{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProtein O‑fucosyltransferase 1 (POFUT1) is an evolutionarily conserved enzyme that catalyzes the addition of O‑fucose to serine or threonine residues within epidermal growth factor‐like repeats—a modification essential for proper Notch receptor folding, trafficking, and ligand binding. In mammalian cells, POFUT1 localizes predominantly to the endoplasmic reticulum where, aside from its glycosyltransferase activity, it contributes to quality control by selectively recognizing correctly folded substrates. Disruption of this enzymatic activity—either through genetic ablation or specific mutations such as the S162L variant—leads to marked reductions in Notch ligand interactions and downstream signaling, thereby perturbing multiple developmental processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental role, aberrant expression of POFUT1 has been implicated in the initiation and progression of diverse malignancies. Elevated POFUT1 levels in hepatocellular carcinoma, colorectal cancer, oral squamous cell carcinoma, gastric cancer, glioblastoma, and head and neck squamous cell carcinoma correlate with enhanced Notch signaling, increased tumor cell proliferation, migration, and invasion, as well as poorer clinical outcomes. In colorectal tumors, gene‐dosage effects and copy number variations further drive its overexpression, while in certain contexts, circular RNAs derived from the POFUT1 locus act as competing endogenous RNAs that modulate oncogenic pathways. Functional studies in a variety of in vitro and in vivo models have demonstrated that POFUT1 silencing suppresses tumor growth, induces cell cycle arrest and apoptosis, and reverses aggressive phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in Notch‐mediated cellular signaling and oncogenesis, POFUT1 is critical for normal embryonic and tissue homeostasis. Mutations in the POFUT1 gene underlie dermatological disorders such as Dowling–Degos disease, where altered enzyme function disrupts melanin synthesis and distribution. Similarly, reduced expression levels of POFUT1 in reproductive tissues correlate with impaired trophoblast migration, defective decidualization, and compromised uterine angiogenesis—processes vital for successful implantation and pregnancy. Collectively, these findings underscore the multifaceted roles of POFUT1 in development, physiology, and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yi Luo, Robert S Haltiwanger "}, {"type": "b", "children": [{"type": "t", "text": "O-fucosylation of notch occurs in the endoplasmic reticulum."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M414574200"}], "href": "https://doi.org/10.1074/jbc.M414574200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15653671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15653671"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mark Stahl, Kazuhide Uemura, Changhui Ge, et al. 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