A Novel Tight Junction-Nuclear Receptor Signaling Pathway Regulating Cancer Progression

Nuclear receptors (NRs) are lipid ligand-binding transcription factors, with 48 members having been identified in humans to date. They are involved in diverse physiological processes, including development and homeostasis, and are also implicated in the pathogenesis of various diseases, most notably cancer. While NR activity is primarily regulated by specific ligand binding, posttranslational modifications, particularly phosphorylation, also play a critical role in modulating their function. Recently, we identified a novel signaling pathway linking claudins (CLDNs), cell-cell adhesion proteins, to NRs. CLDN-mediated cell-cell adhesion activates Src family kinases (SFKs), leading to serine phosphorylation of several NRs. This newly-discovered CLDN-NR pathway contributes to epithelial differentiation in stem cells and promotes cancer progression. In this review, we discuss the biological significance and underlying mechanisms of this, tracing the development of our research.