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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2346-2355.
Prepublished online as a Blood First Edition Paper on November 21, 2006; DOI 10.1182/blood-2006-04-019034.
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Submitted April 25, 2006
Accepted November 2, 2006
RhoH is important for positive thymocyte selection and T cell receptor signaling
Tatjana Dorn, Ursula Kuhn, Gerd Bungartz, Sebastian Stiller, Martina Bauer, Joachim Ellwart, Thorsten Peters, Karin Scharffetter-Kochanek, Monika Semmrich, Melanie Laschinger, Bernhard Holzmann, Wolfgang E.F. Klinkert, Per Thor Straten, Tania Kollgaard, Michael Sixt, and Cord Brakebusch*
Heisenberg Group "Regulation of Cytoskeletal Organization", Max Planck Institute of Biochemistry, Martinsried, Germany
Dept of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany
GSF, Institute of Molecular Immunology, Munchen, Germany
Clinic for Dermatology & Allergology, University of Ulm, Ulm, Germany
Dept of Surgery, Technische Universitaet Muenchen, Munchen, Germany
Dept of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany
Dept of Hematology, Center for Cancer Immunotherapy (CCIT), University Hospital Herlev, Denmark
Dept of Molecular Pathology, University of Copenhagen, Copenhagen, Denmark
* Corresponding author; email: cord{at}pai.ku.dk.
RhoH is a small GTPase expressed only in the hematopoietic system. Using mice with a targeted disruption of the RhoH gene we demonstrate that RhoH is crucial for thymocyte maturation during DN3 to DN4 transition and during positive selection. Furthermore, differentiation and expansion of DN3 and DN4 thymocytes in vitro is severely impaired. These defects correspond to a defective TCR signaling. While RhoH is not required for TCR induced activation of ZAP70 and ZAP70 mediated activation of p38, it is crucial for tyrosine phosphorylation of LAT, PLC 1 and Vav1 and for the activation of Erk and calcium influx. These data suggest that RhoH is important for pre-TCR and TCR signaling by allowing the efficient interaction of ZAP70 with the LAT signalosome, thus regulating thymocyte development.

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