c-Fos transcriptional activity stimulated by H-Ras-activated protein kinase distinct from JNK and ERK

Abstract

Ras proteins exert their mitogenic and oncogenic effects through activation of downstream protein kinases. An important question is how Ras-generated signals reach the nucleus to activate downstream target genes. AP-1, a heterodimeric complex of Jun and Fos proteins, which activates mitogen-inducible genes, is a major nuclear target of Ras. Ras can stimulate AP-1 activity by inducing c-fos transcription, a process which is probably mediated by the ERK1 and -2 mitogen-activated protein (MAP) kinases, which phosphorylate the transcription factor Elk-1/TCF. Besides inducing transcription from fos and jun genes, mitogens and Ras proteins enhance AP-1 activity through phosphorylation of c-Jun. Phosphorylation of the c-Jun activation domain leads to c-jun induction through an autoregulatory loop. Ras- and ultra-violet-responsive protein kinases that phosphorylate c-Jun on serine residues at positions 63 and 73 and stimulate its transcriptional activity have been identified. These proline-directed kinases, termed JNKs, are novel MAP kinases. It is not clear, however, whether c-Jun is the only recipient and JNK the only transducer of the Ras signal to AP-1 proteins. A short sequence surrounding the major JNK phosphorylation site of c-Jun is conserved in c-Fos and is part of its activation domain, suggesting that c-Fos may be similarly regulated. Here we show that Ras does indeed augment the transcriptional activity of c-Fos through phosphorylation at Thr 232, the homologue of Ser 73 of c-Jun. However, this is mediated by a novel Ras- and mitogen-responsive proline-directed protein kinase that is different from JNKs and ERKs. Therefore, at least three types of proline-directed kinases transmit Ras- and mitogen-generated signals to the transcriptional machinery.

Stimulation of urokinase-type plasminogen activator receptor expression by PMA requires JNK1-dependent and -independent signaling modules

“…Finally, we found that the kinase-inactive JNK1 expression construct countered the stimulation of u-PAR promoter activity by c-Ha-Ras (Figure 9c) with an equimolar amount of the dominant negative plasmid resulting in over 65% inhibition compared with the empty vector (SRa Vector). Taken together, these results suggest that while c-Ha-ras can activate multiple downstream signaling cascades (Deng and Karin 1995;RodriguezViciana et al, 1994;Russell et al, 1995;Kolch et al, 1991), u-PAR promoter activity in OVCAR-3 cells is regulated by this oncogene partly through a JNKdependent signaling module.…”

Recruitment of insulin receptor substrate-1 and activation of NF-κB essential for midkine growth signaling through anaplastic lymphoma kinase

“…These results suggest that ALK can drive NF-kB activation, and that activation is increased with the presence of IRS-1. In addition, the lack of activation of AP-1, SRE and SRF promoter/reporter constructs indicates that the ALK/ IRS-1-mediated MAPK and PI3-kinase activity does not cause a global increase of transcription of all mitogenesis-and survival-related pathways Deng and Karin, 1994;Minden et al, 1994;Huang et al, 1996) but instead a relatively selective activation of NF-kB in this cellular context. The significance of this activation is supported by the effect of the knockdown of the p65 subunit of NF-kB, which disrupts the transformed phenotype of the 32D/ IRS-1/ALK cells (Figure 7).…”

“…Furthermore, only cells containing both ALK and IRS-1 showed this NF-kB activity (Figure 6b not show any induction in any of the cell lines, although a small but inconsistent activation of the AP-1 promoter/reporter was seen with the 32D/IRS-1 ALK cells (Figure 6a). This lack of AP-1 activity was particularly surprising as control experiments with 32D cells showed that expression of pFC-MEKK, a constitutively active MEKK, induced activation of the AP-1 promoter/ reporter by eightfold (not shown) and AP-1 had been shown by others to be activated by MAPK (Deng and Karin, 1994;Minden et al, 1994) and PI3-kinase (Huang et al, 1996) signaling.…”

Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

“…PTX-induced changes in intracellular calcium levels may trigger the activation of kinases, such as the ras/JNK pathway, which could then lead to the activation of cfos and cjun and promote expression of costimulatory molecules and cytokine production [28,29].…”