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Signal transduction by tumor necrosis factor mediated by JNK protein kinases
H K Sluss1, T Barrett, B Dérijard
1Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester.
Abstract:
JNK protein kinases are distantly related to mitogen-activated protein kinases (ERKs) and are activated by dual phosphorylation on Tyr and Thr. The JNK protein kinase group includes the 46-kDa isoform JNK1. Here we describe the molecular cloning of a second member of the JNK group, the 55-kDa protein kinase JNK2. The activities of both JNK isoforms are markedly increased by exposure of cells to UV radiation. Furthermore, JNK protein kinase activation is observed in cells treated with tumor necrosis factor. Although both JNK isoforms phosphorylate the NH2-terminal activation domain of the transcription factor c-Jun, the activity of JNK2 was approximately 10-fold greater than that of JNK1. This difference in c-Jun phosphorylation correlates with increased binding of c-Jun to JNK2 compared with JNK1. The distinct in vitro biochemical properties of these JNK isoforms suggest that they may have different functions in vivo. Evidence in favor of this hypothesis was obtained from the observation that JNK1, but not JNK2, complements a defect in the expression of the mitogen-activated protein kinase HOG1 in the yeast Saccharomyces cerevisiae. Together, these data indicate a role for the JNK group of protein kinases in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation.
Insights
Researchers cloned JNK2, a second JNK protein kinase. Both JNK1 and JNK2 activities increase with UV radiation and tumor necrosis factor, suggesting roles in cellular signaling pathways.
Area of Science:
- Molecular biology
- Cell signaling
- Biochemistry
Background:
- JNK (c-Jun N-terminal kinase) protein kinases are related to ERKs.
- JNK activation occurs via dual phosphorylation on Tyr and Thr residues.
- The JNK group includes the 46-kDa JNK1 isoform.
Purpose of the Study:
- To describe the molecular cloning of a second JNK group member, the 55-kDa JNK2.
- To investigate the differential biochemical properties and in vivo functions of JNK1 and JNK2.
Main Methods:
- Molecular cloning of JNK2.
- Assessing JNK activity in response to UV radiation and tumor necrosis factor.
- In vitro phosphorylation assays of c-Jun by JNK1 and JNK2.
- Functional complementation assays in Saccharomyces cerevisiae.
Main Results:
- JNK2, a 55-kDa JNK isoform, was molecularly cloned.
- Activities of both JNK1 and JNK2 increased upon UV radiation and tumor necrosis factor exposure.
- JNK2 exhibited approximately 10-fold greater c-Jun phosphorylation activity than JNK1, correlating with enhanced binding.
- JNK1, but not JNK2, complemented a defect in HOG1 expression in yeast.
Conclusions:
- JNK1 and JNK2 possess distinct in vitro biochemical properties, suggesting differential in vivo functions.
- The JNK group of protein kinases plays a role in signal transduction pathways activated by proinflammatory cytokines and UV radiation.