Meng-Ying Wu1, Yuh-Charn Lin1, Wei-Ju Liao1, Cheng-Fen Tu1, Ming-Huei Chen1, Steve R Roffler1, Ruey-Bing Yang2. 1. From the Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (M.-Y.W., Y.-C.L., W.-J.L., R.-B.Y.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (M.-Y.W., Y.-C.L., W.-J.L., C.-F.T., S.R.R., R.-B.Y.); Molecular Medicine Program, Taiwan International Graduate Program, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.T.); Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan (C.-F.T.); Department of Applied Statistics and Information Science, Ming Chuan University, Taoyuan, Taiwan (M.-H.C.); and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan (R.-B.Y.). 2. From the Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (M.-Y.W., Y.-C.L., W.-J.L., R.-B.Y.); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (M.-Y.W., Y.-C.L., W.-J.L., C.-F.T., S.R.R., R.-B.Y.); Molecular Medicine Program, Taiwan International Graduate Program, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C.-F.T.); Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan (C.-F.T.); Department of Applied Statistics and Information Science, Ming Chuan University, Taoyuan, Taiwan (M.-H.C.); and Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan (R.-B.Y.). rbyang@ibms.sinica.edu.tw.
Abstract
OBJECTIVE: Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1), a secreted and surface-exposed glycoprotein on activated platelets, promotes platelet-platelet interaction and supports platelet-matrix adhesion. Its plasma level is a biomarker of platelet activation in acute thrombotic diseases. However, the exact roles of plasma SCUBE1 in vivo remain undefined. APPROACH AND RESULTS: We generated new mutant (Δ) mice lacking the soluble but retaining the membrane-bound form of SCUBE1. Plasma SCUBE1-depleted Δ/Δ mice showed normal hematologic and coagulant features and expression of major platelet receptors, but Δ/Δ platelet-rich plasma showed impaired platelet aggregation in response to ADP and collagen treatment. The addition of purified recombinant SCUBE1 protein restored the aggregation of platelets in Δ/Δ platelet-rich plasma and further enhanced platelet aggregation in +/+ platelet-rich plasma. Plasma deficiency of SCUBE1 diminished arterial thrombosis in mice and protected against lethal thromboembolism induced by collagen-epinephrine treatment. Last, antibodies directed against the epidermal growth factor-like repeats of SCUBE1, which are involved in trans-homophilic protein-protein interactions, protected mice against fatal thromboembolism without causing bleeding in vivo. CONCLUSIONS: We conclude that plasma SCUBE1 participates in platelet aggregation by bridging adjacent activated platelets in thrombosis. Blockade of soluble SCUBE1 might represent a novel antithrombotic strategy.
OBJECTIVE: Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE1), a secreted and surface-exposed glycoprotein on activated platelets, promotes platelet-platelet interaction and supports platelet-matrix adhesion. Its plasma level is a biomarker of platelet activation in acute thrombotic diseases. However, the exact roles of plasma SCUBE1 in vivo remain undefined. APPROACH AND RESULTS: We generated new mutant (Δ) mice lacking the soluble but retaining the membrane-bound form of SCUBE1. Plasma SCUBE1-depleted Δ/Δ mice showed normal hematologic and coagulant features and expression of major platelet receptors, but Δ/Δ platelet-rich plasma showed impaired platelet aggregation in response to ADP and collagen treatment. The addition of purified recombinant SCUBE1 protein restored the aggregation of platelets in Δ/Δ platelet-rich plasma and further enhanced platelet aggregation in +/+ platelet-rich plasma. Plasma deficiency of SCUBE1 diminished arterial thrombosis in mice and protected against lethal thromboembolism induced by collagen-epinephrine treatment. Last, antibodies directed against the epidermal growth factor-like repeats of SCUBE1, which are involved in trans-homophilic protein-protein interactions, protected mice against fatal thromboembolism without causing bleeding in vivo. CONCLUSIONS: We conclude that plasma SCUBE1 participates in platelet aggregation by bridging adjacent activated platelets in thrombosis. Blockade of soluble SCUBE1 might represent a novel antithrombotic strategy.
Authors: Jennifer A Bohn; Jamie L Van Etten; Trista L Schagat; Brittany M Bowman; Richard C McEachin; Peter L Freddolino; Aaron C Goldstrohm Journal: Nucleic Acids Res Date: 2018-01-09 Impact factor: 16.971
Authors: Carolina Cappi; Melody E Oliphant; Zsanett Péter; Gwyneth Zai; Maria Conceição do Rosário; Catherine A W Sullivan; Abha R Gupta; Ellen J Hoffman; Manmeet Virdee; Emily Olfson; Sarah B Abdallah; A Jeremy Willsey; Roseli G Shavitt; Euripedes C Miguel; James L Kennedy; Margaret A Richter; Thomas V Fernandez Journal: Biol Psychiatry Date: 2019-10-16 Impact factor: 13.382
Authors: Wei Sun; Ying Tang; Yi-Yin Tai; Adam Handen; Jingsi Zhao; Gil Speyer; Yassmin Al Aaraj; Annie Watson; Makenna E Romanelli; John Sembrat; Mauricio Rojas; Marc A Simon; Yingze Zhang; Janet Lee; Zeyu Xiong; Partha Dutta; Sathish Badu Vasamsetti; Dennis McNamara; Bryan McVerry; Charles F McTiernan; Frank C Sciurba; Seungchan Kim; Kerri Akaya Smith; Jeremy A Mazurek; Yuchi Han; Anjali Vaidya; Seyed Mehdi Nouraie; Neil J Kelly; Stephen Y Chan Journal: JACC Basic Transl Sci Date: 2020-11-04