EDA2R

Ectodysplasin-A2 receptor (EDA2R, XEDAR, TNFRSF27) is the X-linked TNF receptor superfamily member that specifically binds the EDA-A2 splice variant of ectodysplasin-A. EDA2R is a type I transmembrane protein with cysteine-rich extracellular domains and a cytoplasmic death domain; unlike canonical death receptors, its apoptotic signaling in ectoderm-derived contexts is FADD-independent and engages TRAF3, TRAF6 and caspase activation cascades together with NF-κB and JNK. During embryogenesis EDA2R is expressed in ectodermal structures and participates, redundantly with EDAR, in skin appendage morphogenesis. EDA2R has attracted major attention in aging research: it was identified as one of the strongest methylation-based biomarkers of chronological age in human blood and tissues, with its promoter demethylation and transcription rising steadily with aging; EDA2R expression accordingly serves as a candidate aging clock gene. The receptor is also upregulated in certain melanomas and prostate cancer, where ligand-dependent apoptosis has been considered for therapy, and EDA2R signaling influences osteoblast activity and bone mass.