{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNEDD4, as a member of the HECT‐domain E3 ubiquitin ligase family, plays a pivotal role in tumorigenesis by modulating the stability of key tumor suppressors and oncoproteins. In cancer cells, enhanced expression of NEDD4‐1 induces polyubiquitination and degradation of the phosphatase PTEN, thereby lowering PTEN levels and promoting cellular transformation and tumor progression. Moreover, aberrant NEDD4 activity has been linked to glioma development through FoxM1B‐mediated NEDD4‐1 upregulation, and genetic studies associate NEDD4 polymorphisms with fibroproliferative disorders such as keloids. NEDD4 also modifies other tumor‐suppressive regulators including Beclin 1, further underscoring its role in reprogramming signaling pathways that favor neoplastic growth."}, {"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 various cell types, NEDD4 and its close paralogue NEDD4‐2 regulate the trafficking, membrane expression, and signaling of critical receptors and ion channels. For instance, NEDD4‐2 negatively regulates the cardiac Na⁺ channel Na_v1.5 and neuronal Na⁺ channels via binding to PY motifs, whereas it modulates the epithelial Na⁺ channel (ENaC) in epithelia—processes that influence cellular excitability and fluid homeostasis. In addition, NEDD4 facilitates beta₂‐adrenergic receptor ubiquitination in cooperation with adaptor proteins, controls dopamine transporter endocytosis following PKC activation, and catalyzes non‐canonical ubiquitination of fibroblast growth factor receptor 1 (FGFR1), hence modulating receptor signaling and downstream Akt trafficking. Such multifaceted regulatory roles highlight NEDD4’s central action in receptor turnover and signal termination."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNEDD4 functions as a key mediator in cellular stress responses. In conditions of oxidative or genotoxic stress, its expression is upregulated to promote ubiquitination events that enable appropriate turnover of damaged proteins. For example, upon erastin‐treatment—a ferroptosis activator—NEDD4 is induced to ubiquitinate voltage‐dependent anion channels, thereby modulating mitochondrial homeostasis. In response to UV‐induced DNA damage, NEDD4 associates with RNA polymerase II to target it for ubiquitin‐dependent degradation, a process central to the DNA damage response. In these settings, calcium signaling can relieve intrinsic autoinhibition of NEDD4, further fine‐tuning its ubiquitination activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}, {"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, NEDD4 contributes to protein quality control and synaptic plasticity. It promotes the ubiquitination of α‐synuclein through K63‐linked chains, facilitating its lysosomal clearance—a mechanism that may protect against Parkinson disease. Similarly, NEDD4‐mediated ubiquitination of AMPA receptors controls their internalization and stability, thereby modulating excitatory synaptic transmission. These regulatory mechanisms are crucial for maintaining neuronal homeostasis and preventing proteotoxic stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNEDD4 is also co‐opted by viruses to facilitate different stages of their life cycles. In Ebola virus infection, NEDD4 ubiquitinates the VP40 matrix protein to promote virus‐like particle budding—a process counteracted by antiviral molecules such as ISG15. Retroviruses including HTLV‐1 hijack NEDD4‐1 for Gag ubiquitination to ensure efficient egress, while hepatitis B virus employs NEDD4 to orchestrate its assembly and release. Moreover, NEDD4‐dependent ubiquitination of IFITM3 modulates its turnover, thereby impacting host resistance to influenza virus infection."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther insights into the mechanistic aspects of NEDD4 function have emerged from structural and developmental studies. High‐resolution analyses of the Ub‐loaded NEDD4 elucidate a sequential addition mechanism governed by Lys63‐specific polyubiquitin chain formation, while intramolecular linker regions have been shown to mediate autoinhibition that can be relieved upon post‐translational modifications. In addition, NEDD4 (and its paralogue NEDD4L) regulates developmental processes by targeting receptors such as the LGR family in intestinal stem cells; such regulation of receptor turnover is critical for controlling stem cell priming and may affect tumor predisposition. Moreover, in lung cancer cells, NEDD4 influences EGFR‐dependent migration, emphasizing its diverse roles in both intracellular trafficking and cell motility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xinjiang Wang, Lloyd C Trotman, Theresa Koppie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2006.11.039"}], "href": "https://doi.org/10.1016/j.cell.2006.11.039"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17218260"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17218260"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mitsuko Nakashima, Suyoun Chung, Atsushi Takahashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.645"}], "href": "https://doi.org/10.1038/ng.645"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20711176"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20711176"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Harald W Platta, Hilde Abrahamsen, Sigrid B Thoresen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20111424"}], "href": "https://doi.org/10.1042/BJ20111424"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21936852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21936852"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nicola Amodio, Marianna Scrima, Lucia Palaia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oncogenic role of the E3 ubiquitin ligase NEDD4-1, a PTEN negative regulator, in non-small-cell lung carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/ajpath.2010.091075"}], "href": "https://doi.org/10.2353/ajpath.2010.091075"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20889565"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20889565"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Natasha Anne Boase, Sharad Kumar "}, {"type": "b", "children": [{"type": "t", "text": "NEDD4: The founding member of a family of ubiquitin-protein ligases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2014.12.020"}], "href": "https://doi.org/10.1016/j.gene.2014.12.