Death Receptor Signaling

• Description
• Reviews
• Pathway Key
• Pathway Products
• Download PDF

Pathway Description:

Apoptosis can be induced through the activation of death receptors including Fas, TNFαR, DR3, DR4 and DR5 by their respective ligands. Death receptor ligands characteristically initiate signaling via receptor oligomerization, which in turn results in the recruitment of specialized adaptor proteins and activation of caspase cascades. Binding of FasL induces Fas trimerization, which recruits initiator caspase-8 via the adaptor protein FADD. Caspase-8 then oligomerizes and is activated via autocatalysis. Activated caspase-8 stimulates apoptosis via two parallel cascades: it can directly cleave and activate caspase-3, or alternatively, it can cleave Bid, a pro-apoptotic Bcl-2 family protein. Truncated Bid (tBid) translocates to mitochondria, inducing cytochrome c release, which sequentially activates caspase-9 and -3. TNF-α and DR-3L can deliver pro- or anti-apoptotic signals. TNFαR and DR3 promote apoptosis via the adaptor proteins TRADD/FADD and the activation of caspase-8. Interaction of TNF-α with TNFαR may activate the NF-κB pathway via NIK/IKK. The activation of NF-κB induces the expression of pro-survival genes including Bcl-2 and FLIP, the latter can directly inhibit the activation of caspase-8. FasL and TNF-α may also activate JNK via ASK1/MKK7 Activation of JNK may lead to the inhibition of Bcl-2 by phosphorylation.

Selected Reviews:

• Humphreys RC, Halpern W (2008) Trail receptors: targets for cancer therapy. Adv. Exp. Med. Biol. 615, 127–58.
• Logue SE, Martin SJ (2008) Caspase activation cascades in apoptosis. Biochem. Soc. Trans. 36(Pt 1), 1–9.
• Zakeri Z, Lockshin RA (2008) Cell death: history and future. Adv. Exp. Med. Biol. 615, 1–11.