Tumor necrosis factor receptor superfamily member 10D (TRAIL-R4) (TRAIL-R4)

Tumor necrosis factor receptor superfamily member 10D (TRAIL-R4), also known as Decoy receptor 2 (DcR2), is a transmembrane protein that serves as a critical regulatory component of the TRAIL signaling pathway. While it possesses an extracellular domain capable of binding the cytotoxic ligand TRAIL with high affinity, it contains a truncated and non-functional intracellular death domain, which renders it unable to independently trigger the apoptotic cascade [4, 8]. TRAIL-R4 primarily functions as a decoy receptor, inhibiting apoptosis by competitively sequestering TRAIL or by forming inactive heteromeric complexes with the functional death receptors TRAIL-R1 and TRAIL-R2 [9, 10]. In the context of oncology, TRAIL-R4 is frequently overexpressed in various malignancies, where it acts as a major mediator of resistance to TRAIL-based therapies [1, 13]. Beyond its decoy function, it can actively promote cell survival through the activation of pro-survival signaling pathways such as NF-kappaB and AKT/ERK [1, 8]. Consequently, TRAIL-R4 is a significant therapeutic target, with research focusing on its inhibition to restore sensitivity to apoptosis-inducing agents like Dulanermin [5, 11]. Its role in immune regulation and potential involvement in autoimmune and neurodegenerative diseases also make it a subject of broader therapeutic interest [5].

Other names

Decoy receptor 2DcR2CD264TRUNDDTRAILR4

TRAIL-R4 acts as a decoy receptor that competitively binds to TRAIL, preventing its interaction with the pro-apoptotic receptors TRAIL-R1 and TRAIL-R2 [4, 9]. It also forms inactive heterotrimers with TRAIL-R1 and TRAIL-R2, effectively sequestering them and inhibiting the formation of the death-inducing signaling complex (DISC) [9, 10]. Furthermore, TRAIL-R4 can activate pro-survival signaling pathways, including NF-kappaB, AKT, and ERK, which contribute to therapeutic resistance in cancer cells [1, 8].