Constitutive tyrosine phosphorylation of the vav proto-oncogene product in MRL/Mp-lpr/lpr mice.
MRL/Mp-lpr/lpr (lpr) mice develop autoantibodies, vasculitis, and glomerulonephritis, which are similar to human systemic lupus erythematosus, and acquire a generalized, nonmalignant, lymphoproliferative disorder. CD4- CD8- CD3+ TCR alphabeta+ (double-negative, DN) T cells accumulate in spleen and lymph nodes, and become a major T cell population in vivo. These DN T cells, however, are refractory to various stimuli, including CD3, IL-2, CD28, PMA, and PHA. Recently, the lpr gene mutation has been identified as a mutant gene for Fas, resulting in expression defects of Fas Ag. It is still unclear, however, what kinds of mechanisms cause the dysfunction of lpr DN T cells. To elucidate the pathogenic mechanisms in abnormal DN T cells, biochemical analyses were conducted for the expression and tyrosine phosphorylation of the vav proto-oncogene product (Vav) in DN T cells from lpr mice. We demonstrated that Vav, a 95-kDa cytoplasmic protein, from lpr mice was constitutively tyrosine phosphorylated several times higher than in control +/+ mice, while expression of Vav protein in lpr and +/+ mice was equal. Additionally, in contrast with +/+ T cells, tyrosine phosphorylation of Vav, which normally increases within a minute of stimulation via TCR, did not increase in lpr DN T cells following PHA or Ab activation. Taken together with the suggested roles of Vav in multiple receptor-mediated signal transductions, our findings suggest that the functional abnormalities of lpr DN T cells may be related to Vav abnormal tyrosine phosphorylation, which could lead to impaired signaling between surface receptors and G proteins in this cell population.
Mimura
T
T
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Minota
S
S
Nojima
Y
Y
Morino
N
N
Hamasaki
K
K
Furuya
H
H
Yazaki
Y
Y
D000818:Animals; D018797:Cell Cycle Proteins; D005260:Female; D008213:Lymphocyte Activation; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D013045:Species Specificity; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D018797:Cell Cycle Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; D019000:Phosphotyrosine; D014443:Tyrosine