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¹ Department of Cell and Developmental Biology and ² Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599
³ Cardiovascular Research Center and ⁴ Department of Microbiology, Mellon Prostate Cancer Institute, University of Virginia, Charlottesville, VA 22908

Correspondence to Jaap D. van Buul: j.vanbuul{at}sanquin.nl; or Keith Burridge: keith_burridge{at}med.unc.edu

During trans-endothelial migration (TEM), leukocytes use adhesion receptors such as intercellular adhesion molecule-1 (ICAM1) to adhere to the endothelium. In response to this interaction, the endothelium throws up dynamic membrane protrusions, forming a cup that partially surrounds the adherent leukocyte. Little is known about the signaling pathways that regulate cup formation. In this study, we show that RhoG is activated downstream from ICAM1 engagement. This activation requires the intracellular domain of ICAM1. ICAM1 colocalizes with RhoG and binds to the RhoG-specific SH3-containing guanine-nucleotide exchange factor (SGEF). The SH3 domain of SGEF mediates this interaction. Depletion of endothelial RhoG by small interfering RNA does not affect leukocyte adhesion but decreases cup formation and inhibits leukocyte TEM. Silencing SGEF also results in a substantial reduction in RhoG activity, cup formation, and TEM. Together, these results identify a new signaling pathway involving RhoG and its exchange factor SGEF downstream from ICAM1 that is critical for leukocyte TEM.

J.D. van Buul's present address is Dept. of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1012 ZA Amsterdam, Netherlands.

Abbreviations used in this paper: GEF, guanine-nucleotide exchange factor; HUVEC, human umbilical vein endothelial cell; ICAM1, intercellular adhesion molecule-1; MHC, major histocompatibility complex; miRNA, micro-RNA; PBD, p21-activated kinase–binding domain; ROCK, Rho-associated coil-containing protein kinase; SDF-1, stromal cell–derived factor-1; SGEF, SH3-containing GEF; TEM, trans-endothelial migration; VE, vascular endothelial; wt, wild type.

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