Editors' ChoiceReceptors

Time to Signal

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Science's STKE  19 Nov 2002:
Vol. 2002, Issue 159, pp. tw431-TW431
DOI: 10.1126/stke.2002.159.tw431

Tumor necrosis factor can interact with its receptor either as a membrane-bound protein or as a soluble cytokine. TNF interacts with two receptors, TNFR1 and TNFR2. TNFR1 responds fully to either ligand, but TNFR2 responds preferentially to membrane-bound TNF. To explore the nature of this differential response, Krippner-Heidenreich et al. constructed chimeric receptors in which the extracellular and transmembrane domains of TNFR1 and TNFR2 were fused with the cytoplamic domain of human Fas and expressed in immortalized fibroblasts from knockout mice lacking both TNFR1 and TNFR2. The TNFR2 chimera coupled TNFR2 ligation to a new signaling output (induction of apoptosis through FADD-mediated activation of caspase 8), rather than having its normal effects on regulation of transcription through the transcription factor NF-κB and JNK (c-Jun NH2-terminal kinase). Nevertheless, the TNFR2 chimera retained a selective response to membrane-bound TNF, whereas the TNFR1 chimera responded to both ligands. This means that the distinction is manifested in the extracellular domain of the receptor. Only membrane-bound TNF could cause formation of receptor induced-signaling complex (RISK), the complex of proteins recruited to activated receptors that mediate an apoptotic signal from Fas. The effectiveness of membrane-bound TNF on the TNFR2 chimera correlated with a slower dissociation rate and longer half-life of receptor binding (as compared to those of soluble TNF). The authors propose that stability of the complex of bound receptor and ligand may be critical in determining whether complexes of signaling proteins in the cytoplasm have time to form and transmit a functional signal.

A. Krippner-Heidenreich, F. Tübing, S. Bryde, S. Willi, G. Zimmermann, P. Scheurich, Control of receptor-induced signaling complex formation by the kinetics of ligand/receptor interaction. J. Biol. Chem. 277, 44155-44163 (2002). [Abstract] [Full Text]

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