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Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73
T Smeal1, B Binetruy, D Mercola
1Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla 92093-0636.
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.
Insights
Oncogenic proteins like Ha-Ras alter c-Jun phosphorylation, enhancing its activity. This phosphorylation cascade, particularly at serines 63 and 73, is crucial for cell transformation and proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- c-Jun, a transcription factor, is regulated by phosphorylation at multiple sites.
- Specific phosphorylation sites on c-Jun influence its DNA binding and transactivation functions.
- Oncogenic Ras proteins are known to modulate cellular signaling pathways.
Purpose of the Study:
- To investigate the role of c-Jun phosphorylation in response to various oncogenic stimuli.
- To identify the specific phosphorylation sites on c-Jun affected by oncogenic proteins.
- To elucidate the signal transduction pathway linking oncogenic proteins to c-Jun activation.
Main Methods:
- Analysis of c-Jun phosphorylation patterns in cells expressing different oncogenic proteins (v-Sis, v-Src, Ha-Ras, Raf-1).
- Assessment of c-Jun transactivation function.
- Investigation of the role of normal c-Ha-Ras in modulating c-Jun activity.
Main Results:
- Oncogenic proteins induce decreased phosphorylation at inhibitory sites and enhanced phosphorylation at activating sites (serines 63 and 73) of c-Jun.
- Phosphorylation of serines 63 and 73 is essential for c-Jun's transactivation function and cooperation with Ha-Ras.
- A common signal transduction pathway involving these oncogenic proteins leads to increased c-Jun phosphorylation.
- Normal c-Ha-Ras regulates c-Jun activity in a serum-dependent manner.
Conclusions:
- c-Jun is a critical downstream target in signaling pathways activated by diverse oncogenic proteins.
- The phosphorylation status of c-Jun, particularly at serines 63 and 73, is a key determinant of its function in cell proliferation and transformation.
- Understanding this pathway provides insights into mechanisms of cancer development.