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Death receptors bind SHP-1 and block cytokine-induced anti-apoptotic signaling in neutrophils

Nature Medicine volume 8, pages 61–67 (2002)Cite this article

Abstract

Death domain–containing receptors of the tumor necrosis factor (TNF)/nerve growth factor (NGF) family can induce apoptosis upon activation in many cellular systems. We show here that a conserved phosphotyrosine-containing motif within the death domain of these receptors can mediate inhibitory functions. The Src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1), SHP-2 and SH2-containing inositol phosphatase (SHIP) bound to this motif in a caspase-independent but cell-dependent manner. We also found that stimulation of death receptors disrupted anti-apoptosis pathways initiated (at least under certain conditions) by survival factors in neutrophils. In these cells, activation of the tyrosine kinase Lyn, an important anti-apoptotic event, was prevented as a consequence of death-receptor stimulation, most likely through association of the receptor with activated SHP-1. Thus, we provide molecular and functional evidence for negative signaling by death receptors.

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Figure 1: Inhibition of cytokine-mediated survival signals by death receptors in neutrophils.
Figure 2: Death-receptor activation blocks the GM-CSF-mediated reduction of Bax expression and prevention of caspase-3 activation in neutrophils.
Figure 3: A YxxL motif in death domain–containing receptors and the potential role of inhibitory phosphatases.
Figure 4: Inhibitory phosphatases bind to the YxxL motif of death receptors in vitro and in vivo in a caspase-independent manner.
Figure 5: Critical role for the tyrosine residue within the YxxL motif of the Fas receptor (Fas-R) for SHP-1 recruitment and blocking of cytokine-mediated survival.
Figure 6: Death-receptor activation blocks GM-CSF-mediated tyrosine phosphorylation of Lyn in a caspase-independent manner in neutrophils, a mechanism that probably involves SHP-1.

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Acknowledgements

We thank L. Rohrschneider for the SHIP-specific antibody; M. Peter for Jurkat (J16) cells; A. Ziemiecki and R. Friis for help with the phosphoamino acid analysis and adenovirus infection experiments; and I. Schmid for technical assistance. This work was supported by grants from the Swiss National Science Foundation and the Helmut Horten Foundation (Madonna del Piano).

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Authors and Affiliations

  1. Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland

    Isabelle Daigle

  2. Department of Pharmacology, University of Bern, Bern, Switzerland

    Shida Yousefi & Hans-Uwe Simon

  3. Basel Institute for Immunology, Basel, Switzerland

    Marco Colonna

  4. La Jolla Institute for Allergy and Immunology, San Diego, California, USA

    Douglas R. Green

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Correspondence to Hans-Uwe Simon.

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Daigle, I., Yousefi, S., Colonna, M. et al. Death receptors bind SHP-1 and block cytokine-induced anti-apoptotic signaling in neutrophils. Nat Med 8, 61–67 (2002). https://doi.org/10.1038/nm0102-61

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