{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T03:45:19Z","timestamp":1781840719476,"version":"3.54.5"},"reference-count":56,"publisher":"American Society of Hematology","issue":"25","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,6,18]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Hemostasis and thrombosis are strongly dependent on the unique ability of platelets to rapidly activate integrin receptors and to firmly adhere to sites of injury under shear stress conditions. Central to integrin activation is the small GTPase RAP1, which itself is activated by guanine nucleotide exchange factors (GEFs). CalDAG-GEFI (RASGRP2) is the highest expressed and functionally dominant platelet RAP-GEF. However, a genome-wide association study also suggested a significant role for RAPGEF2 (PDZ-GEFI), a low-expressed RAP-GEF, in human platelet aggregation. Here, we used mice deficient in RAPGEF2 (megakaryocyte-specific, Rapgef2mKO), CalDAG-GEFI (Caldaggef1\u02d7\/\u02d7), or both RAPGEF2 and CalDAG-GEFI (DKO) to characterize the contribution of RAPGEF2 signaling to platelet function, hemostasis, and thrombosis. RAPGEF2 protein was detected in murine and human platelets. Compared with control or Caldaggef1\u02d7\/\u02d7 platelets, both RAP1 activation and integrin \u03b1IIb\u03b23-mediated aggregation were significantly diminished in DKO platelets. When compared with controls, Rapgef2mKO platelets exhibited reduced integrin activation, a more reversible aggregation response, and impaired adhesion under conditions of shear stress ex vivo and in vivo. Mechanistic studies strongly suggest that RAPGEF2 operates downstream of receptors coupled to the heterotrimeric G protein G13 (GNA13), such as \u03b1IIb\u03b23 and the thromboxane receptor. Together, our studies provide genetic evidence that RAPGEF2 in platelets operates downstream of G13 as an important regulator of RAP1 signaling and integrin activation, especially under conditions of elevated shear stress. These findings markedly improve our understanding of G protein signaling and integrin function in platelets, with potential implications for the development of improved platelet-targeted therapies for cardiovascular disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025032282","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T16:24:46Z","timestamp":1775665486000},"page":"3102-3112","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["A novel G13-RAPGEF2-RAP1 signaling pathway critical for platelet adhesion and aggregation"],"prefix":"10.1182","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6686-8134","authenticated-orcid":false,"given":"David S.","family":"Paul","sequence":"first","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2580-1790","authenticated-orcid":false,"given":"David J.","family":"Rocco","sequence":"additional","affiliation":[{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"3Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily G.","family":"Clark","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9893-1839","authenticated-orcid":false,"given":"Wyatt J.","family":"Schug","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey A.","family":"Martyanov","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7902-1255","authenticated-orcid":false,"given":"Matthew R.","family":"Vander Ploeg","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Summer R.","family":"Jones","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9871-0593","authenticated-orcid":false,"given":"Robert H.","family":"Lee","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-3318","authenticated-orcid":false,"given":"Jean Marie N.","family":"Mwiza","sequence":"additional","affiliation":[{"name":"4Department of Physician Assistant Studies, North Carolina Agricultural and Technical State University, Greensboro, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Ballard-Kordeliski","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8511-4522","authenticated-orcid":false,"given":"Nazli","family":"Deger","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6282-4991","authenticated-orcid":false,"given":"Tomohiro","family":"Kawano","sequence":"additional","affiliation":[{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"5Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Mackman","sequence":"additional","affiliation":[{"name":"2UNC Blood Research Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC"},{"name":"5Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, 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