Wang Hai-Bo, Wang Jin-Tao, Zhang Lei, Geng Zhen H, Xu Wei-Li, Xu Tao, Huo Yuqing, Zhu Xueliang, Plow Edward F, Chen Ming, Geng Jian-Guo
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Nat Immunol. 2007 Aug;8(8):882-92. doi: 10.1038/ni1491. Epub 2007 Jul 15.
Selectins mediate leukocyte rolling and prime leukocytes for integrin-mediated leukocyte adhesion. However, neither the in vivo importance of nor the signaling pathway by which selectin-mediated integrin activation occurs has been determined. We report here that P-selectin-deficient mice manifested impaired leukocyte adhesion, which was 'rescued' by soluble P-selectin. Mechanistically, the cytoplasmic domain of P-selectin glycoprotein ligand 1 formed a constitutive complex with Nef-associated factor 1. After binding of P-selectin, Src kinases phosphorylated Nef-associated factor 1, which recruited the phosphoinositide-3-OH kinase p85-p110delta heterodimer and resulted in activation of leukocyte integrins. Inhibition of this signal-transduction pathway diminished the adhesion of leukocytes to capillary venules and suppressed peritoneal infiltration of leukocytes. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by P-selectin glycoprotein ligand 1.
选择素介导白细胞滚动，并使白细胞为整合素介导的白细胞黏附做好准备。然而，选择素介导的整合素激活在体内的重要性以及其发生的信号通路均尚未确定。我们在此报告，P-选择素缺陷小鼠表现出白细胞黏附受损，而可溶性P-选择素可“挽救”这一现象。从机制上来说，P-选择素糖蛋白配体1的胞质结构域与Nef相关因子1形成组成型复合物。P-选择素结合后，Src激酶使Nef相关因子1磷酸化，后者募集磷酸肌醇-3-OH激酶p85-p110δ异二聚体，从而导致白细胞整合素激活。抑制该信号转导通路可减少白细胞与毛细血管后微静脉的黏附，并抑制白细胞向腹膜的浸润。我们的数据证明了由P-选择素糖蛋白配体1介导的这一新鉴定信号通路的功能重要性。
