{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T19:04:54Z","timestamp":1764875094960,"version":"3.46.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,12,5]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Thrombosis 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Direct binding of recombinant Lyn to glycoprotein Ib\u03b2 (GPIb\u03b2) fragments was performed to map the Lyn-binding site. An inhibitory peptide mPL\u03b2 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Lyn directly binds to GPIb\u03b2 (V144-A161) at the transmembrane\/cytoplasmic domain interface, which is critical for not only the extracellular GPIb-IX ligand\u2013induced intracellular signaling but also transmits outbound signals enhancing VWF-GPIb-IX interaction. The peptide mPL\u03b2 inhibited VWF-induced or \u03b1-thrombin-induced GPIb\u03b2-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 mPL\u03b2 reduces the VWF-A1 domain-GPIb adhesion frequency and inhibits force-induced A1-mediated intraplatelet calcium elevation. Importantly, mPL\u03b2 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Direct binding of Lyn to GPIb\u03b2 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-GPIb\u03b2 interaction has the potential for treating GPIb-IX-dependent thrombosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.124.325616","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T10:00:19Z","timestamp":1762336819000},"page":"1480-1497","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Direct Binding of Lyn to GPIb\u03b2 Transmits 2-Way GPIb-IX Signaling to Stimulate Platelet Activation and VWF Binding"],"prefix":"10.1161","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0205-8807","authenticated-orcid":true,"given":"Yaping","family":"Zhang","sequence":"first","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Liang","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7441-2927","authenticated-orcid":true,"given":"Amir Hossein","family":"Kazemipour Ashkezari","sequence":"additional","affiliation":[{"name":"George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta (A.H.K.A., C.Z.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2665-0269","authenticated-orcid":true,"given":"Can","family":"Wang","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9258-2540","authenticated-orcid":true,"given":"Claire W.","family":"Chang","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-8451","authenticated-orcid":true,"given":"Yanyan","family":"Bai","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4730-9318","authenticated-orcid":true,"given":"Xin","family":"Huang","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7224-7537","authenticated-orcid":true,"given":"Andrew","family":"Mack","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haotian","family":"Yang","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7753-8368","authenticated-orcid":true,"given":"Peiwen","family":"Cong","sequence":"additional","affiliation":[{"name":"Wallace H. 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