Evidence map›Paper›PMID 41190427›Full record

ArticleCirculation research2025

Direct Binding of Lyn to GPIbβ Transmits 2-Way GPIb-IX Signaling to Stimulate Platelet Activation and VWF Binding.

Yaping Zhang, Ying Liang, Amir Hossein Kazemipour Ashkezari, Can Wang, Claire W Chang, Yanyan Bai, Xin Huang, Andrew Mack, Haotian Yang, Peiwen Cong and 3 more

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In one paragraph

Article in Circulation research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

13 authors.

Yaping Zhang *Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).ORCID 0000-0003-0205-8807
Ying Liang *Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).
Amir Hossein Kazemipour AshkezariGeorge W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta (A.H.K.A., C.Z.).ORCID 0000-0002-7441-2927
Can WangDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).ORCID 0000-0002-2665-0269
Claire W ChangDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).ORCID 0000-0002-9258-2540
Yanyan BaiDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).ORCID 0000-0002-8365-8451
Xin HuangDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).ORCID 0000-0002-4730-9318
Andrew MackDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).ORCID 0009-0000-7224-7537
Haotian YangDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).
Peiwen CongWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (P.C., C.Z.).ORCID 0000-0001-7753-8368
Ni ChengDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).ORCID 0000-0002-9013-690X
Cheng ZhuGeorge W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta (A.H.K.A., C.Z.).ORCID 0000-0002-1718-565X
Xiaoping DuDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago (Y.Z., Y.L., C.W., C.W.C., Y.B., X.H., A.M., H.Y., N.C., X.D.).ORCID 0000-0001-9842-8192

Funding

Mechanisms of integrin signaling and a new anti-platelet/anti-inflammatory approachR35HL150797 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI Xiaoping Du · 2020 to 2026
$6.8M
Single-platelet analysis of mechano-reception by GPIb alphaR01HL132019 · NHLBI · GEORGIA INSTITUTE OF TECHNOLOGY · PI ZHU, CHENG · 2016 to 2024
$3.8M
NHLBI NIH HHS R01 HL132019NHLBI NIH HHS R35 HL150797
6 · The paper itself

Abstract

backgroundThrombosis often starts with platelet adhesion via the interaction between VWF (von Willebrand factor) and its platelet receptor, the GPIb-IX (glycoprotein Ib-IX) complex. GPIb-IX also induces intracellular signals, stimulating VWF-, thrombin- and collagen-induced platelet activation. GPIb-IX signaling requires SFK (Src family kinase) Lyn. However, it remains unclear how Lyn mediates GPIb-IX signaling, whether Lyn directly binds to GPIb-IX, and if it is possible to target this signaling node for developing novel antithrombotics.

methodsDirect binding of recombinant Lyn to glycoprotein Ibβ (GPIbβ) fragments was performed to map the Lyn-binding site. An inhibitory peptide mPLβ was then synthesized and tested for its interference with Lyn-GPIb-IX co-immunoprecipitation, platelet adhesion, ristocetin-, thrombin- or collagen-induced platelet aggregation/secretion, FeCl3-induced mouse carotid artery thrombosis and tail bleeding time. Biomembrane force probe was used to determine VWF-GPIb molecular bonding and consequent signaling.

resultsLyn directly binds to GPIbβ (V144-A161) at the transmembrane/cytoplasmic domain interface, which is critical for not only the extracellular GPIb-IX ligand-induced intracellular signaling but also transmits outbound signals enhancing VWF-GPIb-IX interaction. The peptide mPLβ inhibited VWF-induced or α-thrombin-induced GPIbβ-Lyn interaction, Lyn/SFK activation, stable platelet adhesion and aggregation, and, notably, reduced GPIb-mediated platelet adhesion to VWF even in the presence of integrin inhibitors. BFP study further shows that mPLβ reduces the VWF-A1 domain-GPIb adhesion frequency and inhibits force-induced A1-mediated intraplatelet calcium elevation. Importantly, mPLβ formulated as a high-loading peptide nanoparticle inhibited platelet adhesion/aggregation induced by collagen and in vivo arterial thrombosis with a mild effect in prolonging bleeding time.

conclusionsDirect binding of Lyn to GPIbβ mediates 2-way GPIb-IX signaling to activate platelets and modulate VWF-GPIb interaction. Lyn-mediated GPIb-IX signaling is critical for platelet adhesion and aggregation induced by VWF and collagen and in arterial thrombosis. Targeting the Lyn-GPIbβ interaction has the potential for treating GPIb-IX-dependent thrombosis.

Indexed as

Blood PlateletsPlatelet ActivationPlatelet Glycoprotein GPIb-IX ComplexSignal Transductionsrc-Family Kinasesvon Willebrand FactorAnimalsHumansMaleMiceMice, Inbred C57BLPlatelet AdhesivenessPlatelet AggregationProtein BindingThrombosisglycoprotein receptor GPIb-IXlyn protein-tyrosine kinasePlatelet Glycoprotein GPIb-IX Complexsrc-Family Kinasesvon Willebrand Factorblood plateletscardiovascular diseasesplatelet glycoprotein GPIb-IX complexsrc-family kinasesthrombosisvon Willebrand factor

Identifiers

PMID41190427
PMCPMC12872482

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.