{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCASTOR3P, a member of the inactive rhomboid family, plays a central regulatory role in the maturation and function of the metalloprotease ADAM17. Loss‐of-function studies in mouse models, including those lacking both iRhom1 and iRhom2, have demonstrated that impaired ADAM17-dependent shedding of key substrates—such as epidermal growth factor receptor (EGFR) ligands and transforming growth factor α (TGFα)—leads to diverse developmental defects including abnormal skin, heart valve malformation, and impaired skeletal growth. These findings underscore that CASTOR3P (as part of the iRhom regulatory group) is essential for normal embryonic development and the posttranslational activation of ADAM17."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to developmental functions, CASTOR3P is implicated in the regulation of immune and neural processes. Endogenous studies have revealed its presence at the cell surface, where it stabilizes ADAM17 and thereby facilitates the shedding of membrane proteins that are critical for inflammatory signaling and neural homeostasis. In the brain, for example, CASTOR3P-dependent regulation of ADAM17 activity is necessary for the release of substrates such as MEGF10—a receptor involved in phagocytosis and clearance of toxic protein aggregates. Furthermore, modulation of ADAM17 activity in oligodendrocytes has been linked to remyelination processes, highlighting its potential influence in demyelinating conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional evidence implicates CASTOR3P in oncogenic and proliferative signaling pathways. Overexpression studies of a related rhomboid family member (RHBDF1) in colorectal and head and neck cancers have shown that its upregulation can promote cell proliferation, invasion, and epithelial-to-mesenchymal transition via activation of the Wnt/β-catenin signaling cascade. Complementarily, investigations in breast cancer models have revealed that alterations in associated regulatory genes may drive autophagy-mediated tumor cell proliferation and migration through the PI3K/Akt pathway. These findings suggest that dysregulation of CASTOR3P-related mechanisms can contribute to malignancy and may represent attractive targets for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xue Li, Thorsten Maretzky, Gisela Weskamp, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Mammalian iRhoms have distinct physiological functions including an essential role in TACE regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/embor.2013.128"}], "href": "https://doi.org/10.1038/embor.2013.128"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23969955"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23969955"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Renpeng Fang, Coline Haxaire, Miguel Otero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of iRhoms 1 and 2 in Endochondral Ossification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms21228732"}], "href": "https://doi.org/10.3390/ijms21228732"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33227998"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33227998"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Gisela Weskamp, Johanna Tüshaus, Daniel Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ADAM17 stabilizes its interacting partner inactive Rhomboid 2 (iRhom2) but not inactive Rhomboid 1 (iRhom1)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA119.011136"}], "href": "https://doi.org/10.1074/jbc.RA119.011136"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32060096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32060096"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Johanna Tüshaus, Stephan A Müller, Joshua Shrouder, et al. 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