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Lookup NU author(s): Dr Anja Krippner-Heidenreich
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Endocytosis is an important mechanism to regulate tumor necrosis factor (TNF) signaling. In contrast to TNF receptor 1 (TNFR1; CD120a), the relevance of receptor internalization for signaling as well as the fate and route of internalized TNF receptor 2 (TNFR2; CD120b) is poorly understood. To analyze the dynamics of TNFR2 signaling and turnover at the plasma membrane we established a human TNFR2 expressing mouse embryonic fibroblast cell line in a TNFR1-/-/TNFR2-/- background. TNF stimulation resulted in a decrease of constitutive TNFR2 ectodomain shedding. We hypothesized that reduced ectodomain release is a result of TNF/TNFR2 complex internalization. Indeed, we could demonstrate that TNFR2 was internalized together with its ligand and cytoplasmic binding partners. Upon endocytosis the TNFR2 signaling complex colocalized with late endosome/lysosome marker Rab7 and entered the lysosomal degradation pathway. Furthermore, we identified a di-leucin motif in the cytoplasmic part of TNFR2 suggesting clathrin-dependent internalization of TNFR2. Internalization defective TNFR2 mutants are capable to signal, i.e. activate NFκB, demonstrating that the di-leucin motif dependent internalization is dispensable for this response. We therefore propose that receptor internalization primarily serves as a negative feed-back to limit TNF responses via TNFR2. © 2010 Elsevier Inc.
Author(s): Fischer R, Maier O, Naumer M, Krippner-Heidenreich A, Scheurich P, Pfizenmaier K
Publication type: Article
Publication status: Published
Journal: Cellular Signalling
Year: 2011
Volume: 23
Issue: 1
Pages: 161-170
Print publication date: 31/08/2010
ISSN (print): 0898-6568
ISSN (electronic): 1873-3913
Publisher: Elsevier
URL: http://dx.doi.org/10.1016/j.cellsig.2010.08.016
DOI: 10.1016/j.cellsig.2010.08.016
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