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.
Daigle
Isabelle
I
Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
Yousefi
Shida
S
Colonna
Marco
M
Green
Douglas R
DR
Simon
Hans-Uwe
HU
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D017124:Conserved Sequence; D016207:Cytokines / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000502:physiology*; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D020800:Receptor, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D054645:Protein Phosphatase 1; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse