Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte
S. Tartare-deckert et al., Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte, J BIOL CHEM, 276(24), 2001, pp. 20849-20857
Vav1 and Vav2 are members of the Dbl family of guanine nucleotide exchange
factors for the Rho family of small GTPases. Although the role of Vav1 duri
ng lymphocyte development and activation is well characterized, the functio
n of Vav2 is still unclear. In this study, we compared the signaling pathwa
ys regulated by Vav1 and Vav2 following engagement of the T cell receptor (
TCR). We show that Vav2 is tyrosine-phosphorylated upon TCR stimulation and
by co-expressed Src and Syk family kinases, Using glutathione S-transferas
e fusion proteins, we observed that the Src homology 2 domain of Vav2 binds
tyrosine-phosphorylated proteins from TCR-stimulated Jurkat T cell lysates
, including c-Cbl and SLP-76, Like Vav1, Vav2 cooperated with TCR stimulati
on to increase extracellular signal-regulated kinase activation and to prom
ote c-fos serum response element transcriptional activity. Moreover, both p
roteins displayed a similar action in increasing the expression of the earl
y activation marker CD69 in Jurkat T cells. However, in contrast to Vav1, V
av2 dramatically suppressed TCR signals leading to nuclear factor of activa
ted T cells (NF-AT)dependent transcription and induction of the interleukin
-a promoter. Vav2 appears to act upstream of the phosphatase calcineurin be
cause a constitutively active form of calcineurin rescued the effect of Vav
2 by restoring TCR-induced NF-AT activation. Interestingly, the Dbl homolog
y and Src homology 2 domains of Vav2 were necessary for its inhibitory effe
ct on NF-AT activation and far induction of serum response element transcri
ptional activity. Taken together, our results indicate that Vav1 and Vav2 e
xert overlapping but nonidentical functions in T cells. The negative regula
tory pathway elicited by Vav2 might play an important role in regulating ly
mphocyte activation processes.