{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPMEPA1 (also known as TMEPAI) is a transmembrane protein whose expression is tightly regulated by convergent TGF‐β and Wnt/β‐catenin signaling. In cancer cell models, TGF‐β stimulation recruits Smad proteins that, together with TCF7L2 from the Wnt pathway, modulate the activity of the TMEPAI promoter through a critical intronic cis-element. This synergistic regulation suggests that PMEPA1 functions as a negative feedback regulator of TGF‐β signaling, contributing to tumor-associated cellular responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn bone biology, PMEPA1 is induced in osteoclast precursor cells by RANKL via the p38 MAPK pathway. Its upregulation is critical for optimal osteoclast differentiation and function; knockdown studies have demonstrated that reduced PMEPA1 levels impair the formation of mature, multinucleated osteoclasts and decrease the expression of key osteoclast markers such as cathepsin K and c‐fos. Furthermore, loss of PMEPA1 disrupts the regulation of RANK surface expression, highlighting its role in osteoclast signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in differentiation, PMEPA1 exerts essential functions in the resorptive activity of osteoclasts by regulating intracellular vesicular trafficking. It interacts with NEDD4 family ubiquitin ligases, a partnership that appears critical for proper targeting of vacuolar ATPase components and the ensuing proton secretion needed for bone resorption. In addition, epigenetic modulation—illustrated by Hdac3 deficiency leading to upregulation of PMEPA1 and altered osteoclast fusion—emphasizes PMEPA1’s contribution to both bone homeostasis and healing. These findings point to PMEPA1 as a potential therapeutic target for pathologic bone destruction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Naoko Nakano, Susumu Itoh, Yukihide Watanabe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Requirement of TCF7L2 for TGF-beta-dependent transcriptional activation of the TMEPAI gene."}]}, {"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.M110.132209"}], "href": "https://doi.org/10.1074/jbc.M110.132209"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20889500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20889500"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Andrea S Link, Svitlana Kurinna, Steven Havlicek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Neurobiol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12035-015-9363-3"}], "href": "https://doi.org/10.1007/s12035-015-9363-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26215835"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26215835"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Noboru Funakubo, Xianghe Xu, Toshio Kukita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pmepa1 induced by RANKL-p38 MAPK pathway has a novel role in osteoclastogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.26147"}], "href": "https://doi.org/10.1002/jcp.26147"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28802000"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28802000"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xianghe Xu, Hirohito Hirata, Makoto Shiraki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.201801573R"}], "href": "https://doi.org/10.1096/fj.201801573R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30557043"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30557043"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "David H H Molstad, Elizabeth Zars, Andrew Norton, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hdac3 deletion in myeloid progenitor cells enhances bone healing in females and limits osteoclast fusion via Pmepa1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-020-78364-5"}], "href": "https://doi.org/10.1038/s41598-020-78364-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33311522"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33311522"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hirohito Hirata, Xianghe Xu, Kenichi Nishioka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PMEPA1 and NEDD4 control the proton production of osteoclasts by regulating vesicular trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.202001795R"}], "href": "https://doi.org/10.1096/fj.202001795R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33484199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33484199"}]}]}]}