Faculty Collaboration Database

PACSIN2 regulates platelet integrin β1 hemostatic function. J Thromb Haemost 2023 Dec;21(12):3619-3632

Date

09/08/2023

Pubmed ID

37678551

Pubmed Central ID

PMC10841284

DOI

10.1016/j.jtha.2023.08.026

Scopus ID

2-s2.0-85172148046 (requires institutional sign-in at Scopus site)

Abstract

BACKGROUND: Upon vessel injury, platelets adhere to exposed matrix constituents via specific membrane receptors, including the von Willebrand factor receptor glycoprotein (GP)Ib-IX-V complex and integrins β1 and β3. In platelets, the Fes/CIP4-homology Bin-Amphiphysin-Rvs protein PACSIN2 associates with the cytoskeletal and scaffolding protein filamin A (FlnA), linking GPIbα and integrins to the cytoskeleton.

OBJECTIVES: Here we investigated the role of PACSIN2 in platelet function.

METHODS: Platelet parameters were evaluated in mice lacking PACSIN2 and platelet integrin β1.

RESULTS: Pacsin2^-/- mice displayed mild thrombocytopenia, prolonged bleeding time, and delayed thrombus formation in a ferric chloride-mediated carotid artery injury model, which was normalized by injection of control platelets. Pacsin2^-/- platelets formed unstable thrombi that embolized abruptly in a laser-induced cremaster muscle injury model. Pacsin2^-/- platelets had hyperactive integrin β1, as evidenced by increased spreading onto surfaces coated with the collagen receptor α2β1-specific peptide GFOGER and increased binding of the antibody 9EG7 directed against active integrin β1. By contrast, Pacsin2^-/- platelets had normal integrin αIIbβ3 function and expressed P-selectin normally following stimulation through the collagen receptor GPVI or with thrombin. Deletion of platelet integrin β1 in Pacsin2^-/- mice normalized platelet count, hemostasis, and thrombus formation. A PACSIN2 peptide mimicking the FlnA-binding site mediated the pull-down of a FlnA rod 2 construct by integrin β7, a model for integrin β-subunits.

CONCLUSIONS: Pacsin2^-/- mice displayed severe thrombus formation defects due to hyperactive platelet integrin β1. The data suggest that PACSIN2 binding to FlnA negatively regulates platelet integrin β1 hemostatic function.

Author List

Biswas R, Boyd EK, Eaton N, Steenackers A, Schulte ML, Reusswig F, Yu H, Drew C, Kahr WHA, Shi Q, Plomann M, Hoffmeister KM, Falet H

Authors

Herve Falet PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Hemostasis
Hemostatics
Integrin beta1
Mice
Peptides
Platelet Activation
Platelet Adhesiveness
Platelet Glycoprotein GPIIb-IIIa Complex
Platelet Membrane Glycoproteins
Receptors, Collagen
Thrombosis