Figure 8. Schematic depicting of EP3 induced signaling pathway contribution to apoptosis during cytokine withdrawal.

Withdrawal of cytokines results in activation of intrinsic apoptotic pathway due to imbalance between Bcl-2 anti-apoptotic protein family members and BH3 only pro-apoptotic proteins. Intrinsic apoptotic pathway in mast cells is upregulated by PGE₂ via EP3 receptor and Ca²⁺-CaMII-ERK1/2 pathway. While Erk 1/2 mediated phosphorylation of Bim_EL and Bim _L immediately after PGE₂ stimulation and this leads to ubiquination and degradation of these isoforms, Erk also induces expression of c-Jun, a potent upregulator of Bim expression. Final outcome of Erk regulation of Bim is a balance between Bim degradation after its phosphorylation and increase in its expression due to c-Jun. Data presented here support view that increase expression of Bim and proapoptotic action of EP3-Ca²⁺-CamKII –Erk1/2 pathway is prevalent in mast cells in presence of PGE₂ and during cytokine withdrawal.