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


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.

DOI: 10.1038/nm0102-61
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@article{Daigle2002DeathRB, title={Death receptors bind SHP-1 and block cytokine-induced anti-apoptotic signaling in neutrophils}, author={Isabelle Daigle and Shida Yousefi and Marco Colonna and Douglas R Green and Hans-Uwe Simon}, journal={Nature Medicine}, year={2002}, volume={8}, pages={61-67} }