{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMESD is fundamentally a specialized endoplasmic reticulum chaperone that orchestrates the proper folding and intracellular trafficking of multiligand receptors in the low‐density lipoprotein (LRP) family, most notably the Wnt co-receptors LRP5 and LRP6. Through its dual-domain structure—with a chaperone domain that stabilizes the immature β-propeller regions and an escort domain that safeguards the receptors during transit from the ER to the Golgi—MESD ensures that these complex proteins achieve conformations that allow them to reach the cell surface and engage in canonical Wnt signaling. Disruption of MESD function, as seen in cases where truncation or frameshift mutations cause its mislocalization (and in genetic rearrangements that prevent proper ER targeting), results in hypomorphic alleles that compromise receptor maturation, leading to severe developmental defects including defects in skeletal and dental formation, and even early embryonic lethality in animal models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its intracellular role, MESD exhibits important extracellular functions. The recombinant MESD protein—and particularly peptides derived from its C-terminal region—can bind mature LRP5 and LRP6 receptors on the cell surface, antagonizing Wnt/β-catenin signaling by interfering with the binding of various Wnt ligands and modulators. This inhibitory capability has been demonstrated across different cell contexts, including prostate and breast cancer models, where it not only suppresses aberrant Wnt signaling but also enhances the cytotoxic effects of chemotherapeutic agents. Moreover, co-expression of MESD has been shown to markedly enhance the functional display of LRP5/6, thereby affecting the binding of secreted antagonists such as Dkk1."}, {"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": "\nCollectively, these findings underscore the dual functional roles of MESD both as an essential intracellular chaperone facilitating the maturation and safe trafficking of LRP receptors and as an extracellular modulator that can dampen Wnt signaling. The critical nature of MESD’s activity is highlighted by its association with developmental disorders such as osteogenesis imperfecta and its emerging potential as a therapeutic target in oncology, where modulating Wnt pathway dynamics could offer significant clinical benefits.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Imke M Veltman, Lilian A Vreede, Jinke Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fusion of the SUMO/Sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12;15)(q13;q25)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddi200"}], "href": "https://doi.org/10.1093/hmg/ddi200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15917269"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15917269"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yonghe Li, Wenyan Lu, Xi He, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of LRP6-mediated Wnt signaling by molecular chaperone Mesd."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2006.09.011"}], "href": "https://doi.org/10.1016/j.febslet.2006.09.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16989816"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16989816"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Janet K Lighthouse, Liqun Zhang, Jen-Chih Hsieh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Dyn (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dvdy.22477"}], "href": "https://doi.org/10.1002/dvdy.22477"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21337463"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21337463"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jianglei Chen, Chia-Chen Liu, Qianqian Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two structural and functional domains of MESD required for proper folding and trafficking of LRP5/6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2011.01.010"}], "href": "https://doi.org/10.1016/j.str.2011.01.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21397183"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21397183"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Shahida Moosa, Guilherme L Yamamoto, Lutz Garbes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2019.08.008"}], "href": "https://doi.org/10.1016/j.ajhg.2019.08.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31564437"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31564437"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Julian Stürznickel, Katharina Jähn-Rickert, Jozef Zustin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.4277"}], "href": "https://doi.org/10.1002/jbmr.4277"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33596325"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33596325"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Richard J Murrills, Jeanne J Matteo, Bheem M Bhat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A cell-based Dkk1 binding assay reveals roles for extracellular domains of LRP5 in Dkk1 interaction and highlights differences between wild-type and the high bone mass mutant LRP5(G171V)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.22335"}], "href": "https://doi.org/10.1002/jcb.22335"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19746449"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19746449"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Cuihong Lin, Wenyan Lu, Ling Zhai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mesd is a general inhibitor of different Wnt ligands in Wnt/LRP signaling and inhibits PC-3 tumor growth in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2011.08.046"}], "href": "https://doi.org/10.1016/j.febslet.2011.08.046"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21907199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21907199"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Cuihong Lin, Wenyan Lu, Wei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The C-terminal region Mesd peptide mimics full-length Mesd and acts as an inhibitor of Wnt/β-catenin signaling in cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0058102"}], "href": "https://doi.org/10.1371/journal.pone.0058102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23469146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23469146"}]}]}]}