{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTTYH3 is a member of the Tweety protein family characterized by five membrane‐spanning domains and an extended extracellular region that is subject to N‐glycosylation. Although initially described as a calcium‐activated chloride channel, recent high‐resolution cryo–electron microscopy studies have shown that TTYH3 lacks features typical of conventional anion conduction and instead reveals a distinctive hydrophobic pocket suggesting an alternative role in interacting with lipid‐like compounds. In addition, the presence of conserved PY motifs enables TTYH3 to be recognized and ubiquitinated by the HECT type E3 ligase Nedd4–2, thereby regulating its cellular and cell surface levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTTYH3 has also emerged as an important mediator in oncogenic processes. In glioblastoma, a fusion between TTYH3 and BRAF was identified, whereby TTYH3 tethers near full–length BRAF to the membrane, leading to aberrant activation of the MEK/ERK signaling cascade."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In other malignancies, overexpression of TTYH3 is associated with enhanced cell proliferation, migration, invasion, and promotion of epithelial–mesenchymal transition. For example, in hepatocellular carcinoma, TTYH3 increases calcium influx and intracellular chloride concentration, modulates interactions with MK5, and subsequently activates the GSK3β/β–catenin pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "; in bladder cancer, its upregulation influences the H–Ras/A–Raf/MEK/ERK cascade via modulation of FGFR1 phosphorylation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "; and in cervical cancer, TTYH3 has been shown to promote oncogenesis through activation of the Wnt/β–catenin signaling pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have investigated the role of TTYH3 in other tumor types. Its expression and biological significance have been examined in cholangiocarcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "and oral squamous cell carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", with findings that support a correlation between TTYH3 upregulation, aggressive disease phenotypes, and poor clinical outcomes. Together, these observations underscore the diverse functional roles of TTYH3 in membrane biology and its potential as a prognostic biomarker and therapeutic target across multiple cancer types.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yaowu He, Deanne H Hryciw, Melanie L Carroll, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ubiquitin-protein ligase Nedd4-2 differentially interacts with and regulates members of the Tweety family of chloride ion channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M803361200"}], "href": "https://doi.org/10.1074/jbc.M803361200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18577513"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18577513"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Anastasiia Sukalskaia, Monique S Straub, Dawid Deneka, et al. 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