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Molecular and Cellular Biology, May 2001, p. 3126-3136, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3126-3136.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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†

Osamu Kaminuma,1,2 Marcel Deckert,1,Dagger Chris Elly,1 Yun-Cai Liu,1 and Amnon Altman1,*

Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California,1 and Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan2

Received 7 July 2000/Returned for modification 4 August 2000/Accepted 2 February 2001

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 Ca2+ 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 Ca2+/NFAT pathway, plays the predominant role in NFAT-IL-2 activation by Vav.

* Corresponding author. Mailing address: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Phone: (858) 558-3527. Fax: (858) 558-3526. E-mail: amnon{at}liai.org.

dagger Publication 377 from the La Jolla Institute for Allergy and Immunology.

Dagger Present address: INSERM U343, Hopital de l'Archet, Nice, France.

Molecular and Cellular Biology, May 2001, p. 3126-3136, Vol. 21, No. 9
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.9.3126-3136.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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