{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSMPD3 encodes neutral sphingomyelinase 2 (nSMase2), a key enzyme that hydrolyzes sphingomyelin into the bioactive lipid ceramide. Ceramide in turn functions as an important second messenger that regulates stress‐induced signaling, apoptosis, cell cycle arrest, and exosome biogenesis. nSMase2 activity is tightly controlled by multiple regulatory mechanisms – it is dependent on Mg²⁺ and is activated by phosphatidylserine through conformational re‐arrangements (including a critical “DK switch”) and interdomain interactions. In addition, nSMase2 is modulated by post‐translational modifications such as phosphorylation (which can be rapidly altered via kinases like p38 MAPK and protein kinase Cs, and reversed by calcineurin) and is transcriptionally induced by stress signals including p53 activation and all‐trans retinoic acid, a process that involves specific promoter elements and histone acetylation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer and developmental contexts, nSMase2‐generated ceramide has been shown to drive the secretion of ceramide‐rich exosomes that convey microRNAs between cells, thereby promoting angiogenesis and metastasis. In response to pro‐inflammatory cytokines such as tumor necrosis factor‐α, nSMase2 translocates to the plasma membrane to enhance the expression of adhesion molecules that aid in cell–cell interactions. Moreover, loss‐of‐function mutations or deletions in the SMPD3 gene have been implicated in oncogenic processes including leukemias, while proper nSMase2 activity is essential for neuroprogenitor ciliogenesis through the regulation of signaling cascades involving atypical protein kinase C and HDAC6."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer, SMPD3 influences a broad spectrum of metabolic, vascular, and immune cell functions. In the intestine, for example, nSMase2 is transcriptionally regulated by the farnesoid X receptor to alter ceramide synthesis, thereby modulating atherosclerotic processes. Endothelial cells respond to low concentrations of oxidized lipoproteins by engaging nSMase2/sphingosine kinase‐1 signaling to promote angiogenesis, and nSMase2 regulates the extracellular release of microRNAs. In hepatocytes, palmitic acid triggers nSMase2 palmitoylation and plasma membrane translocation, leading to local ceramide generation and the onset of insulin resistance. In immune cells, nSMase2 plays roles in T cell receptor signaling and metabolic reprogramming (including association with lipid droplets) and has even been linked to altered cytokine responses in autoimmune conditions such as systemic lupus erythematosus. Furthermore, nSMase2 has been implicated in triggering inflammatory cascades through regulation of IRAK‐1 degradation and mediating uPA‐stimulated mitogenic signaling, as well as in promoting the cytodifferentiation of periodontal ligament cells. Finally, altered SMPD3 expression has been associated with neuropsychiatric features, bone mineralization deficits, and vascular calcification, and emerging small‐molecule inhibitors targeting nSMase2 offer novel therapeutic avenues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Norma Marchesini, Chiara Luberto, Yusuf A Hannun "}, {"type": "b", "children": [{"type": "t", "text": "Biochemical properties of mammalian neutral sphingomyelinase 2 and its role in sphingolipid metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M212262200"}], "href": "https://doi.org/10.1074/jbc.M212262200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12566438"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12566438"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hiromi Ito, Masashi Murakami, Ayako Furuhata, et al. 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