{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNardilysin (NRDC/NRD1) is emerging as a multifunctional regulator of cell signaling, acting both as a receptor and as an enzymatic modulator. It directly binds heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), thereby enhancing HB‐EGF–induced cell migration through erbB1-dependent mechanisms—even when its own protease activity is dispensable. In addition, its intrinsic regulatory domains, including an acidic (DAC) region that interacts with polyamines, fine-tune its activity and ligand binding."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNRDC also functions as a critical enhancer of ectodomain shedding, forming complexes with ADAM proteases such as TACE/ADAM17 and ADAM10. Through this association, it potently promotes the cleavage and release of membrane-tethered growth factors and cytokines—including HB‐EGF and TNF-α—which in turn activates downstream signaling pathways that drive cell migration and inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in modulating extracellular signals, NRDC participates in intracellular immune and transcriptional regulation. In the cytosol it complements proteasome activity by aiding in the generation of cytotoxic T lymphocyte epitopes—thereby broadening the antigenic peptide repertoire—while it also acts as a specific reader of dimethylated histone H3 lysine 4 (H3K4me2), recruiting the NCoR/SMRT corepressor complex to influence gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in NRDC expression and activity have significant implications in cancer. In cells expressing mutant p53, NRDC interacts with p53R273H to promote an invasive response in the presence of HB‐EGF. Its aberrant or elevated expression not only correlates with advanced disease and poorer prognosis in esophageal squamous cell carcinoma but is also implicated in gastric cancer progression through dysregulated circular RNA (circNRD1)–mediated molecular sponging, which influences key downstream determinants of tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, NRDC is widely expressed in neurons and contributes to neural development, axonal maturation, and synaptic regulation. It interacts with brain-specific factors—such as the adaptor protein p42(IP4) and components of the cytoskeleton like tubulin—and its levels increase during neuronal differentiation. Moreover, genetic studies have linked NRD1 with alcohol dependence, while reduced NRDC expression in specific brain regions has been observed under chronic ethanol exposure; epigenetic regulation, including differential methylation patterns impacting NRDC and related genes, may further modulate its neural functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional roles for NRDC extend to diverse physiological systems. In smooth muscle, it regulates the plasma membrane expression of maxi-K channel splice variants, thereby influencing cellular excitability. Its regulatory function in ectodomain shedding has also been associated with the release of biomarkers relevant to myocardial ischemia/infarction, and its proteolytic activity toward cell-surface costimulatory molecules suggests a potential contribution to autoimmune pathologies such as vitiligo."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "E Nishi, A Prat, V Hospital, et al. 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