Erk1/2 Inactivation-Induced c-Jun Degradation Is Regulated by Protein Phosphatases, UBE2d3, and the C-Terminus of c-Jun

Abstract

Constitutive photomorphogenic 1 (COP1) is the ubiquitin E3 ligase that mediates degradation of c-Jun protein upon Erk1/2 inactivation. It remains unknown how this protein degradation pathway is regulated. In this study, we investigated the roles of protein phosphatases, ubiquitin-conjugating E2 enzymes (UBE2), and an intrinsic motif of c-Jun in regulating this degradation pathway. By using pharmacological inhibitors and/or gene knockdown techniques, we identified protein phosphatase 1 (PP1) and PP2A as the phosphatases and UBE23d as the UBE2 promoting c-Jun degradation, triggered by Erk1/2 inactivation. In addition, we report that the C-terminus of c-Jun protein facilitates its degradation. The addition of a C-terminal tag or deletion of the last four amino acid residues from the C-terminus of c-Jun protects it from degradation under Erk1/2-inactivating conditions. Taken together, this study reveals that the Erk1/2 inactivation-triggered and COP1-mediated c-Jun degradation is extrinsically and intrinsically regulated, providing a new understanding of the mechanisms underlying this protein degradation pathway.

Organoprotective Properties of Argon (Review)

“…Были также определены нижестоящие эффекторы активации MAPkinase. c-Jun, член семейства транскрипционных факторов белка-активатора-1 (AP-1), активируется путями ERK1/2 и JNK и участвует в пролиферации и прогрессировании клеточного цикла, при этом активность c-Jun сильно повышается при обработке аргоном [85][86][87]. Активация Akt происходила посредством фосфорилирования Ser473, а ингибитор Akt MK2206 мог полностью обратить вспять защитный эффект аргона.…”

Development of a New Cell-Based AP-1 Gene Reporter Potency Assay for Anti-Anthrax Toxin Therapeutics

“…c-Jun regulates numerous cellular activities in mammals [ 43 , 44 , 45 ]. Inactivation of the MKK1/2–Erk1/2 signaling pathway following LT treatment induces a rapid reduction in levels of the c-Jun protein by promoting its degradation via a COP1-dependent pathway [ 18 , 46 , 47 ]. In this study, we developed a cell-based AP-1 reporter assay for the potency control of anti-PA antibodies that is based on the rapid reduction of c-Jun protein levels in LT-treated cells, an effect relevant to human cells.…”