Cell. 2003 Jul 25;114(2):181-90.

Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.External

Micheau, O., Tschopp, J.,
--- - Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.
PMID: 12887920External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DED Caspase10 Link Caspase8 Co-immunoprecipitation HT1080 12887920
DED Caspase10 Link Caspase8 Co-immunoprecipitation HEK293 Not specified Not specified Not specified Not specified 12887920
DED Caspase10 Link FLIP Co-immunoprecipitation HEK293 Not specified Not specified Not specified Not specified 12887920
DED Caspase8 Link FADD Co-immunoprecipitation HT1080 12887920
DED Caspase8 Link FLIP Co-immunoprecipitation HT1080 12887920
DED Caspase8 Link FLIP Co-immunoprecipitation HEK293 Not specified Not specified Not specified Not specified 12887920
(Link: click this icon to show interactions only between the two corresponding DDs)
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
Functional Role
Family DD1 DD2 Method Death-related Death-unrelated Reference
DED Caspase8 Link FADD Hoechst staining Apoptosis (DISC) 12887920
(Link: click this icon to show interactions only between the two corresponding DDs)