Blood Journal
Leading the way in experimental and clinical research in hematology

E-selectin engages PSGL-1 and CD44 through a common signaling pathway to induce integrin αLβ2-mediated slow leukocyte rolling

  1. Tadayuki Yago1,
  2. Bojing Shao2,
  3. Jonathan J. Miner2,
  4. Longbiao Yao1,
  5. Arkadiusz G. Klopocki1,
  6. Kenichiro Maeda3,
  7. K. Mark Coggeshall3,4, and
  8. Rodger P. McEver1,2
  1. 1Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City;
  2. 2Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City;
  3. 3Immunobiology & Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City; and
  4. 4Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City

Abstract

In inflamed venules, neutrophils rolling on E-selectin induce integrin αLβ2-dependent slow rolling on intercellular adhesion molecule-1 by activating Src family kinases (SFKs), DAP12 and Fc receptor-γ (FcRγ), spleen tyrosine kinase (Syk), and p38. E-selectin signaling cooperates with chemokine signaling to recruit neutrophils into tissues. Previous studies identified P-selectin glycoprotein ligand-1 (PSGL-1) as the essential E-selectin ligand and Fgr as the only SFK that initiate signaling to slow rolling. In contrast, we found that E-selectin engagement of PSGL-1 or CD44 triggered slow rolling through a common, lipid raft–dependent pathway that used the SFKs Hck and Lyn as well as Fgr. We identified the Tec kinase Bruton tyrosine kinase as a key signaling intermediate between Syk and p38. E-selectin engagement of PSGL-1 was dependent on its cytoplasmic domain to activate SFKs and slow rolling. Although recruiting phosphoinositide-3-kinase to the PSGL-1 cytoplasmic domain was reported to activate integrins, E-selectin–mediated slow rolling did not require phosphoinositide-3-kinase. Studies in mice confirmed the physiologic significance of these events for neutrophil slow rolling and recruitment during inflammation. Thus, E-selectin triggers common signals through distinct neutrophil glycoproteins to induce αLβ2-dependent slow rolling.

  • Submitted December 15, 2009.
  • Accepted February 27, 2010.
View Full Text