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.
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.
Fujikawa
Keiko
K
660 S. Euclid Ave., Dept. of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Miletic
Ana V
AV
Alt
Frederick W
FW
Faccio
Roberta
R
Brown
Tracie
T
Hoog
Jeremy
J
Fredericks
Jessica
J
Nishi
Shinzo
S
Mildiner
Shirly
S
Moores
Sheri L
SL
Brugge
Joan
J
Rosen
Fred S
FS
Swat
Wojciech
W
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism*
D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; C490565:Vav2 protein, mouse; C496622:Vav3 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium