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Review
. 2002 Feb;109(4):437-41.
doi: 10.1172/JCI15077.

Death receptors couple to both cell proliferation and apoptosis

Ralph C Budd  1
Affiliations
Review

Death receptors couple to both cell proliferation and apoptosis

Ralph C Budd. J Clin Invest. 2002 Feb.
No abstract available

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Figures

Figure 1
Figure 1
The death receptor pathway as typified by Fas (CD95/APO-1). Oligomerization of Fas by FasL induces recruitment of FADD to the cytoplasmic tail of Fas by their mutual DDs (black boxes). The opposite end of FADD contains a death effector domain (DED; hatched boxes) that allows recruitment of either procaspase-8 or the related protein c-FLIP, which contains a sequence change in the sequence corresponding to the active site of procaspase-8 (black bar), rendering it enzymatically inactive. Caspase-8 can cleave the BH3-only protein Bid, and the resulting truncated Bid (tBid) can inactivate Bcl-2 in the mitochondrial membrane. This allows the escape of cytochrome c, which clusters with Apaf-1 and caspase-9 in the presence of dATP to activate caspase-9. Smac/DIABLO is also released from the mitochondria and inactivates inhibitors of apoptosis (IAPs). Active caspase-9 can cleave and activate procaspase-3 to its active form, leading to breakdown of several cytoskeletal proteins and degradation of the inhibitor of caspase-activated DNase (ICAD).
Figure 2
Figure 2
FLIP as a switch molecule that diverts Fas signals from cell death to proliferation. FLIP is homologous to caspase-8 in containing two DEDs that can interact with the DED of FADD, but its caspase domain is nonfunctional. FLIP physically associates with Raf-1 and TRAF1 and TRAF2, which connect, respectively, with the ERK and NF-κB pathways involved in cell proliferation or differentiation. In this capacity, primary cells that express high levels of FLIP would not only be resistant to Fas-induced death but might also receive a proliferative signal.
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