Tumor necrosis factor receptor superfamily member 9 (4-1BB) intracellular signaling complex (4-1BB signaling complex)

The 4-1BB (CD137) intracellular signaling complex is a multi-protein assembly formed upon the activation of the Tumor Necrosis Factor Receptor Superfamily Member 9 (TNFRSF9). Activation occurs through trimerization of the 4-1BB receptor, typically triggered by its natural ligand (4-1BBL) or agonistic therapeutic agents [PMID: 30718315]. This trimerization facilitates the recruitment of Tumor Necrosis Factor Receptor-Associated Factors (TRAFs), specifically TRAF1, TRAF2, and TRAF3, to the receptor's cytoplasmic tail [PMID: 29343438]. The assembly of this complex initiates downstream signaling pathways, including the canonical and non-canonical NF-κB pathways, as well as the mitogen-activated protein kinase (MAPK) cascades involving JNK and p38 [UniProt: Q07011]. These pathways are essential for enhancing T-cell metabolic fitness, promoting long-term survival, and preventing activation-induced cell death (AICD) [PMID: 28341640]. In clinical applications, the 4-1BB signaling domain is a cornerstone of second-generation Chimeric Antigen Receptor (CAR) T-cell therapies, where it provides the necessary costimulatory signals to ensure T-cell persistence and anti-tumor efficacy [PMID: 29343438]. Furthermore, agonistic monoclonal antibodies targeting this complex are being investigated for their ability to potentiate anti-tumor immune responses in various malignancies [PMID: 24161905]. However, systemic activation of the 4-1BB signaling complex has been associated with significant safety concerns, most notably dose-limiting hepatotoxicity observed in early clinical trials [PMID: 24161905].

Other names

CD137 signaling complexTNFRSF9 signaling complex4-1BB/TRAF complexCD137 intracellular signaling complex4-1BB costimulatory signalosome

Agonistic activation of the 4-1BB receptor leads to the assembly of the intracellular signaling complex, which recruits TRAF proteins to initiate pro-survival and pro-proliferative signaling cascades.