors: Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.|Division of Vascular Surgery, Department of Surgery, University of Utah, Salt Lake City, UT, USA.
authors: L W
authors: LW
authors: Kraiss
authors: Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.
authors: Z
authors: Z
authors: Franks
authors: Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.|Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
authors: G A
authors: GA
authors: Zimmerman
authors: Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.|Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
authors: A S
authors: AS
authors: Weyrich
authors: Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.|Department of Immunology and Transfusion Medicine, University of Greifswald, Greifswald, Germany.|Division of Vascular Surgery, Department of Surgery, University of Utah, Salt Lake City, UT, USA.|Lichtenberg-Professor for Experimental Hemostasis, University of Greifswald, Greifswald, Germany.
authors: H
authors: H
authors: Schwertz
mesh_terms: D051377:Actin-Related Protein 2 / Q000378:metabolism; D051378:Actin-Related Protein 3 / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D001792:Blood Platelets / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D020869:Gene Expression Profiling; D064368:Healthy Volunteers; D006801:Humans; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D000072482:Retinoic Acid Receptor alpha / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C495926:ACTR2 protein, human; C495928:ACTR3 protein, human; D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins; D018952:Antigens, CD34; C000607071:RARA protein, human; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors
keywords: actin; actin-related protein 2-3 complex; blood platelets; protein interaction domains and motifs; retinoic acid receptors