Molecular ordering of the initial signaling events of CD95.
Binding of either ligand or agonistic antibodies to the death receptor CD95 (APO-1/Fas) induces the formation of the death-inducing signaling complex (DISC). We now show that signal initiation of CD95 in type I cells can be further separated into at least four distinct steps. (i) The first step is ligand-induced formation of CD95 microaggregates at the cell surface. (ii) The second step is recruitment of FADD to form a DISC. This step is dependent on actin filaments. (iii) The third step involves formation of large CD95 surface clusters. This event is positively regulated by DISC-generated caspase 8. (iv) The fourth step is internalization of activated CD95 through an endosomal pathway. The latter step is again dependent on the presence of actin filaments. The data indicate that the signal initiation by CD95 is a complex process actively regulated at various levels, providing a number of new drug targets to specifically modulate CD95 signaling.
Algeciras-Schimnich
Alicia
A
The Ben May Institute for Cancer Research. Department of Medicine. Department of Pathology University of Chicago, Chicago, Illinois 60637, USA.
Shen
Le
L
Barnhart
Bryan C
BC
Murmann
Andrea E
AE
Burkhardt
Janis K
JK
Peter
Marcus E
ME
D008841:Actin Cytoskeleton / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003505:Cyclodextrins / Q000494:pharmacology; D004705:Endocytosis / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein; D005372:Filipin / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008024:Ligands; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D021962:Membrane Microdomains / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009761:Nystatin / Q000494:pharmacology; D011940:Receptor Aggregation / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D047392:beta-Cyclodextrins; D019014:fas Receptor / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones; D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D003505:Cyclodextrins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D005456:Fluorescent Dyes; D007476:Ionophores; D008024:Ligands; D013844:Thiazoles; D053778:Thiazolidines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D047392:beta-Cyclodextrins; D019014:fas Receptor; D009761:Nystatin; D005372:Filipin; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C031215:betadex; C037067:latrunculin A