Retinoid X receptor alpha (truncated form) (tRXRα)

The truncated retinoid X receptor alpha (tRXRα) is a tumor-specific isoform of the nuclear receptor RXRα, produced through proteolytic cleavage of the N-terminal A/B domain by cathepsin L (Zhou et al., 2010, Cancer Cell). While full-length RXRα primarily functions as a ligand-dependent transcription factor in the nucleus, tRXRα is predominantly cytoplasmic and promotes cell survival by interacting with the p85α subunit of phosphoinositide 3-kinase (PI3K), thereby activating the AKT pathway (Lin et al., 2010, Science Signaling). The tetramer interface of tRXRα has emerged as a critical therapeutic target because it contains a unique pocket that can be occupied by small molecules like sulindac and its analog K-80003 (Zhang et al., 2011, Nature Chemical Biology). Binding at this interface stabilizes a tetrameric configuration of the receptor, which prevents its interaction with PI3K and triggers apoptosis in cancer cells (Chen et al., 2014, Oncotarget). This mechanism provides a basis for developing selective anti-cancer agents that target the non-genomic activities of RXRα without disrupting its essential physiological roles in the nucleus.

Other names

tRXR-alphaTruncated RXR-alphaNR2B1Retinoid X receptor alpha tetramer interfaceRXRA

Binding to the tetramer interface of truncated RXRα to stabilize an inactive tetrameric state, thereby disrupting its interaction with PI3K and inhibiting the AKT survival pathway.