TNFRSF9 Gene: CD137, 4-1BB – Function, Expression, Mutations & Disease

TNFRSF9 (CD137, 4-1BB) encodes a member of the tumor necrosis factor (TNF) receptor superfamily. This transmembrane protein is expressed on activated T cells, NK cells, dendritic cells, and other immune cells. It provides co-stimulatory signals that promote T cell proliferation, survival, and cytokine production. TNFRSF9 is a key target in cancer immunotherapy, with agonist antibodies (e.g., urelumab, utomilumab) under investigation. The gene is also implicated in autoimmune diseases and graft-versus-host disease.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• TNF receptor superfamily signaling (KEGG: hsa04668)

• T cell receptor signaling pathway (KEGG: hsa04660)

• NF-kappa B signaling pathway (KEGG: hsa04064)

TNFRSF9 (CD137, 4-1BB) is a 255-amino-acid type I transmembrane glycoprotein with four cysteine-rich extracellular domains characteristic of the TNFR superfamily. It forms homodimers and binds to its ligand TNFSF9 (4-1BBL). Upon ligand binding, it recruits TRAF adaptor proteins (TRAF1, TRAF2, TRAF3) and activates NF-κB, JNK, and PI3K/Akt signaling pathways, leading to enhanced T cell survival, proliferation, and effector function. The protein is a target for cancer immunotherapy (agonist antibodies) and for modulating autoimmune inflammation.