{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CBLL2 appears to belong to a family of E3 ubiquitin ligases that regulate key cellular processes by targeting specific substrates for ubiquitination. For example, proteins with similar domain architectures—including a zinc‐coordinating or RING finger domain and specialized phosphotyrosine binding regions—mediate the ubiquitination and subsequent turnover of cell adhesion molecules such as E‐cadherin. In doing so, they influence cell–cell contacts and contribute to the regulation of epithelial–mesenchymal transition and tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, members of this protein family with structural resemblance to c‐Cbl, such as the testis‐specific zinc finger protein ZNF645, have been shown to exhibit intrinsic E3 ubiquitin ligase activity. Their expression profiles—tightly controlled by mechanisms including promoter demethylation—suggest roles in specialized processes like spermatogenesis and cellular quality control in germ cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Thus, by orchestrating the ubiquitination of substrates involved in cell adhesion, signaling, and tissue‐specific functions, CBLL2 and related proteins emerge as key regulators of both normal physiology and pathologic conditions, including cancer progression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Manjeet Mukherjee, Soah Yee Chow, Permeen Yusoff, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of a novel phosphotyrosine-binding domain in Hakai that targets E-cadherin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.496"}], "href": "https://doi.org/10.1038/emboj.2011.496"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22252131"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22252131"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Luis A Aparicio, Manuel Valladares, Moisés Blanco, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biological influence of Hakai in cancer: a 10-year review."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Metastasis Rev (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10555-012-9348-x"}], "href": "https://doi.org/10.1007/s10555-012-9348-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22349934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22349934"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yun-Qiang Liu, Gang Bai, Hao Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human RING finger protein ZNF645 is a novel testis-specific E3 ubiquitin ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Asian J Androl (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/aja.2010.54"}], "href": "https://doi.org/10.1038/aja.2010.54"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20657603"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20657603"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Gang Bai, Yunqiang Liu, Hao Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Promoter demethylation mediates the expression of ZNF645, a novel cancer/testis gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMB Rep (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.5483/bmbrep.2010.43.6.400"}], "href": "https://doi.org/10.5483/bmbrep.2010.43.6.400"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20587329"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20587329"}]}]}]}