Multiple p21ras effector pathways regulate nuclear factor of activated T cells.

AUTOR(ES)

Genot, E

RESUMO

The transcription factor, Nuclear Factor of Activated T cells (NFAT) is a major target for p21ras and calcium signalling pathways in the IL-2 gene and is induced by p21ras signals acting in synergy with calcium/calcineurin signals. One p21ras effector pathway involves the MAP kinase ERK-2, and we have examined its role in NFAT regulation. Expression of dominant negative MAPKK-1 prevents NFAT induction. Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1, but does not substitute for activated p21ras and synergize with calcium/calcineurin signals to induce NFAT. Expression of dominant negative N17Rac also prevents TCR and p21ras activation of NFAT, but without interfering with the ERK-2 pathway. The transcriptional activity of the NFAT binding site is mediated by a complex comprising a member of the NFAT group and AP-1 family proteins. The induction of AP-1 by p21ras also requires Rac-1 function. Activated Rac-1 could mimic activated p21ras to induce AP-1 but not to induce NFAT. Moreover, the combination of activated MAPKK-1 and Rac-1 could not substitute for activated p21ras and synergize with calcium signals to induce NFAT. Thus, p21ras regulation of NFAT in T cells requires the activity of multiple effector pathways including those regulated by MAPKK-1/ERK-2 and Rac-1.

Documentos Relacionados

• Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells.
• Effector domain mutations dissociate p21ras effector function and GTPase-activating protein interaction.
• v-K-ras leads to preferential farnesylation of p21ras in FRTL-5 cells: Multiple interference with the isoprenoid pathway
• Association of p21ras with phosphatidylinositol 3-kinase.
• Calcium inhibits epidermal growth factor-induced activation of p21ras in human primary keratinocytes.