Apo-3, a new member of the tumor necrosis factor receptor family, contains a death domain and activates apoptosis and NF-kappa B

Curr Biol. 1996 Dec 1;6(12):1669-76. doi: 10.1016/s0960-9822(02)70791-4.


Background: Two receptors that contain the so-called "death domain' have been described to date: tumor necrosis factor receptor 1 (TNFR1) and Fas/Apo-1 (CD95); both belong to the TNFR gene family. The death domain of TNFR1 mediates the activation of programmed cell death (apoptosis) and of the transcription factor NF-kappa B, whereas the death domain of CD95 only appears to activate apoptosis.

Results: We have identified an additional member of the TNFR family, which we have named Apo-3. Apo-3 is a transmembrane protein of approximately 47 kDa that has similarity of members of the TNFR family in its extracellular, cysteine-rich domains. In addition, Apo-3 resembles TNFR1 and CD95 in that it contains a cytoplasmic death domain. The Apo-3 gene mapped to human chromosome 1p36.3, and Apo-3 mRNA was detected in several human tissues, including spleen, thymus, peripheral blood lymphocytes, small intestine and colon. Ectopic expression of Apo-3 in HEK293 or HeLa cells induced marked apoptosis. CrmA, a poxvirus inhibitor of Ced-3-like proteases which blocks death signaling by TNFR1 and CD95, inhibited Apo-3-induced apoptosis. Ectopic expression of Apo-3 also induced the activation of NF-kappa B. Apo-3 did not specifically bind to the Apo-2 ligand, suggesting the existence of a distinct ligand for Apo-3.

Conclusions: These results identify Apo-3 as a third member of the TNFR family that activates apoptosis, and suggest that Apo-3, TNFR1 and CD95 engage a common apoptotic cell-death machinery. Apo-3 resembles TNFR1 because it can stimulate NF-kappa B activity and regulate apoptosis. Apo-3 mRNA is expressed in various tissues, consistent with the possibility that this receptor may regulate multiple signaling functions.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Base Sequence
  • Binding Sites
  • Chromosome Mapping
  • Chromosomes, Human, Pair 1*
  • DNA, Complementary
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Membrane Glycoproteins / metabolism
  • Molecular Sequence Data
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / metabolism
  • Receptors, Tumor Necrosis Factor, Member 25
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Serpins / genetics
  • Serpins / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / metabolism
  • Viral Proteins*


  • Apoptosis Regulatory Proteins
  • DNA, Complementary
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Member 25
  • Recombinant Fusion Proteins
  • Serpins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF25 protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Viral Proteins
  • interleukin-1beta-converting enzyme inhibitor

Associated data

  • GENBANK/U74611