Sci. STKE, 19 September 2006
JNK Signaling Challenging the JNK2 Knockout Data
Nancy R. Gough
Science's STKE, AAAS, Washington, DC 20005, USA
Data from mouse knockouts suggested that c-Jun N-terminal kinases 1 and 2 (JNK1 and JNK2) exhibited opposing effects, with JNK1 stimulating the JNK pathway and JNK2 inhibiting the pathway. Jaeschke et al. challenge this result using a chemical genetics approach in which JNK2 activity is acutely inhibited in cells expressing a mutant form of JNK2 (JNK2MG) that is sensitive to derivatives of the protein kinase inhibitor PP1. The authors genetically engineered mice to be either JNK1+/+, JNK2MG/MG, or JNK1/, JNK2MG/MG. In multiple assays, in the presence of the inhibitor, the response of the JNK1+/+, JNKMG/MG mouse embryo fibroblasts (MEFs) was the same as that of wild-type MEFs, suggesting that JNK1 and JNK2 are redundant activators of the pathway. Furthermore, the responses of the JNK1/, JNK2MG/MG MEFs to activation of the JNK pathway in the presence of the inhibitor were decreased. This was unexpected, given that JNK1+/+, JNK2/ MEFs showed enhanced responses and JNK1/, JNK2+/+ MEFs showed decreased responses to activators of the JNK pathway, such as ultraviolet radiation, which suggested a negative role for JNK2. The authors showed that JNK2/ MEFs exhibited enhanced JNK1 activity, suggesting that under the chronic absence of JNK2, there is a compensatory increase in JNK1, which explains why JNK signaling appears to be enhanced in the absence of JNK2 activity. This compensatory increase in JNK1 does not occur when the chemical genetics approach is used to modulate the activity of JNK2, because both enzymes are present at wild-type abundance and only the activity of JNK2 is acutely inhibited, allowing the contribution of this protein to be assessed in a more normal environment.
A. Jaeschke, M. Karasarides, J.-J. Ventura, A. Ehrhardt, C. Zhang, R. A. Flavell, K. M. Shokat, R. J. Davis, JNK2 is a positive regulator of the cJun transcription factor. Mol. Cell 23, 899-911 (2006). [Online Journal]
Citation: N. R. Gough, Challenging the JNK2 Knockout Data. Sci. STKE 2006, tw320 (2006).
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