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Background: TWEAK and its receptor Fn14 are targets in oncology and autoimmunity. Results: Ligand oligomerization has no major effect on Fn14-TWEAK interaction but strongly enhances TWEAK-induced IL8 production. Conclusion: Avidity is irrelevant for TWEAK trimer binding to Fn14 but required for robust IL8 induction. Significance: Enhanced activity of oligomerized TWEAK trimers is not related to an avidity-related increase in Fn14 occupancy.

Since their identification more than 20 years ago, the death receptors CD95, TRAILR1, and TRAILR2 have been intensively studied with respect to their cell death-inducing activities. These receptors, however, can also trigger a variety of cell death-independent cellular responses reaching from the activation of proinflammatory gene transcription programs over the stimulation of proliferation and differentiation to induction of cell migration. The cell death-inducing signaling mechanisms of CD95 and the TRAIL death receptors are well understood. In contrast, despite the increasing recognition of the biological and pathophysiological relevance of the cell death-independent activities of CD95, TRAILR1, and TRAILR2, the corresponding signaling mechanisms are less understood and give no fully coherent picture. This review is focused on the cell death-independent activities of CD95 and the TRAIL death receptors and addresses mainly three questions: (a) how are these receptors linked to noncell death pathways at the molecular level, (b) which factors determine the balance of cell death and cell death-independent activities of CD95 and the TRAIL death receptors at the cellular level, and (c) what are the consequences of the cell death-independent functions of these receptors for their role in cancer and inflammatory diseases.

(2014) A novel llama antibody targeting Fn14 exhibits anti-metastatic activity in vivo, mAbs, 6:1, 297-308,

Background: Mechanisms of activation of the prototypical death receptor CD95 have been described. Results: Highly active CD95L variants (Fc-CD95L, membrane CD95L) stimulate the association of unliganded CD40-CD95 chimeras or of inactive complexes of CD95L trimers and CD95 with the lipid raft compartment. Conclusion: CD95 signaling triggers association of active and inactive CD95 species with lipid rafts. Significance: Identification of inactive CD95 species as targets of their active counterparts is described.