Fig. 2.

Downstream signalling events after receptor activation. Cytokine stimulation results in initiation of several signalling cascades influencing the transcription and post-translational modification of certain downstream targets. Three well-examined signalling pathways that are activated by IL-3 or GM-CSF via beta-chain activation are briefly illustrated here. Jak/Stat pathway: receptor activation leads to JAK2 phosphorylation, in turn phosphorylating the Stat family proteins which translocates to the nucleus to control genes responsible for survival and proliferation, such as Bcl-x_L, Pim1 and Pim2. Ras/Raf/MAPK pathway: receptor activation induces phosphorylation and activation of Ras, which in turn activates Raf and the MAP kinases. Post-translational as well as possible transcriptional regulation of Bim is controlled in part by the Ras/Raf/MAPK pathway. PI3K/AKT pathway: activation of PI3K through cytokine signalling induces activation and phosphorylation of AKT that in turn phosphorylates and inactivates Bad by binding to 14-3-3. FoxO3a is also phosphorylated, in turn negatively regulating the BH3 only proteins, Bim and Puma. Phosphorylated AKT also regulates GSK-3, indirectly maintaining Mcl-1 levels