MEK1 AND THE EXTRACELLULAR SIGNAL-REGULATED KINASES ARE REQUIRED FOR THE STIMULATION OF IL-2 GENE-TRANSCRIPTION IN T-CELLS

TCR engagement stimulates the activation of the protein kinase Raf-1, Active Raf-1 phosphorylates and activates the mitogen-activated protei n (MAP) kinase/extracellular signal-regulated kinase kinase 1 (MEK1), which in turn phosphorylates and activates the MAP kinases/extracellul ar signal regulated kinases, ERK1 and ERK2. Raf-1 activity promotes IL -2 production in activated T lymphocytes, Therefore, we sought to dete rmine whether MEK1 and ERK activities also stimulate IL-2 gene transcr iption, Expression of constitutively active Raf-1 or MEK1 in Jurkat T cells enhanced the stimulation of IL-2 promoter-driven transcription s timulated by a calcium ionophore and PMA, and together with a calcium ionophore the expression of each protein was sufficient to stimulate N F-AT activity, Expression of MEK1-interfering mutants inhibited the st imulation of IL-2 promoter-driven transcription and blocked the abilit y of constitutively active Ras and Raf-1 to costimulate NF-AT activity with a calcium ionophore. Expression of the MAP kinase-specific phosp hatase, MKP-1, which blocks ERK activation, inhibited IL-2 promoter an d NF-AT-driven transcription stimulated by a calcium ionophore and PMA , and in addition, MKP-1 neutralized the transcriptional enhancement c aused by active Raf-1 and MEK1 expression, We conclude that the MAP ki nase signal transduction pathway consisting of Raf-1, MEK1, and ERK1 a nd ERK2 functions in the stimulation IL-2 gene transcription in activa ted T lymphocytes.