Treatment of cells with pro-inflammatory cytokines or ultraviolet radiation causes activation of the c-Jun NH2-terminal protein kinase (JNK). Activating transcription factor-2 (ATF2) was found to be a target of the JNK signal transduction pathway. ATF2 was phosphorylated by JNK on two closely spaced threonine residues within the NH2-terminal activation domain. The replacement of these phosphorylation sites with alanine inhibited the transcriptional activity of ATF2. These mutations also inhibited ATF2-stimulated gene expression mediated by the retinoblastoma (Rb) tumor suppressor and the adenovirus early region 1A (E1A) oncoprotein. Furthermore, expression of dominant-negative JNK inhibited ATF2 transcriptional activity. Together, these data demonstrate a role for the JNK signal transduction pathway in transcriptional responses mediated by ATF2.

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The major site of epidermal growth factor receptor (EGF-R) serine phosphorylation is located within the COOH-terminal domain of the receptor at Ser1046/7. We have previously demonstrated that this phosphorylation site accounts for the acute desensitization of the EGF-R observed in EGF-treated cells. Here we show that the mutational removal of this negative regulatory phosphorylation site causes potentiation of signal transduction by the EGF-R. This potentiation can be accounted for in part by a block in the EGF-stimulated down-regulation of the EGF-R. These data indicate that the SER1046/7 phosphorylation site may have a regulatory role during long term incubation of cells with mitogenic concentrations of EGF.