title: High cell surface death receptor expression determines type I versus type II signaling.
abstract: Previous studies have suggested that there are two signaling pathways leading from ligation of the Fas receptor to induction of apoptosis. Type I signaling involves Fas ligand-induced recruitment of large amounts of FADD (FAS-associated death domain protein) and procaspase 8, leading to direct activation of caspase 3, whereas type II signaling involves Bid-mediated mitochondrial perturbation to amplify a more modest death receptor-initiated signal. The biochemical basis for this dichotomy has previously been unclear. Here we show that type I cells have a longer half-life for Fas message and express higher amounts of cell surface Fas, explaining the increased recruitment of FADD and subsequent signaling. Moreover, we demonstrate that cells with type II Fas signaling (Jurkat or HCT-15) can signal through a type I pathway upon forced receptor overexpression and that shRNA-mediated Fas down-regulation converts cells with type I signaling (A498) to type II signaling. Importantly, the same cells can exhibit type I signaling for Fas and type II signaling for TRAIL (TNF-α-related apoptosis-inducing ligand), indicating that the choice of signaling pathway is related to the specific receptor, not some other cellular feature. Additional experiments revealed that up-regulation of cell surface death receptor 5 levels by treatment with 7-ethyl-10-hydroxy-camptothecin converted TRAIL signaling in HCT116 cells from type II to type I. Collectively, these results suggest that the type I/type II dichotomy reflects differences in cell surface death receptor expression.
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Department of Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota 55905. Electronic address: Meng.Xue@Mayo.edu.
authors.forename: Xue Wei
authors.initials: XW
authors.lastname: Meng
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Haiming
authors.initials: H
authors.lastname: Dai
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Paula
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Jin-San
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koenig
authors.affiliation: Division of Gastroenterology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Steve
authors.initials: S
authors.lastname: Bronk
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Division of Gastroenterology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905; Department of Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota 55905. Electronic address: Kaufmann.Scott@Mayo.edu.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D053200:Fas-Associated Death Domain Protein / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D019014:fas Receptor