{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T23:50:45Z","timestamp":1791935445479,"version":"4.3.4"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T00:00:00Z","timestamp":1737417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92169114"],"award-info":[{"award-number":["92169114"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81802932"],"award-info":[{"award-number":["81802932"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Fund of Hubei Province","award":["2022CFA054"],"award-info":[{"award-number":["2022CFA054"]}]},{"name":"Natural Science Fund of Hubei Province","award":["2024AFB077"],"award-info":[{"award-number":["2024AFB077"]}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2018YFE0113600"],"award-info":[{"award-number":["2018YFE0113600"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Global Research Award"},{"name":"Supplement Award from the American Society of Hematology"},{"name":"HUST-QMUL","award":["2022-HUST-QMUL-SPRF-01"],"award-info":[{"award-number":["2022-HUST-QMUL-SPRF-01"]}]},{"name":"HUST-USYD-JRC"},{"name":"Wuhan Dawn Program","award":["2022020801020100"],"award-info":[{"award-number":["2022020801020100"]}]},{"name":"Open Project of Hubei Key Laboratory of Wudang Local Chinese Medicine Research from the Hubei University of Medicine","award":["WDCM2023001\/2022001"],"award-info":[{"award-number":["WDCM2023001\/2022001"]}]},{"name":"Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Dedicator of cytokinesis 2 (DOCK2), a member of the DOCK family of guanine nucleotide exchange factors that specifically act on the Rho GTPases including Rac and Cdc42, plays pivotal roles in the regulation of leukocyte homeostasis. However, its functions in platelets remain unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Using mice with genetic deficiency of DOCK2 (Dock2\u2212\/\u2212), we showed that Dock2\u2212\/\u2212 mice exhibited a macrothrombocytopenic phenotype characterized as decreased platelet count and enlarged platelet size by transmission electron microscopy. Dock2\u2212\/\u2212 megakaryocytes had reduced polyploidization determined by propidium iodide staining and defective proplatelet formation by confocal microscopy. DOCK2 deficiency led to enriched F-actin level in resting platelets but defective F-actin assembly in activated platelets by phalloidin staining, and mechanistically, attenuated activity of Rac1, unchanged Cdc42 but enhanced RhoA measured by immunoprecipitation of GTP-bound proteins. Immunoblotting analysis showed that Dock2\u2212\/\u2212 platelets had reduced immunoreceptor tyrosine-based activation motif signaling downstream of impaired clustering of GPVI receptors determined by stochastic optical reconstruction microscopy. Further, DOCK2 deficiency resulted in reduced density and branches of fibrin fibres in the clots in vitro and diminished platelet aggregation in a microfluidic chamber ex vivo. Dock2\u2212\/\u2212 platelets exhibited impaired incorporation into a growing thrombus in cremaster arterioles following allogeneic transfusion into a WT recipient and defective heterotypic interactions with neutrophils in cremaster venules as reflected by decreased platelet-neutrophil aggregate formation in vitro under stirring condition. In addition, myeloid deficiency of DOCK2 caused prolonged tail bleeding times. Finally, pharmacological inhibition of DOCK2 using a small-molecular inhibitor CPYPP suppressed actin dynamics leading to impaired responses to GPVI activation and defects in platelet spreading, clot retraction, and thrombus formation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>DOCK2 plays critical roles in the regulation of platelet biogenesis and functions by controlling Rac1 activity and cytoskeletal actin dynamics and may be a novel target for the treatment of thrombotic and thrombo-inflammatory diseases.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf009","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T18:17:47Z","timestamp":1737483467000},"page":"479-491","source":"Crossref","is-referenced-by-count":7,"title":["Dedicator of cytokinesis 2 regulates cytoskeletal actin dynamics and is essential for platelet biogenesis and functions"],"prefix":"10.1093","volume":"121","author":[{"given":"Jiani","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology , Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xulin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology , Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Key Laboratory of Chinese Medicinal Resource and Chinese Herbal Compound of the Ministry of Education , Wuhan, Hubei 430065 ,","place":["China"]},{"name":"The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province , Wuhan, Hubei 430030 ,","place":["China"]},{"name":"Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology , Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology , Wuhan, Hubei 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, 200025 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