PMID- 9418902 OWN - NLM STAT- MEDLINE DCOM- 19980122 LR - 20210526 IS - 0270-7306 (Print) IS - 1098-5549 (Electronic) IS - 0270-7306 (Linking) VI - 18 IP - 1 DP - 1998 Jan TI - 4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB. PG - 558-65 AB - Members of the tumor necrosis factor (TNF)-nerve growth factor (NGF) receptor family have been shown to be important costimulatory molecules for cellular activation. 4-1BB and Ox40 are two recently described members of this protein family which are expressed primarily on activated T cells. To gain insight into the signaling pathways employed by these factors, yeast two-hybrid library screens were performed with the cytoplasmic domains of 4-1BB and Ox40 as baits. TNF receptor-associated factor 2 (TRAF2) was identified as an interacting protein in both screens. The ability of both 4-1BB and Ox40 to interact with TRAF2 was confirmed in mammalian cells by coimmunoprecipitation studies. When the binding of the receptors to other TRAF proteins was investigated, 4-1BB and Ox40 displayed distinct binding patterns. While 4-1BB bound TRAF2 and TRAF1, Ox40 interacted with TRAF3 and TRAF2. Using deletion and alanine scanning analysis, we defined the elements in the cytoplasmic domains of both receptors that mediate these interactions. The 4-1BB receptor was found to have two independent stretches of acidic residues that can mediate association of the TRAF molecules. In contrast, a single TRAF binding domain was identified in the cytoplasmic tail of Ox40. The cytoplasmic domains of both receptors were shown to activate nuclear factor kappaB in a TRAF-dependent manner. Taken together, our results indicate that 4-1BB and Ox40 bind TRAF proteins to initiate a signaling cascade leading to activation of nuclear factor kappaB. FAU - Arch, R H AU - Arch RH AD - Department of Medicine, Howard Hughes Medical Institute, The University of Chicago, Illinois 60637, USA. FAU - Thompson, C B AU - Thompson CB LA - eng PT - Journal Article PL - United States TA - Mol Cell Biol JT - Molecular and cellular biology JID - 8109087 RN - 0 (Antigens, CD) RN - 0 (Membrane Glycoproteins) RN - 0 (NF-kappa B) RN - 0 (Receptors, Nerve Growth Factor) RN - 0 (Receptors, OX40) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (TNFRSF4 protein, human) RN - 0 (TNFRSF9 protein, human) RN - 0 (Tumor Necrosis Factor Receptor Superfamily, Member 7) RN - 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9) SB - IM MH - Amino Acid Sequence MH - Antigens, CD MH - Humans MH - Membrane Glycoproteins/genetics/metabolism MH - Molecular Sequence Data MH - NF-kappa B/genetics/*metabolism MH - Receptors, Nerve Growth Factor/genetics/*metabolism MH - Receptors, OX40 MH - Receptors, Tumor Necrosis Factor/genetics/*metabolism MH - *Signal Transduction MH - Tumor Cells, Cultured MH - Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics/*metabolism MH - Tumor Necrosis Factor Receptor Superfamily, Member 9 PMC - PMC121523 EDAT- 1998/01/07 00:00 MHDA- 1998/01/07 00:01 PMCR- 1998/01/01 CRDT- 1998/01/07 00:00 PHST- 1998/01/07 00:00 [pubmed] PHST- 1998/01/07 00:01 [medline] PHST- 1998/01/07 00:00 [entrez] PHST- 1998/01/01 00:00 [pmc-release] AID - 0543 [pii] AID - 10.1128/MCB.18.1.558 [doi] PST - ppublish SO - Mol Cell Biol. 1998 Jan;18(1):558-65. doi: 10.1128/MCB.18.1.558.