Life and death by death receptors

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA.
The FASEB Journal (Impact Factor: 5.04). 02/2009; 23(6):1625-37. DOI: 10.1096/fj.08-111005
Source: PubMed


Death receptors are members of the tumor necrosis factor receptor superfamily characterized by a cytoplasmic region known as the "death domain" that enables the receptors to initiate cytotoxic signals when engaged by cognate ligands. Binding to the ligand results in receptor aggregation and recruitment of adaptor proteins, which, in turn, initiates a proteolytic cascade by recruiting and activating initiator caspases 8 and 10. Death receptors were once thought to primarily induce cytotoxic signaling cascades. However, recent data indicate that they initiate multiple signaling pathways, unveiling a number of nonapoptosis-related functions, including regulation of cell proliferation and differentiation, chemokine production, inflammatory responses, and tumor-promoting activities. These noncytotoxic cascades are not simply a manifestation of inhibiting proapoptotic pathways but are intrinsically regulated by adaptor protein and receptor internalization processes. Insights into these various death receptor signaling pathways provide new therapeutic strategies targeting these receptors in pathophysiological processes.

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Available from: Maria Eugenia Guicciardi, Nov 12, 2015
    • "Apoptosis is induced by two distinct, yet tightly interconnected signaling pathways: the extrinsic (Fig. 1) and the intrinsic (Fig. 2) apoptotic pathways. The extrinsic pathway is triggered by extracellular ligands such as those of the TNF superfamily (FasL, TNF␣ or TRAIL), which specifically bind to their respective surface receptors causing their oligomerization (Strasser et al., 2009; Guicciardi and Gores, 2009; Gonzalvez and Ashkenazi, 2010; Li et al., 2013a, 2013b). A conformational change on the cytoplasmic side of these receptors leads to the recruitment of the adapter protein FADD whose function is to attract pro-caspase-8 from the cytosol to the death receptor in order to bring two monomeric pro-caspase-8 molecules in close proximity for autoprocessing and subsequent activation (Fig. 1). "
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    Virus Research 03/2015; 13. DOI:10.1016/j.virusres.2015.02.026 · 2.32 Impact Factor
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    • "Here, the most extensively studied death ligands are type II transmembrane proteins, including FasL (for Fas receptor), TNF (for TNFR1 receptor), and TRAIL (for TRAIL receptor) [41, 42]. After proteolytic cleavage of the membrane-anchored ligand, these ligands are released from the plasma membrane and enable them to bind to death receptors and trigger their activation [40]. Upon contacting with their corresponding ligands, these receptors are triggered, leading to the recruitment of a different set of adaptor molecules to the death domain and subsequent activation of the signaling cascade, where the major signals transmitted by death receptors such as Fas, TNFR1, TRAILR1, and TRAILR2 result in an apoptotic response mediated by intracellular caspases [43–48]. "
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    BioMed Research International 04/2014; DOI:10.1155/2014/690103 · 2.71 Impact Factor
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    • "TRAIL-R1(TNF-related apoptosis-inducing ligand receptor 1)/DR4 and Fas/Apo-1/CD95 are members of tumor necrosis factor receptors which link exogenous stimuli via transmembrane surface receptors to the intracellular signaling machinery that mediates and executes the death signal. These pathways are one of the major extrinsic apoptotic signaling pathway [7] and defects in death receptor signaling can confer resistance to apoptosis. The role of apoptosis in tumorigenesis has been well-documented [8] and resistance to apoptosis is believed to be a hallmark of cancer [9]. "
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