The role of receptor internalization in CD95 signaling.
Activation of the cell surface CD95 receptor triggers a cascade of signaling events, including assembly of the death-inducing signaling complex (DISC), that culminate in cellular apoptosis. In this study, we demonstrate a general requirement of receptor internalization for CD95 ligand-mediated DISC amplification, caspase activation and apoptosis in type I cells. Recruitment of DISC components to the activated receptor predominantly occurs after the receptor has moved into an endosomal compartment and blockade of CD95 internalization impairs DISC formation and apoptosis. In contrast, CD95 ligand stimulation of cells unable to internalize CD95 results in activation of proliferative Erk and NF-kappaB signaling pathways. Hence, the subcellular localization and internalization pathways of CD95 play important roles in controlling activation of distinct signaling cascades to determine divergent cellular fates.
Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
Kyeong-Hee
KH
Lee
Christine
C
Feig
Vladimir
V
Tchikov
Robert
R
Schickel
Cora
C
Hallas
Stefan
S
Schütze
Marcus E
ME
Peter
Andrew C
AC
Chan
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002966:Clathrin; D053418:Death Domain Receptor Signaling Adaptor Proteins; C505533:FADD protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D048069:Tumor Necrosis Factors; D019014:fas Receptor; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases