BBB seminar: John Eriksson
Transcription-independent control of death receptor signaling
Turku Centre for Biotechnology, University of Turku and Department of Biology, Åbo Akademi University, Turku, Finland
Reversible protein phosphorylation is a key determinant in many fundamental cellular functions, such as survival, differentiation, structural organization, and stress responses. We are especially interested in phosphorylation-mediated signaling that maintains normal cellular and structural homeostasis, and how disturbances in the processing of this type of signaling are reflected as alterations in cellular survival and organization. As model systems for signal processing and integration, we are studying apoptotic, stress-mediated, and cytoskeletal signaling, and their interrelationship. By exploring the interactions between these completely different signaling modes, we hope to advance our understanding how critical intracellular signals are processed and integrated.
There is an intriguing relationship between mitogenic, stress-induced, and death-mediating signaling, as the outcome to any given stimulus depends on all three facets of signaling. We have observed that growth signaling through the mitogen-activated kinase (MAPK) pathway has a dominant inhibiting effect on apoptosis induced by death receptors (Fas, TRAIL, and TNF receptors). We have shown that this mode of regulation has ramifications both in regulating death receptor responses of recently activated T-cells and in the resistance of certain tumor cell lines to death receptor stimulation. We have determined that the MAPK-mediated inhibition takes place by inhibiting the apoptotic signaling from the death-inducing signaling complex (DISC) of proteins assembled at the death receptor. We aim at determining the molecular mechanisms of this inhibition and how the DISC proteins and their interactions are regulated. Apoptosis is also affected by stress-mediated signaling. We are dissecting the role of stress-induced signaling and of heat shock protein 70 (HSP70) in regulating receptor-mediated vs. mitochondrial apoptosis. While stress, through the action of HSP70, inhibits mitochondrially induced apoptosis, we have observed that stress facilitates death receptor-mediated apoptosis. The stress-mediated sensitization seems to be due to selective degradation of FLIP, a specific inhibitor of death receptor signaling. Targeted FLIP degradation by ubiquitylation is also responsible for the sensitization to TRAIL receptor-induced apoptosis that we observed in differentiating erythroid cells. These findings could help understanding the regulation of death receptor responses during stress, fever, or inflammation, as well as during differentiation-related processes.