{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T21:30:17Z","timestamp":1768685417416,"version":"3.49.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,1,31]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Platelets are anuclear cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity but may also cause pathological vessel occlusion. One major pathway of platelet activation is triggered by 2 receptors that signal through an (hem)immunoreceptor tyrosine-based activation motif (ITAM), the activating collagen receptor glycoprotein (GP) VI and the C-type lectin-like receptor 2 (CLEC-2). Growth factor receptor\u2013bound protein 2 (Grb2) is a ubiquitously expressed adapter molecule involved in signaling processes of numerous receptors in different cell types, but its function in platelets and MKs is unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>We tested the hypothesis that Grb2 is a crucial adapter protein in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              Here, we show that genetic ablation of Grb2 in MKs and platelets did not interfere with MK differentiation or platelet production. However, Grb2-deficiency severely impaired glycoprotein VI\u2013mediated platelet activation because of defective stabilization of the linker of activated T-cell (LAT) signalosome and activation of downstream signaling proteins that resulted in reduced adhesion, aggregation, and coagulant activity on collagen in vitro. Similarly, CLEC-2\u2013mediated signaling was impaired in Grb2-deficient platelets, whereas the cells responded normally to stimulation of G protein\u2013coupled receptors. In vivo, this selective (hem)immunoreceptor tyrosine-based activation motif signaling defect resulted in prolonged bleeding times but affected arterial thrombus formation only after concomitant treatment with acetylsalicylic acid, indicating that defective glycoprotein VI signaling in the absence of Grb2 can be compensated through thromboxane A\n              <jats:sub>2<\/jats:sub>\n              \u2013induced G protein\u2013coupled receptor signaling pathways.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>These results reveal an important contribution of Grb2 in (hem)immunoreceptor tyrosine-based activation motif signaling in platelets in hemostasis and thrombosis by stabilizing the LAT signalosome.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.114.302670","type":"journal-article","created":{"date-parts":[[2013,11,22]],"date-time":"2013-11-22T02:37:40Z","timestamp":1385087860000},"page":"444-453","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Growth Factor Receptor\u2013Bound Protein 2 Contributes to (Hem)Immunoreceptor Tyrosine-Based Activation Motif\u2013Mediated Signaling in Platelets"],"prefix":"10.1161","volume":"114","author":[{"given":"Sebastian","family":"D\u00fctting","sequence":"first","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timo","family":"V\u00f6gtle","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Morowski","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Schiessl","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen M.","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie K.","family":"Watson","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig E.","family":"Hughes","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jochen A.","family":"Ackermann","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Radtke","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heike M.","family":"Hermanns","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of 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University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (S.K.W., C.E.H., S.P.W.); and Department of Biology, Division of Genetics, University of Erlangen..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhard","family":"Nieswandt","sequence":"additional","affiliation":[{"name":"From the Department of Experimental Biomedicine, University Hospital W\u00fcrzburg (S.D., T.V., M.M., S.S., B.N.) and Rudolf Virchow Center for Experimental Biomedicine (S.D., T.V., C.M.S., H.M.H., B.N.), University of W\u00fcrzburg, W\u00fcrzburg, Germany; Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of 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