The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published 17 November 2003. doi:10.1084/jem.20030874
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© Rockefeller University Press, 0022-1007/2003/11/1595 $5.00
The Journal of Experimental Medicine, Volume 198, Number 10, 1595-1608

Vav1/2/3-null Mice Define an Essential Role for Vav Family Proteins in Lymphocyte Development and Activation but a Differential Requirement in MAPK Signaling in T and B Cells

Keiko Fujikawa1,3,4, Ana V. Miletic3, Frederick W. Alt1,2, Roberta Faccio3, Tracie Brown3, Jeremy Hoog3, Jessica Fredericks3, Shinzo Nishi4, Shirly Mildiner3, Sheri L. Moores5, Joan Brugge5, Fred S. Rosen1 and Wojciech Swat1,3

1 The Center for Blood Research, Department of Pediatrics, The Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115
2 Howard Hughes Medical Institute, Department of Pediatrics, The Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115
3 Department of Pathology and Immunology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO 63110
4 Department of Biochemistry, Hokkaido University Graduate School of Medicine, 060-8638 Sapporo, Japan
5 Department of Cell Biology, Harvard Medical School, Boston, MA 02115

Address correspondence to Wojciech Swat, 660 S. Euclid Ave., Dept. of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 747-8889; Fax: (314) 362-4096; email: swat{at}pathbox.wustl.edu

The Vav family of Rho guanine nucleotide exchange factors is thought to orchestrate signaling events downstream of lymphocyte antigen receptors. Elucidation of Vav function has been obscured thus far by the expression of three highly related family members. We generated mice lacking all Vav family proteins and show that Vav-null mice produce no functional T or B cells and completely fail to mount both T-dependent and T-independent humoral responses. Whereas T cell development is blocked at an early stage in the thymus, immature B lineage cells accumulate in the periphery but arrest at a late "transitional" stage. Mechanistically, we show that the Vav family is crucial for both TCR and B cell receptor (BCR)–induced Ca2+ signaling and, surprisingly, is only required for mitogen-activated protein kinase (MAPK) activation in developing and mature T cells but not in B cells. Thus, the abundance of immature B cells generated in Vav-null mice may be due to intact Ras/MAPK signaling in this lineage. Although the expression of Vav1 alone is sufficient for normal lymphocyte development, our data also reveal lineage-specific roles for Vav2 and Vav3, with the first demonstration that Vav3 plays a critical compensatory function in T cells. Together, we define an essential role for the entire Vav protein family in lymphocyte development and activation and establish the limits of functional redundancy both within this family and between Vav and other Rho–guanine nucleotide exchange factors.

Key Words: thymocyte • antigen receptor • signal transduction • Ca++ • mitogen-activated protein kinase


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