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J Biol Chem, Vol. 275, Issue 19, 14307-14315, May 12, 2000
From the LIGHT is a tumor necrosis factor (TNF) ligand
superfamily member, which binds two known cellular receptors,
lymphotoxin-
The Lymphotoxin-
Receptor Is Necessary and Sufficient for
LIGHT-mediated Apoptosis of Tumor Cells*
,,,,,¶
Division of Molecular Immunology, La Jolla
Institute for Allergy and Immunology, San Diego, California 92121 and
the § Department of Microbiology and Center for Oral Health
Research, School of Dental Medicine and Department of Pathobiology,
School of Veterinary Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania 19104
receptor (LTR) and the herpesvirus entry mediator
(HveA). LIGHT is a homotrimer that activates proapoptotic and
integrin-inducing pathways. Receptor binding residues via LIGHT were
identified by introducing point mutations in the A' 
A" and D E
loops of LIGHT, which altered binding to LTR and HveA. One mutant of LIGHT exhibits selective binding to HveA and is inactive triggering cell death in HT29.14s cells or induction of ICAM-1 in fibroblasts. Studies with HveA- or LTR-specific antibodies further indicated that
HveA does not contribute, either cooperatively or by direct signaling,
to the death pathway activated by LIGHT. LTR, not HveA, recruits TNF
receptor-associated factor-3 (TRAF3), and LIGHT-induced death is
blocked by a dominant negative TRAF3 mutant. Together, these results
indicate that TRAF3 recruitment propagates death signals initiated by
LIGHT-LTR interaction and implicates a distinct biological role for
LIGHT-HveA system.
*
This work was supported in part by U. S. Public Health
Service, National Institutes of Health Grants CA69381, AI03368 (to C. F. W.), and NS-36731 (to R. J. E.), American Cancer Society Grant IM663 (to C. F. W), and fellowships from National Institutes of
Health Grants T32AI07469 (to A. A. G.) and AG00252 (to C. A. B.).
This is publication 332 from the La Jolla Institute for Allergy and
Immunology.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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