{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTrophinin (TRO) is an atypical cell adhesion molecule that plays a critical role in human embryo implantation. It is expressed on both the trophectoderm of the blastocyst and on endometrial epithelial cells, where homophilic trophinin‐trophinin binding mediates the initial attachment of the embryo. Engagement of trophinin activates intracellular signaling cascades that include tyrosine phosphorylation of ErbB family receptors, reorganization of the actin cytoskeleton, and heightened proliferation and motility of trophoblastic cells—all of which facilitate the transition from adhesion to invasion necessary for placental formation."}, {"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": "\nIn addition to its role on the embryonic side, trophinin expression in maternal tissues is dynamically regulated. For instance, the human blastocyst secretes hCG, which upregulates trophinin in the endometrial epithelium to promote cell adhesion at implantation sites—a mechanism that may also contribute to conditions such as ectopic pregnancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its transmembrane role, trophinin has notable intracellular functions. Studies have shown that a fraction of endogenous trophinin localizes to the nuclear envelope, suggesting involvement in nuclear architecture or other nuclear processes. Moreover, alternative splicing of the TRO gene gives rise to magphinin proteins—with differing cytoplasmic and nuclear localizations—that appear to influence cell cycle progression and differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant trophinin expression has also been observed in various malignancies. In cancers such as colon, gallbladder, and ovarian tumors, altered trophinin levels are associated with enhanced invasive properties and metastatic potential. For example, trophinin has been implicated in upregulating pro‐invasive factors including HMGB1/RAGE signaling, and its expression correlates with chemosensitivity in ovarian cancer, suggesting a complex, context‐dependent role in tumor progression and suppression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, experimental engagement of trophinin with mimetic peptides such as the GWRQ motif can trigger divergent signaling outcomes depending on the cell type. In trophoblastic cells, such interactions release intracellular inhibitors (e.g., bystin) to allow ErbB4 activation and consequent cell activation for invasion, whereas in endometrial epithelial cells GWRQ binding can lead to tyrosine phosphorylation of PKC-δ, its nuclear translocation, and apoptosis. This dual functionality underscores the multifaceted nature of TRO-mediated signaling in both normal implantation and disease states."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hua-Yun Wang, Fu-Qi Xing, Shi-Ling Chen "}, {"type": "b", "children": [{"type": "t", "text": "Expression of trophinin in the cycling endometrium and its association with infertility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Di Yi Jun Yi Da Xue Xue Bao (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12297480"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12297480"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jun Nakayama, Daisuke Aoki, Tomoaki Suga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Implantation-dependent expression of trophinin by maternal fallopian tube epithelia during tubal pregnancies: possible role of human chorionic gonadotrophin on ectopic pregnancy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9440(10)63579-1"}], "href": "https://doi.org/10.1016/S0002-9440(10"}, {"type": "t", "text": "63579-1) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14633596"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14633596"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kazuhiro Sugihara, Daijiro Sugiyama, James Byrne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trophoblast cell activation by trophinin ligation is implicated in human embryo implantation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0611516104"}], "href": "https://doi.org/10.1073/pnas.0611516104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17360433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17360433"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Michiko N Fukuda, Kazuhiro Sugihara "}, {"type": "b", "children": [{"type": "t", "text": "Signal transduction in human embryo implantation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.6.10.4266"}], "href": "https://doi.org/10.4161/cc.6.10.4266"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17495530"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17495530"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kazuhiro Sugihara, Maryam Kabir-Salmani, James Byrne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Induction of trophinin in human endometrial surface epithelia by CGbeta and IL-1beta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2007.12.001"}], "href": "https://doi.org/10.1016/j.febslet.2007.12.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18078818"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18078818"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Elif Gelenli Dolanbay, Melda Yardimoglu, Ender Yalcinkaya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of trophinin and dipeptidyl peptidase IV in endometrial co-culture in the presence of an embryo: A comparative immunocytochemical study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2016.5020"}], "href": "https://doi.org/10.3892/mmr.2016.5020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27035766"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27035766"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Mathieu Bertrand, Ivo Huijbers, Patrick Chomez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative expression analysis of the MAGED genes during embryogenesis and brain development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Dyn (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dvdy.20026"}], "href": "https://doi.org/10.1002/dvdy.20026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15162511"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15162511"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Junya Aoyama, Yuji Nakayama, Daijiro Sugiyama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Apical cell adhesion molecule, trophinin, localizes to the nuclear envelope."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2005.10.012"}], "href": "https://doi.org/10.1016/j.febslet.2005.10.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16288751"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16288751"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Junya Aoyama, Yusuke Akazawa, Kousuke Kasahara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear localization of magphinins, alternative splicing products of the human trophinin gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.21446"}], "href": "https://doi.org/10.1002/jcb.21446"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17559068"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17559068"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Oi Harada, Tomoaki Suga, Takefumi Suzuki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of trophinin, an adhesion molecule unique to human trophoblasts, in progression of colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.22821"}], "href": "https://doi.org/10.1002/ijc.22821"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17487845"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17487845"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Tsukasa Baba, Seiichi Mori, Noriomi Matsumura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trophinin is a potent prognostic marker of ovarian cancer involved in platinum sensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2007.06.070"}], "href": "https://doi.org/10.1016/j.bbrc.2007.06.070"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17597582"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17597582"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Xin-Zhong Chang, Jie Yu, Xue-Hui Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Enhanced expression of trophinin promotes invasive and metastatic potential of human gallbladder cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cancer Res Clin Oncol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00432-008-0492-1"}], "href": "https://doi.org/10.1007/s00432-008-0492-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18846386"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18846386"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Naoaki Tamura, Kazuhiro Sugihara, Tomoya O Akama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trophinin-mediated cell adhesion induces apoptosis of human endometrial epithelial cells through PKC-δ."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.10.1.14448"}], "href": "https://doi.org/10.4161/cc.10.1.14448"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21191175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21191175"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Michiko N Fukuda, Kazuhiro Sugihara "}, {"type": "b", "children": [{"type": "t", "text": "Trophinin in cell adhesion and signal transduction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Biosci (Elite Ed) (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2741/381"}], "href": "https://doi.org/10.2741/381"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22201876"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22201876"}]}]}]}