Viral FLIP enhances Wnt signaling downstream of stabilized beta-catenin, leading to control of cell growth.
Death receptor-mediated apoptosis is potently inhibited by viral FLIP (FLICE/caspase 8 inhibitory protein), which is composed of two tandemly repeated death effector domains (DEDs), through reduced activation of procaspase 8. Here, we show that equine herpesvirus 2-encoded viral FLIP E8 enhances Wnt/beta-catenin signaling in a variety of cell lines. E8 was shown to strikingly augment Wnt3a signaling, as shown both in a luciferase assay for T-cell factor/beta-catenin and through induction of endogenous cyclin D1. The effect of E8 was independent of its direct binding activity with DED-containing signaling molecules, including caspase 8 and FADD, in death receptor-mediated apoptosis. E8 enhanced Wnt signaling downstream of stabilized beta-catenin, while a long form of cellular FLIP (c-FLIP(L)) enhanced stabilization of beta-catenin in 293T cells. Consequently, coexpression of E8 and c-FLIP(L) synergistically increased Wnt signaling in 293T cells. Moreover, E8-mediated stimulation of Wnt signaling induced dramatic growth retardation in untransformed cell lines but not in transformed cell lines. Thus, viral FLIP E8 not only inhibits death receptor-mediated apoptosis but also enhances Wnt signaling pathways that are closely related to those of both ontogenesis and oncogenesis.
Nakagiri
Shiho
S
Graduate School of Biostudies, Kyoto University, SCRB/Building G, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Murakami
Akira
A
Takada
Shinji
S
Akiyama
Tetsu
T
Yonehara
Shin
S
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D017434:Protein Structure, Tertiary; D051381:Rats; D018144:Rhadinovirus / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism / Q000502:physiology*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C506387:Cflar protein, mouse; C505533:FADD protein, human; C505534:Fadd protein, mouse; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D019938:Cyclin D1; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases