{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMEM9 is a highly conserved transmembrane protein that features an N‐terminal signal peptide, a single transmembrane domain, multiple potential N‐glycosylation sites, and conserved cysteine‐rich regions. It is widely expressed and predominantly localizes to membranes of the lysosome, late endosomes, and the endoplasmic reticulum, suggesting a role in intracellular transport and organelle function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in intracellular trafficking, TMEM9 promotes vesicular acidification through binding to and facilitating the assembly of the vacuolar‐ATPase complex. This activity enhances lysosomal acidification and vesicle trafficking, which in turn leads to amplification of the canonical Wnt/β‐catenin signaling pathway through mechanisms such as lysosome‐dependent degradation of APC. TMEM9 also interacts with key autophagy regulators – for example, by binding to Beclin1 and displacing Bcl-2, it activates Rab9-dependent, LC3-independent alternative autophagy. A variant in the TMEM9 family (TMEM9A) similarly boosts Wnt/β‐catenin signaling in breast cancer, thereby contributing to enhanced cell proliferation and survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, TMEM9 (and its homolog TMEM9B) plays an important role in modulating inflammatory responses. It is required for the production of proinflammatory cytokines in response to TNF, IL-1β, and Toll-like receptor ligands by acting in the signaling cascade downstream of RIP1 and upstream of TAK1, thereby facilitating the activation of both NF-κB and MAPK pathways. Dysregulated expression of TMEM9 is associated with enhanced tumor progression in diverse malignancies—promoting cell cycle progression, proliferation, invasion, metastasis, and even angiogenesis (via upregulation of VEGF through the MEK/ERK/STAT3 axis) in hepatocellular carcinoma and lung adenocarcinoma. Collectively, these multifaceted functions underscore the potential of TMEM9 and its associated pathways as promising targets for novel therapeutic interventions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marit Kveine, Ellen Tenstad, Guri Døsen, et al. 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