Tumor necrosis factor (TNF) is a potent mediator of inflammation as well as many normal physiological functions in homeostasis and health, and anti-microbial immunity.

The TNF receptor superfamily member 19 (also known as TROY, TNFRSF19) is a type I cell surface transmembrane protein with disulfide bonds that form “cysteine-rich domains” (CRDs). These 40 amino acid pseudo-repeats are defined by 3 intra-chain disulfides generated by 6 highly conserved cysteines¹. Unlike other members of the TNF receptor superfamily, TROY lacks a cytoplasmic death domain but contains a single TNF receptor-associated factor (TRAF)-binding site². TROY is expressed on migrating or proliferating progenitor cells of the hippocampus, thalamus and cerebral cortex.

TROY is involved in the pathogenesis of various neoplasms. Glioblastoma multiforme (GBM) is the most malignant form of all primary adult brain tumors in which patient survival remains approximately 1 year. Overexpression of TROY in glioma cells activates Rac1 signaling in a Pyk2-dependent manner to drive glioma cell invasion and migration. TROY expression has been found to correlate inversely with overall patient survival in glioblastoma³.

TROY is also involved in the lack of successful axon regeneration in the adult central nervous system. Inhibition of axonal growth arises from inhibitory molecules in CNS myelin, which signal through a common receptor complex on neurons consisting of the ligand-binding Nogo-66 receptor (NgR) and two transmembrane co-receptors, p75^NTR and LINGO-1. TROY can substitute p75 and form a tri-receptor complex with NgR and LINGO-1. This complex can reconstitute the activation of RhoA, a required step in the signaling pathways of myelin inhibition. Additionally, both overexpression of a truncated form of TROY lacking its intracellular domain and addition of a TROY-Fc fusion protein can block neuronal response to myelin inhibitors in a dominant-negative manner⁴.