Phosphorylation-dependent targeting of c-Jun ubiquitination by Jun N-kinase.

Ubiquitination of key cellular regulatory proteins marks them for efficient degradation via the proteasome pathway. The delta domain of c-jun is essential for its ubiquitination and also for the activating phosphorylation of neighboring serines by the stress activated jun-N-terminal kinases (JNK). Using an in vitro model system we demonstrate that JNK is among the hydrophobic binding proteins that target c-jun for efficient ubiquitination. Immunodepletion of JNK markedly inhibits c-jun ubiquitination. Conversely, c-jun ubiquitination is increased by adding purified JNK2 or extracts prepared from cells transfected with JNK2. Although c-jun ubiquitination is enhanced by JNK, the phosphorylation of c-jun on Ser73 by JNK protects c-jun from ubiquitination and prolongs its half-life. The dual activity of JNK in targeting c-jun for ubiquitination or in protecting c-jun from entering this pathway via phosphorylation points to the role of JNK in the control of c-jun stability in cells exposed to environmental stress or inflammatory cytokines.