Crossing paths: interactions between the cell death machinery and growth factor survival signals

Abstract

Cytokines and growth factors play a crucial role in the maintenance of haematopoietic homeostasis. They transduce signals that regulate the competing commitments of haematopoietic stem cells, quiescence or proliferation, retention of stem cell pluripotency or differentiation, and survival or demise. When the balance between these commitments and the requirements of the organisms is disturbed, particularly when it favours survival and proliferation, cancer may result. Cell death provoked by loss of growth factor signalling is regulated by the Bcl-2 family of apoptosis regulators, and thus survival messages transduced by growth factors must regulate the activity of these proteins. Many aspects of direct interactions between cytokine signalling and regulation of apoptosis remain elusive. In this review, we explore the mechanisms by which cytokines, in particular Interleukin-3 and granulocyte-macrophage colony-stimulating factor, promote cell survival and suppress apoptosis as models of how cytokine signalling and apoptotic pathways intersect.

Fig. 1

Cytokine signalling and Bcl-2 family members. One of the mechanisms by which cytokine signalling promotes cell survival is through inhibition of apoptotic pathways. Bcl-2 family members are crucial for the regulation of cell death signalling. Activation of beta-chain signalling can suppress expression of BH3-only pro-apoptotic proteins, in particular, Bim, Puma and Bad. Induction and maintenance of anti-apoptotic proteins Mcl-1, Bcl-2, A1 and Bcl-x during activation of cytokine signalling is also crucial to prevent cell death induced by cytokine deprivation

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