The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

Christine Richter, Sylvia Messerschmidt, Gerlinde Holeiter, Jessica Tepperink, Sylvia Osswald, Andrea Zappe, Marcus Branschädel, Verena Boschert, Derek A. Mann, Peter Scheurich, Anja Krippner-Heidenreicha

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

47 Citaten (Scopus)

Samenvatting

The family of tumor necrosis factor receptors (TNFRs) and their ligands form a regulatory signaling network that controls immune responses. Various members of this receptor family respond differently to the soluble and membrane-bound forms of their respective ligands. However, the determining factors and underlying molecular mechanisms of this diversity are not yet understood. Using an established system of chimeric TNFRs and novel ligand variants mimicking the bioactivity of membranebound TNF (mTNF), we demonstrate that the membrane-proximal extracellular stalk regions of TNFR1 and TNFR2 are crucial in controlling responsiveness to soluble TNF (sTNF). We show that the stalk region of TNFR2, in contrast to the corresponding part of TNFR1, efficiently inhibits both the receptor's enrichment/clustering in particular cell membrane regions and ligandindependent homotypic receptor preassembly, thereby preventing sTNF-induced, but not mTNF-induced, signaling. Thus, the stalk regions of the two TNFRs not only have implications for additional TNFR family members, but also provide potential targets for therapeutic intervention.

Originele taal-2Engels
Pagina's (van-tot)2515-2529
Aantal pagina's15
TijdschriftMolecular and Cellular Biology
Volume32
Nummer van het tijdschrift13
DOI's
StatusGepubliceerd - jul. 2012
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand'. Samen vormen ze een unieke vingerafdruk.

Citeer dit