Vav modulation of the Ras/MEK/ERK signaling pathway plays a role in NFAT activation and CD69 up-regulation.
Vav is expressed exclusively in hematopoietic cells and becomes phosphorylated on tyrosine in response to antigen receptor ligation. Although Vav can act as a Rac-specific guanine nucleotide exchange factor in vitro and as a c-Jun N-terminal kinase (JNK) activator in ectopic expression systems, its physiological functions in lymphocytes remain unclear. Indirect evidence suggests that Vav interacts with the Ras/ERK pathway in T cells. Here, we analyzed the effects of Vav on three known downstream targets of Ras, i. e. activation of ERK and NFAT, and up-regulation of the activation antigen CD69. The MEK inhibitor PD90859 inhibited Vav-induced activation of ERK, and Vav- or anti-CD3-induced activation of NFAT, suggesting that MEK and ERK are involved in Vav-mediated NFAT activation. Similarly to Ras, Vav cooperated with constitutively active calcineurin and with ERK to activate NFAT, and was capable of up-regulating CD69 expression in T cells. Moreover, these Vav-mediated functions were all inhibited by a dominant negative Ras mutant. Conversely, however, dominant negative Vav did not inhibit NFAT and ERK activation or CD69 expression induced by an active Ras mutant. These findings indicate that Ras functions as an important downstream target of Vav in signaling pathways that lead to NFAT and ERK activation, and to CD69 expression. Moreover, the finding that Vav- (or Ras-) induced CD69 expression was not inhibited by a dominant negative Rac mutant indicates that Vav mediates some Ras-dependent, but Rac-independent, functions in T cells.
Villalba
M
M
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego 92121, USA.
Hernandez
J
J
Deckert
M
M
Tanaka
Y
Y
Altman
A
A
D015703:Antigens, CD / Q000096:biosynthesis*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis*; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D037181:Lectins, C-Type; D048728:MAP Kinase Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D018716:Molecular Mimicry; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D037181:Lectins, C-Type; D048728:MAP Kinase Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D014157:Transcription Factors; D018631:ras Proteins; D000099192:CD69 Antigens; C496618:VAV1 protein, human; C482576:MAP3K1 protein, human