{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n LNX2 is an evolutionarily conserved E3 ubiquitin ligase that functions as a signaling scaffold to regulate the stability and localization of key modulators in diverse cellular contexts. In colorectal cancer, for example, overexpression and amplification of LNX2 result in downregulation of the Notch inhibitor Numb, thereby constitutively activating both Notch and WNT pathways to promote tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In bone biology, LNX2 has been shown to be up‐regulated during osteoclast differentiation; its ubiquitin ligase activity reduces Numb accumulation, which in turn stabilizes Notch1 and supports proper activation of downstream signaling during osteoclastogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In the nervous system, LNX2 interacts with the intracellular tail of the coxsackievirus and adenovirus receptor (CAR) as well as with neural adhesion molecules such as Caspr4, thereby influencing neural progenitor cell differentiation and synaptic organization. Moreover, studies in mice lacking both LNX1 and LNX2 report altered synaptic composition and reduced anxiety‐related behavior, implicating these proteins in the modulation of neuronal signaling and gap junction dynamics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": " In the immune compartment, LNX2 plays a role in regulating T‐cell function by binding to the CD8α co‐receptor, promoting its ubiquitination and subsequent lysosomal degradation, which may influence immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " LNX2 is also targeted by pathogens; the PDZ-binding motif of the SARS-CoV-2 envelope protein interacts with LNX2, suggesting that viruses may hijack LNX2-dependent pathways to perturb cell polarity and signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Finally, genetic association studies have identified variants within the LNX2 locus that correlate with traits as diverse as weight gain in beef cattle and increased susceptibility to diffuse large B-cell lymphoma, underscoring its multifaceted role in cellular signaling networks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jordi Camps, Jason J Pitt, Georg Emons, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic amplification of the NOTCH modulator LNX2 upregulates the WNT/β-catenin pathway in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-12-3159"}], "href": "https://doi.org/10.1158/0008-5472.CAN-12-3159"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23319804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23319804"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jian Zhou, Toshifumi Fujiwara, Shiqiao Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitin E3 Ligase LNX2 is Critical for Osteoclastogenesis In Vitro by Regulating M-CSF/RANKL Signaling and Notch2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Calcif Tissue Int (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00223-015-9967-7"}], "href": "https://doi.org/10.1007/s00223-015-9967-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25712254"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25712254"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Momina Mirza, Elisabeth Raschperger, Lennart Philipson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The cell surface protein coxsackie- and adenovirus receptor (CAR) directly associates with the Ligand-of-Numb Protein-X2 (LNX2)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2005.05.023"}], "href": "https://doi.org/10.1016/j.yexcr.2005.05.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15979067"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15979067"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Feng-Ting Yin, Toshitaka Futagawa, Di Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Caspr4 interaction with LNX2 modulates the proliferation and neuronal differentiation of mouse neural progenitor cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells Dev (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/scd.2014.0261"}], "href": "https://doi.org/10.1089/scd.2014.0261"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25279559"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25279559"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Joan A Lenihan, Orthis Saha, Victoria Heimer-McGinn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Neurobiol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12035-016-0261-0"}], "href": "https://doi.org/10.1007/s12035-016-0261-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27889896"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27889896"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Massimo D'Agostino, Giusy Tornillo, Maria Gabriella Caporaso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ligand of Numb proteins LNX1p80 and LNX2 interact with the human glycoprotein CD8α and promote its ubiquitylation and endocytosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.081224"}], "href": "https://doi.org/10.1242/jcs.081224"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22045731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22045731"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yanlei Zhu, Flavio Alvarez, Nicolas Wolff, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interactions of Severe Acute Respiratory Syndrome Coronavirus 2 Protein E With Cell Junctions and Polarity PSD-95/Dlg/ZO-1-Containing Proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Microbiol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fmicb.2022.829094"}], "href": "https://doi.org/10.3389/fmicb.2022.829094"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35283834"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35283834"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "M H A Santana, R C Gomes, Y T Utsunomiya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide association with residual body weight gain in Bos indicus cattle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Mol Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4238/2015.May.18.14"}], "href": "https://doi.org/10.4238/2015.May.18.14"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26125717"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26125717"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Vinod Kumar, Keitaro Matsuo, Atsushi Takahashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common variants on 14q32 and 13q12 are associated with DLBCL susceptibility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hum Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/jhg.2011.35"}], "href": "https://doi.org/10.1038/jhg.2011.35"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21471979"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21471979"}]}]}]}