The different signaling capabilities of soluble and membrane-bound TWEAK and their relevance for cellular proliferation and differentiation

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TWEAK (Tumor necrosis factor (TNF)-like weak inducer of apoptosis) and its receptor Fn14 (fibroblast growth factor (FGF)-induced 14) regulate the activity of a variety of signaling pathways and control a diverse panel of cellular functions especially in the context of tissue injury. Indeed, the TWEAK/Fn14-system has been implicated in tissue repair and regeneration but it also promotes adverse effects that can emerge from overshooting and chronic inflam-matory/regenerative responses.TWEAK occurs as a single spanning transmembrane protein but is also found in form of a soluble ligand that is released from the membrane-bound molecule by proteolytic processing. Previously, we demonstrated that soluble processed TWEAK binds with high affinity to Fn14 and strongly triggers activation of the alternative NF-kappaB pathway and enhancement of TNFR1-induced cell death but also antagonizes TRAF2-mediated signaling by other TNF re-ceptors. Intriguingly, we also noted that soluble TWEAK does not stimulate robust activation of the classical NF-kappaB pathway. In contrast, membrane TWEAK triggers all Fn14-associated pathways with high efficacy including the classical NF-kappaB pathway. Although we have some initial evidence that the different ability to transactivate TRAF2- cIAP1 and TRAF2-cIAP2 complexes plays a crucial role for the varying signaling capacities of soluble and membrane TWEAK, the underlying mechanisms have still to be considered as poorly understood. Moreover, the question whether the two TWEAK forms also differ in their ability to stimulate other Fn14 associated signaling pathways and cellular functions has not been addressed so far. We will therefore focus in the project on the following questions:1. How does the soluble TWEAK-induced Fn14 signaling complex differ from that induced by membrane TWEAK, and how affects TWEAK/Fn14-mediated depletion of cytosolic TRAF2-cIAP1 and TRAF2-cIAP2 complexes the formation, modification and stability of death recep-tor-induced RIP/caspase-8 containing complexes?2. Does Fn14 have the ability to signal independently from TRAF2?3. How do soluble and membrane TWEAK differ in their effects on cellular proliferation and differentiation and which signaling pathways are of relevance in these contexts?So far, we observed the differential responsiveness of Fn14 to soluble and membrane TWEAK in all Fn14-expressing cell lines (n>10) and primary cell types (n=3) we have investi-gated. Thus, it must be assumed that the underlying biochemical mechanisms are operative in most cells and are of general importance for Fn14 biology. Moreover, it is possible that the molecular mechanisms that define the differential responsiveness of Fn14 to soluble and membrane TWEAK also applies to other TRAF2-interacting receptors of the TNF family. The molecular mechanisms that are identified on the example of TWEAK/Fn14 signaling have therefore the potential to be of general relevance for the TNF receptor superfamily as a whole.