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 NF??B, 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.
%0 Journal Article
%1 Fischer2011a
%A Fischer, Roman
%A Maier, Olaf
%A Naumer, Matthias
%A Krippner-Heidenreich, Anja
%A Scheurich, Peter
%A Pfizenmaier, Klaus
%D 2011
%J Cellular Signalling
%K 2011 izi pfizenmaier
%N 1
%P 161--170
%R 10.1016/j.cellsig.2010.08.016
%T Ligand-induced internalization of TNF receptor 2 mediated by a di-leucin motif is dispensable for activation of the NFκB pathway
%U https://www.ncbi.nlm.nih.gov/pubmed/20807567
%V 23
%X 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 NF??B, 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.
%7 2010/09/03
%@ 1873-3913 (Electronic)$\backslash$r0898-6568 (Linking)
@article{Fischer2011a,
abstract = {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 NF??B, 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.},
added-at = {2023-06-29T13:07:55.000+0200},
author = {Fischer, Roman and Maier, Olaf and Naumer, Matthias and Krippner-Heidenreich, Anja and Scheurich, Peter and Pfizenmaier, Klaus},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/28b83434ecc5452f6b7c052ac101593b4/fabian},
doi = {10.1016/j.cellsig.2010.08.016},
edition = {2010/09/03},
interhash = {dc34d6971a21bb0257a17bb2bbea1202},
intrahash = {8b83434ecc5452f6b7c052ac101593b4},
isbn = {1873-3913 (Electronic)$\backslash$r0898-6568 (Linking)},
issn = {08986568},
journal = {Cellular Signalling},
keywords = {2011 izi pfizenmaier},
number = 1,
pages = {161--170},
pmid = {20807567},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{Ligand-induced internalization of TNF receptor 2 mediated by a di-leucin motif is dispensable for activation of the NFκB pathway}},
url = {https://www.ncbi.nlm.nih.gov/pubmed/20807567},
volume = 23,
year = 2011
}