{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMEM88 is a transmembrane protein that functions primarily by interacting with Dishevelled (Dvl) proteins to modulate the canonical Wnt/β‐catenin signaling pathway. By binding via its C‐terminal VWV motif to the PDZ domain of Dvl, TMEM88 can attenuate Wnt ligand–induced β‐catenin activation. In some contexts—such as in non–small cell lung and breast cancers—the aberrant cytosolic localization of TMEM88 disrupts its normal membrane‐bound inhibitory role, leading to activation of downstream effectors (p38, GSK3β, and Snail) that promote invasion, metastasis, and aggressive tumor phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its involvement in oncogenesis, TMEM88 plays a crucial role during embryonic development and cell fate specification. For example, during the transition from lateral plate mesoderm to pre‐cardiac progenitor cells, upregulation of TMEM88 suppresses canonical Wnt/β‐catenin signaling thereby favoring cardiomyocyte differentiation over endothelial fate. Similarly, in hepatocellular carcinoma, as well as in thyroid and bladder cancers, restoration of TMEM88 expression is associated with reduced expression of oncogenic Wnt targets (such as c-myc and cyclin D1), leading to decreased proliferation, colony formation, and invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in tumor biology and development, TMEM88 is emerging as an important regulator in fibrotic and inflammatory processes. Overexpression of TMEM88 in keloid‐derived fibroblasts and pleural mesothelial cells counteracts TGF‐β1–induced proliferation, epithelial–mesenchymal transition, and extracellular matrix (ECM) accumulation by suppressing β‐catenin activity. In liver fibrosis, downregulation of TMEM88—mediated in part by miR‑708—leads to heightened activation of hepatic stellate cells and increased deposition of ECM components. Moreover, in hepatic stellate cell models, TMEM88 levels have been linked to the modulation of proinflammatory cytokine (IL‑6 and IL‑1β) secretion, indicating a broader involvement in inflammatory signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": " \n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these findings underscore the context‐dependent functions of TMEM88. Its ability to regulate canonical Wnt/β‐catenin signaling through direct interactions with Dishevelled proteins impacts developmental cell fate decisions as well as pathological processes including tumor progression, metastasis, and fibrogenesis. The subcellular localization of TMEM88 appears critical for its function, with membrane‐associated protein favoring tumor suppressor activities and cytosolic mislocalization correlating with enhanced oncogenic and invasive properties. As such, TMEM88 represents both a promising biomarker and a potential therapeutic target across a range of diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ho-Jin Lee, David Finkelstein, Xiaofeng Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of transmembrane protein 88 (TMEM88) as a dishevelled-binding protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.193383"}], "href": "https://doi.org/10.1074/jbc.M110.193383"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21044957"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21044957"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Nathan J Palpant, Lil Pabon, Jeremy S Rabinowitz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.094789"}], "href": "https://doi.org/10.1242/dev.094789"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23924634"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23924634"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xinmiao Yu, Xiupeng Zhang, Yong Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytosolic TMEM88 promotes triple-negative breast cancer by interacting with Dvl."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.4379"}], "href": "https://doi.org/10.18632/oncotarget.4379"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26325443"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26325443"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xiupeng Zhang, Xinmiao Yu, Guiyang Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cytosolic TMEM88 promotes invasion and metastasis in lung cancer cells by binding DVLS."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-14-3828"}], "href": "https://doi.org/10.1158/0008-5472.CAN-14-3828"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26359454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26359454"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xin Zhang, Jin-Xiang Wan, Zun-Ping Ke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TMEM88, CCL14 and CLEC3B as prognostic biomarkers for prognosis and palindromia of human hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tumour Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/1010428317708900"}], "href": "https://doi.org/10.1177/1010428317708900"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28718365"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28718365"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Qianqian Geng, Xu Chen, Nanzheng Chen "}, {"type": "b", "children": [{"type": "t", "text": "Transmembrane protein 88 exerts a tumor-inhibitory role in thyroid cancer through restriction of Wnt/β-catenin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2020.112193"}], "href": "https://doi.org/10.1016/j.yexcr.2020.112193"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32710906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32710906"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Xu Zhao, Gang Li, Tie Chong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TMEM88 exhibits an antiproliferative and anti-invasive effect in bladder cancer by downregulating Wnt/β-catenin signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biochem Mol Toxicol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbt.22835"}], "href": "https://doi.org/10.1002/jbt.22835"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34057764"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34057764"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Tao Xu, Lin-Xin Pan, Yun-Xuan Ge, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-708 modulates Hepatic Stellate Cells activation and enhances extracellular matrix accumulation via direct targeting TMEM88."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.15119"}], "href": "https://doi.org/10.1111/jcmm.15119"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32463570"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32463570"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Zhongmin Sun, Qian Ning, Hong Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transmembrane protein 88 inhibits transforming growth factor-β1-induced-extracellular matrix accumulation and epithelial-mesenchymal transition program in human pleural mesothelial cells through modulating TGF-β1/Smad pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Recept Signal Transduct Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/10799893.2020.1843493"}], "href": "https://doi.org/10.1080/10799893.2020.1843493"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33167758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33167758"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Huafei Zhao, Fei Lu, Shuo Cui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TMEM88 inhibits extracellular matrix expression in keloid fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2017.09.047"}], "href": "https://doi.org/10.1016/j.biopha.2017.09.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28946191"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28946191"}]}]}]}