Rap1a activation by CalDAG-GEFI and p38 MAPK is involved in E-selectin-dependent slow leukocyte rolling

Anika Stadtmann, Laura Brinkhaus, Helena Mueller, Jan Rossaint, Matteo Bolomini-Vittori, Wolfgang Bergmeier, Hugo Van Aken, Denisa D. Wagner, Carlo Laudanna, Klaus Ley, Alexander Zarbock

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Rolling leukocytes are exposed to different adhesion molecules and chemokines. Neutrophils rolling on E-selectin induce integrin αLβ2-mediated slow rolling on ICAM-1 by activating a phospholipase C (PLC)γ2-dependent and a separate PI3Kγ-dependent pathway. E-selectin-signaling cooperates with chemokine signaling to recruit neutrophils into inflamed tissues. However, the distal signaling pathway linking PLCγ2 (Plcg2) to αLβ2-activation is unknown. To identify this pathway, we used different Tat-fusion-mutants and gene-deficient mice in intravital microscopy, autoperfused flow chamber, peritonitis, and biochemical studies. We found that the small GTPase Rap1 is activated following E-selectin engagement and that blocking Rap1a in Pik3cg-/- mice by a dominant-negative Tat-fusion mutant completely abolished E-selectin-mediated slow rolling. We identified CalDAG-GEFI (Rasgrp2) and p38 MAPK as key signaling intermediates between PLCγ2 and Rap1a. Gαi-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster muscle were completely abolished in Rasgrp2-/- mice. The physiological importance of CalDAG-GEFI in E-selectin-dependent integrin activation is shown by complete inhibition of neutrophil recruitment into the inflamed peritoneal cavity of Rasgrp2-/- leukocytes treated with pertussis toxin to block Gαi-signaling. Our data demonstrate that Rap1a activation by p38 MAPK and CalDAG-GEFI is involved in E-selectin-dependent slow rolling and leukocyte recruitment.

Original languageEnglish (US)
Pages (from-to)2074-2085
Number of pages12
JournalEuropean Journal of Immunology
Issue number7
StatePublished - Jul 2011
Externally publishedYes


  • Integrin
  • P38
  • Rap1a
  • Signaling

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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