TNFRSF19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumorigenesis

Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFkB activation or associated with TRAF proteins. We identified TGF beta receptor type I (T beta RI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of T beta RI in the cytoplasm, thereby blocking Smad2/3 association with T beta RI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGF beta, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGF beta response characterized by upregulation of Smad2/3 phosphorylation and TGF beta target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGF beta activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGF beta. Significance: TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGF beta signaling pathway. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3469/F1.large.jpg. (C) 2018 AACR.