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A human suppressor of c-Jun N-terminal kinase 1 activation by tumor necrosis factor alpha
D Y Jin1, H Teramoto, C Z Giam
1Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892-0460, USA.
Abstract:
Tumor necrosis factor alpha (TNFalpha) has pleiotropic effects on cellular metabolism. One of the signaling paths from the TNFalpha receptor induces a stress-activated protein kinase cascade. Components within this TNFalpha kinase cascade include mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and stress-activated protein kinase/extracellular signal-regulated kinase kinase (SEK), which regulate the activity of c-Jun N-terminal kinase 1 (JNK1). Currently, molecules upstream of MEKK1 that link TNFalpha receptor to downstream kinases are not well understood. Besides TNFalpha, many other stimuli including several oncoproteins can activate JNK1. In most cases, the signaling cascade(s) leading from oncoproteins to JNK1 is poorly elucidated. We report here that the human T-cell lymphotrophic virus, type I (HTLV-I) oncoprotein, Tax, can activate JNK1. We isolated a novel human cell factor, G-protein pathway suppressor 2 (GPS2), by its ability to bind the HTLV-I oncoprotein, and we show that this factor can potently suppress Tax activation of JNK1. In trying to understand the mechanism of GPS2 activity, we found that it also suppressed TNFalpha activation of JNK1 but not TNFalpha activation of p38 kinase nor phorbol activation of extracellular signal-regulated kinase 2. Because GPS2 has minimal effect on MEKK1- or SEK-regulated JNK1 activity, it could act at a point between the TNFalpha receptor and MEKK1 in the initial step(s) of this kinase cascade. Alternatively, it is not excluded that GPS2 could work in a parallel pathway that leads from TNFalpha to JNK1. GPS2 represents a new molecule that could contribute important insights toward how cytokine- and oncoprotein-mediated signal transduction might converge.
Insights
A novel protein, G-protein pathway suppressor 2 (GPS2), was identified that inhibits the activation of c-Jun N-terminal kinase 1 (JNK1) by both the HTLV-I oncoprotein Tax and tumor necrosis factor alpha (TNFalpha). GPS2 may act upstream of MEKK1 in the TNFalpha signaling pathway.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Oncology
Background:
- Tumor necrosis factor alpha (TNFalpha) influences cellular metabolism through stress-activated protein kinase cascades, including the MEKK1-SEK-JNK1 pathway.
- The upstream regulators linking TNFalpha receptor to these kinases and the signaling cascades from oncoproteins to JNK1 are not fully understood.
Purpose of the Study:
- To identify novel regulators of JNK1 activation.
- To elucidate the mechanism by which the HTLV-I oncoprotein Tax activates JNK1.
- To investigate the role of G-protein pathway suppressor 2 (GPS2) in cytokine and oncoprotein signaling.
Main Methods:
- Isolation of GPS2 based on its binding to the HTLV-I oncoprotein Tax.
- Assays to measure the effect of GPS2 on Tax- and TNFalpha-induced JNK1 activation.
- Assessment of GPS2's impact on TNFalpha-induced p38 kinase and phorbol-induced ERK2 activation.
- Evaluation of GPS2's effect on MEKK1- and SEK-regulated JNK1 activity.
Main Results:
- GPS2 was identified as a novel human cell factor that binds to the HTLV-I oncoprotein Tax.
- GPS2 potently suppresses Tax-induced activation of JNK1.
- GPS2 also suppresses TNFalpha-induced JNK1 activation, but not TNFalpha-induced p38 kinase or phorbol-induced ERK2 activation.
- GPS2 shows minimal effect on MEKK1- or SEK-regulated JNK1 activity, suggesting it acts upstream of MEKK1 or in a parallel pathway.
Conclusions:
- GPS2 is a novel suppressor of JNK1 activation by both oncoproteins and cytokines.
- GPS2 may function upstream of MEKK1 in the TNFalpha signaling cascade.
- GPS2 provides new insights into the convergence of cytokine- and oncoprotein-mediated signal transduction pathways.