Submitted August 26, 2008
Accepted March 27, 2009
Cytohesin-1 controls the activation of RhoA and modulates integrin-dependent adhesion and migration of dendritic cells
Thomas Quast, Barbara Tappertzhofen, Cora Schild, Jessica Grell, Niklas Czeloth, Reinhold Forster, Ronen Alon, Line Fraemohs, Katrin Dreck, Christian Weber, Tim Lammermann, Michael Sixt, and Waldemar Kolanus*
Life and Medical Sciences (LIMES) Institute, Laboratory for Molecular Immunology, University of Bonn, Bonn, Germany
Institute of Immunology, Hannover Medical School, Hannover, Germany
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
Institute for Molecular Cardiovascular Research (IMCAR), RWTH University Aachen, Aachen, Germany
Max-Planck-Institute for Biochemistry, Martinsried, Germany
* Corresponding author; email: wkolanus{at}uni-bonn.de.
Adhesion and motility of mammalian leukocytes are essential requirements for innate and adaptive immune defence mechanisms. We show here that the guanine nucleotide exchange factor cytohesin-1 which had previously been demonstrated to be an important component of beta-2 integrin activation in lymphocytes, regulates the activation of the small GTPase RhoA in primary dendritic cells (DC). Cytohesin-1 and RhoA are both required for the induction of chemokine-dependent conformational changes of the integrin beta-2 subunit of DC during adhesion under physiological flow conditions. Furthermore, employment of RNAi in murine BM-DC revealed that interference with cytohesin-1 signaling impairs migration of wild type dendritic cells in complex 3D environments and in vivo. This phentoype was not observed in the complete absence of integrins. We thus demonstrate an essential role of cytohesin-1/RhoA during amoeboid migration in the presence of integrins and further suggest that DCs without integrins switch to a different migration mode.
