Vav-Rac1-mediated activation of the c-Jun N-terminal kinase/c-Jun/AP-1 pathway plays a major role in stimulation of the distal NFAT site in the interleukin-2 gene promoter.
Vav, a hematopoiesis-specific signaling protein, plays an important role in T-cell development and activation. Vav upregulates the expression of the interleukin-2 (IL-2) gene, primarily via activation of the distal NFAT site in the IL-2 gene promoter (NFAT-IL-2). However, since this site cooperatively binds NFAT and AP-1, the relative contribution of ... Vav to NFAT versus AP-1 activation has not been determined. Here, we studied the respective roles of the AP-1 and NFAT pathways in the T-cell receptor (TCR)-mediated, Vav-dependent activation of NFAT-IL-2. Although Vav stimulated the transcriptional activity of an NFAT-IL-2 reporter gene, it failed to stimulate the transcriptional or DNA-binding activities of an AP-1-independent NFAT site derived from the human gamma interferon gene promoter. Vav also did not stimulate detectable Ca(2+) mobilization and nuclear translocation of NFATc or NFATp. On the other hand, Vav induced the activation of Rac1 or Cdc42 and c-Jun N-terminal kinase (JNK), enhanced the transcriptional and DNA-binding activities of AP-1, and induced increased phosphorylation of c-Jun. Dominant-negative Vav and/or Rac1 mutants blocked the TCR-mediated stimulation of these events, demonstrating the physiological relevance of these effects. Vav also associated with Rac1 or Cdc42 in T cells, and anti-CD3 antibody stimulation enhanced this association. These findings indicate that a Rac1-dependent JNK/c-Jun/AP-1 pathway, rather than the Ca(2+)/NFAT pathway, plays the predominant role in NFAT-IL-2 activation by Vav.
Mesh Terms:
Active Transport, Cell Nucleus, Binding Sites, Calcium, Cell Cycle Proteins, Cell Nucleus, DNA, DNA-Binding Proteins, Enzyme Activation, Guanine Nucleotide Exchange Factors, Humans, Interleukin-2, JNK Mitogen-Activated Protein Kinases, Jurkat Cells, Mitogen-Activated Protein Kinases, NFATC Transcription Factors, Nuclear Proteins, Phosphorylation, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-vav, Signal Transduction, Transcription Factor AP-1, Transcription Factors, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein
Active Transport, Cell Nucleus, Binding Sites, Calcium, Cell Cycle Proteins, Cell Nucleus, DNA, DNA-Binding Proteins, Enzyme Activation, Guanine Nucleotide Exchange Factors, Humans, Interleukin-2, JNK Mitogen-Activated Protein Kinases, Jurkat Cells, Mitogen-Activated Protein Kinases, NFATC Transcription Factors, Nuclear Proteins, Phosphorylation, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-vav, Signal Transduction, Transcription Factor AP-1, Transcription Factors, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein
Mol. Cell. Biol.
Date: May. 01, 2001
PubMed ID: 11287617
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