Ligand-induced internalization of TNF receptor 2 mediated by a di-leucin motif is dispensable for activation of the NFκB pathway
| Autor: | Peter Scheurich, Roman Fischer, Klaus Pfizenmaier, Anja Krippner-Heidenreich, Matthias Naumer, Olaf Maier |
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| Rok vydání: | 2010 |
| Předmět: |
TRAF2
media_common.quotation_subject education Amino Acid Motifs Biology Endocytosis Cytoplasmic part Ligands Cell Line Mice Leucine Animals Humans Receptors Tumor Necrosis Factor Type II FADD Internalization health care economics and organizations Late endosome media_common Tumor Necrosis Factor-alpha NF-kappa B rab7 GTP-Binding Proteins Cell Biology Fibroblasts Molecular biology Clathrin Cell biology Ectodomain rab GTP-Binding Proteins biology.protein Signal transduction Signal Transduction |
| Zdroj: | Cellular signalling. 23(1) |
| ISSN: | 1873-3913 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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