The Ubiquitin Ligase SCFFbw7 Antagonizes Apoptotic JNK Signaling

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Science  27 Feb 2004:
Vol. 303, Issue 5662, pp. 1374-1378
DOI: 10.1126/science.1092880

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Jun N-terminal kinases (JNKs) are essential for neuronal microtubule assembly and apoptosis. Phosphorylation of the activating protein 1 (AP1) transcription factor c-Jun, at multiple sites within its transactivation domain, is required for JNK-induced neurotoxicity. We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCFFbw7, which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation. Fbw7 depletion resulted in accumulation of phosphorylated c-Jun, stimulation of AP1 activity, and neuronal apoptosis. SCFFbw7 therefore antagonizes the apoptotic c-Jun–dependent effector arm of JNK signaling, allowing neurons to tolerate potentially neurotoxic JNK activity.

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