Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73.

Abstract

In resting cells, c-Jun is phosphorylated on five sites. Three of these sites reside next to its DNA binding domain and negatively regulate DNA binding. In response to expression of oncogenic Ha-Ras, phosphorylation of these sites decreases, while phosphorylation of two other sites within c-Jun's activation domain is greatly enhanced. Phosphorylation of these residues, serines 63 and 73, stimulates the transactivation function of c-Jun and is required for oncogenic cooperation with Ha-Ras. We now show that the same changes in c-Jun phosphorylation are elicited by a variety of transforming oncoproteins with distinct biochemical activities. These oncoproteins, v-Sis, v-Src, Ha-Ras, and Raf-1, participate in a signal transduction pathway that leads to increased phosphorylation of serines 63 and 73 on c-Jun. While oncogenic Ha-Ras is a constitutive stimulator of c-Jun activity and phosphorylation, the normal c-Ha-Ras protein is a serum-dependent modulator of c-Jun's activity. c-Jun is therefore a downstream target for a phosphorylation cascade involved in cell proliferation and transformation.

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

“…We found no significant change in mRNA levels of the AP-1 components JUNB and JUND and FOS, FOSB, FRA1 and FRA2 (Supplementary Figure S1). Stimulation of JUN expression in GLI1HaCaT and GLI2actHaCaT cells was also observed on the protein level as shown by western blot (Figures 1c and d) and Nterminal phosphorylation at Ser63 of JUN protein is detectable in both cell lines, suggesting that transcriptionally active JUN is present (Smeal et al, 1992). In agreement with the qRT-PCR results, JUN protein expression is weaker and delayed in GLI1HaCaT compared to GLI2actHaCaT cells, where a distinct signal is already detectable 12 h after induction.…”

c-Jun, at the crossroad of the signaling network

“…The other two phosphorylation sites are located within the N-terminal transcription activation domain at serines 63 and 73. TPA significantly increases the Nterminal phosphorylation, resulting in a robust induction of cJun transactivation activity Lin et al, 1992;Smeal et al, 1992;Nikolakaki et al, 1993). In contrast, Jun B, lacking serine-63 and-73, is irresponsive to TPA induced transcriptional activation (Franklin et al, 1992).…”

Helicobacter pylori Induces ERK-dependent Formation of a Phospho-c-Fos·c-Jun Activator Protein-1 Complex That Causes Apoptosis in Macrophages

“…When c-Fos heterodimerizes with c-Jun, this results in a more stable AP-1 complex that increases the capacity of c-Jun to transactivate target genes (21). JNK can phosphorylate c-Jun at Ser 73 in the transactivation domain and thus potentiate its ability to induce transcription (22). Similarly, phosphorylation of c-Fos at Ser 374 by ERK potentiates AP-1 transactivation capabilities and primes c-Fos for phosphorylation at Thr 325 ; this stabilizes c-Fos heterodimers and enhances promoter transactivation by AP-1 complexes (23).…”