The 14-3-3ζ-c-Src-integrin-β3 complex is vital for platelet activation. Blood, 2020 Title: The 14-3-3ζ-c-Src-integrin-β3 complex is vital for platelet activation. Author: Shen C, Liu M, Xu R, Wang G, Li J, Chen P, Ma W, Mwangi J, Lu Q, Duan Z, Zhang Z, Dahmani FZ, Mackeigan DT, Ni H, Lai R. Publication Name: Blood Pub Year: 2020 Doi: 10.1182/blood.2019002314 IF: 17.543 Abstract: Several adaptor molecules bind to cytoplasmic tails of beta-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 14-3-3zeta-c-Src-integrin-beta3 complex is formed during platelet activation. 14-3-3zeta-c-Src interaction is mediated by the -PIRLGLALNFSVFYYE- fragment (PE16) on the 14-3-3zeta and SH2-domain on c-Src, whereas the 14-3-3zeta-integrin-beta3 interaction is mediated by the -ESKVFYLKMKGDYYRYL- fragment (EL17) on the 14-3-3zeta and -KEATSTF- fragment (KF7) on the beta3-integrin cytoplasmic tail. The EL17-motif inhibitor, or KF7 peptide, interferes with the formation of the 14-3-3zeta-c-Src-integrin-beta3 complex and selectively inhibits beta3 outside-in signaling without affecting the integrin-fibrinogen interaction, which suppresses thrombosis without causing significant bleeding. This study characterized a previously unidentified 14-3-3zeta-c-Src-integrin-beta3 complex in platelets and provided a novel strategy for the development of safe and effective antithrombotic treatments. |
