Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function

Erika S. Wittchen, Rebecca A. Worthylake, Patrick Kelly, Patrick J. Casey, Lawrence Quilliam, Keith Burridge

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

The passage of leukocytes out of the blood circulation and into tissues is necessary for the normal inflammatory response, but it also occurs inappropriately in many pathological situations. This process is limited by the barrier presented by the junctions between adjacent endothelial cells that line blood vessels. Here we show that activation of the Rap1 GTPase in endothelial cells accelerated de novo assembly of endothelial cell-cell junctions and increased the barrier function of endothelial monolayers. In contrast, depressing Rap1 activity by expressing Rap1GAP led to disassembly of these junctions and increased their permeability. We also demonstrate that endogenous Rap1 was rapidly activated at early stages of junctional assembly, confirming the involvement of Rap1 during junctional assembly. Intriguingly, elevating Rap1 activity selectively within endothelial cells decreased leukocyte transendothelial migration, whereas inhibiting Rap activity by expression of Rap1GAP increased leukocyte transendothelial migration, providing physiological relevance to our hypothesis that Rap1 augments barrier function of interendothelial cell junctions. Furthermore, these results suggest that Rap1 may be a novel therapeutic target for clinical conditions in which an inappropriate inflammatory response leads to disease.

Original languageEnglish
Pages (from-to)11675-11682
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number12
DOIs
StatePublished - Mar 25 2005

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Transendothelial and Transepithelial Migration
GTP Phosphohydrolases
Endothelial cells
Leukocytes
Endothelial Cells
Intercellular Junctions
Blood Circulation
Blood vessels
Hemodynamics
Blood Vessels
Monolayers
Permeability
Chemical activation
Tissue
Cell Line

ASJC Scopus subject areas

  • Biochemistry

Cite this

Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function. / Wittchen, Erika S.; Worthylake, Rebecca A.; Kelly, Patrick; Casey, Patrick J.; Quilliam, Lawrence; Burridge, Keith.

In: Journal of Biological Chemistry, Vol. 280, No. 12, 25.03.2005, p. 11675-11682.

Research output: Contribution to journalArticle

Wittchen, Erika S. ; Worthylake, Rebecca A. ; Kelly, Patrick ; Casey, Patrick J. ; Quilliam, Lawrence ; Burridge, Keith. / Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 12. pp. 11675-11682.
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