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The 14-3-3ζ-c-Src-integrin-β3 complex is vital for platelet activation

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机构: [1]Key Laboratory of Bioactive Peptides, Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. [2]Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. [3]Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada. [4]Toronto Platelet Immunobiology Group, Toronto, ON, Canada. [5]Department of Molecular and Cell Biology, School of Life Sciences, University of Science and Technology of China, Hefei, China. [6]Canadian Blood Services Centre for Innovation, Toronto, ON, Canada. [7]University of Chinese Academy of Sciences, Beijing, China. [8]Department of Physiology and. [9]Department of Medicine, University of Toronto, Toronto, ON, Canada [10]Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
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Several adaptor molecules bind to cytoplasmic tails of β-integrins and facilitate bidirectional signaling, which is critical in thrombosis and hemostasis. Interfering with integrin-adaptor interactions spatially or temporally to inhibit thrombosis without affecting hemostasis is an attractive strategy for the development of safe antithrombotic drugs. We show for the first time that the 14-3-3ζ-c-Src-integrin-β3 complex is formed during platelet activation. 14-3-3ζ-c-Src interaction is mediated by the -PIRLGLALNFSVFYYE- fragment (PE16) on the 14-3-3ζ and SH2-domain on c-Src, whereas the 14-3-3ζ-integrin-β3 interaction is mediated by the -ESKVFYLKMKGDYYRYL- fragment (EL17) on the 14-3-3ζ and -KEATSTF- fragment (KF7) on the β3-integrin cytoplasmic tail. The EL17-motif inhibitor, or KF7 peptide, interferes with the formation of the 14-3-3ζ-c-Src-integrin-β3 complex and selectively inhibits β3 outside-in signaling without affecting the integrin-fibrinogen interaction, which suppresses thrombosis without causing significant bleeding. This study characterized a previously unidentified 14-3-3ζ-c-Src-integrin-β3 complex in platelets and provided a novel strategy for the development of safe and effective antithrombotic treatments.© 2020 by The American Society of Hematology.

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大类 | 1 区 医学
小类 | 1 区 血液学
最新[2023]版:
大类 | 1 区 医学
小类 | 1 区 血液学
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第一作者机构: [1]Key Laboratory of Bioactive Peptides, Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. [2]Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. [3]Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada. [4]Toronto Platelet Immunobiology Group, Toronto, ON, Canada.
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通讯机构: [1]Key Laboratory of Bioactive Peptides, Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. [2]Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. [3]Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada. [4]Toronto Platelet Immunobiology Group, Toronto, ON, Canada. [6]Canadian Blood Services Centre for Innovation, Toronto, ON, Canada. [8]Department of Physiology and. [9]Department of Medicine, University of Toronto, Toronto, ON, Canada [10]Sino-African Joint Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China. [*1]Department of Laboratory Medicine and Pathobiology, Department of Medicine and Department of Physiology, University of Toronto Canadian Blood Services Centre for Innovation St. Michael’s Hospital, Room 421, LKSKI - Keenan Research Centre, 209 Victoria Street, Toronto, ON M5B 1W8, Canada [*2]Kunming Institute of Zoology, Chinese Academy of Sciences, 32 Jiaochang Donglu, Kunming 650223, Yunnan, China
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