P-selectin primes leukocyte integrin activation during inflammation.
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.
Wang
Hai-Bo
HB
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.
Wang
Jin-Tao
JT
Zhang
Lei
L
Geng
Zhen H
ZH
Xu
Wei-Li
WL
Xu
Tao
T
Huo
Yuqing
Y
Zhu
Xueliang
X
Plow
Edward F
EF
Chen
Ming
M
Geng
Jian-Guo
JG
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D016023:Integrins / Q000276:immunology* / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019007:P-Selectin / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection
D004268:DNA-Binding Proteins; D016023:Integrins; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; C117046:TNIP1 protein, human; D019869:Phosphatidylinositol 3-Kinases