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25527121"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25527121"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Bingbing Dai, Russell O Pieper, Dawei Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FoxM1B regulates NEDD4-1 expression, leading to cellular transformation and full malignant phenotype in immortalized human astrocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-3909"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-3909"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20332230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20332230"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Miguel X van Bemmelen, Jean-Sébastien Rougier, Bruno Gavillet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.RES.0000136816.05109.89"}], "href": "https://doi.org/10.1161/01.RES.0000136816.05109.89"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15217910"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15217910"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sudha K Shenoy, Kunhong Xiao, Vidya Venkataramanan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M709668200"}], "href": "https://doi.org/10.1074/jbc.M709668200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18544533"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18544533"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Tatiana Sorkina, Manuel Miranda, Kalen R Dionne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNA interference screen reveals an essential role of Nedd4-2 in dopamine transporter ubiquitination and endocytosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.1301-06.2006"}], "href": "https://doi.org/10.1523/JNEUROSCI.1301-06.2006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16885233"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16885233"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Peter M Snyder, Jennifer C Steines, Diane R Olson "}, {"type": "b", "children": [{"type": "t", "text": "Relative contribution of Nedd4 and Nedd4-2 to ENaC regulation in epithelia determined by RNA interference."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M312477200"}], "href": "https://doi.org/10.1074/jbc.M312477200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14645220"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14645220"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jean-Sébastien Rougier, Miguel X van Bemmelen, M Christine Bruce, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Cell Physiol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpcell.00460.2004"}], "href": "https://doi.org/10.1152/ajpcell.00460.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15548568"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15548568"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Joseph Murdaca, Caroline Treins, Marie-Noëlle Monthouël-Kartmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M311802200"}], "href": "https://doi.org/10.1074/jbc.M311802200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15060076"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15060076"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Jian Wang, Qisheng Peng, Qiong Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.086405"}], "href": "https://doi.org/10.1074/jbc.M109.086405"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20172859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20172859"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Chuan-Dong Fan, Michelle A Lum, Chao Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.416339"}], "href": "https://doi.org/10.1074/jbc.M112.416339"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23195959"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23195959"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Avinash Persaud, Philipp Alberts, Sara Mari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tyrosine phosphorylation of NEDD4 activates its ubiquitin ligase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2005290"}], "href": "https://doi.org/10.1126/scisignal.2005290"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25292214"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25292214"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Yongfei Yang, Meiying Luo, Kexin Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-020-14324-x"}], "href": "https://doi.org/10.1038/s41467-020-14324-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31974380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31974380"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Roy Anindya, Ozan Aygün, Jesper Q Svejstrup "}, {"type": "b", "children": [{"type": "t", "text": "Damage-induced ubiquitylation of human RNA polymerase II by the ubiquitin ligase Nedd4, but not Cockayne syndrome proteins or BRCA1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2007.10.008"}], "href": "https://doi.org/10.1016/j.molcel.2007.10.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17996703"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17996703"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "George K Tofaris, Hyoung Tae Kim, Raphael Hourez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitin ligase Nedd4 promotes alpha-synuclein degradation by the endosomal-lysosomal pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1109356108"}], "href": "https://doi.org/10.1073/pnas.1109356108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21953697"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21953697"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Amy Lin, Qingming Hou, Larissa Jarzylo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2011.07221.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2011.07221.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21338354"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21338354"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Atsushi Okumura, Paula M Pitha, Ronald N Harty "}, {"type": "b", "children": [{"type": "t", "text": "ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0710629105"}], "href": "https://doi.org/10.1073/pnas.0710629105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18305167"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18305167"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Oxana A Malakhova, Dong-Er Zhang "}, {"type": "b", "children": [{"type": "t", "text": "ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C800030200"}], "href": "https://doi.org/10.1074/jbc.C800030200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18287095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18287095"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Vincent Blot, Fabien Perugi, Bernard Gay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nedd4.1-mediated ubiquitination and subsequent recruitment of Tsg101 ensure HTLV-1 Gag trafficking towards the multivesicular body pathway prior to virus budding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.01095"}], "href": "https://doi.org/10.1242/jcs.01095"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15126635"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15126635"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Nicholas M Chesarino, Temet M McMichael, Jacob S Yount "}, {"type": "b", "children": [{"type": "t", "text": "E3 Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing Levels of the Antiviral Protein IFITM3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1005095"}], "href": "https://doi.org/10.1371/journal.ppat.1005095"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26263374"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26263374"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Martina Rost, Sylvia Mann, Carsten Lambert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gamma-adaptin, a novel ubiquitin-interacting adaptor, and Nedd4 ubiquitin ligase control hepatitis B virus maturation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M603517200"}], "href": "https://doi.org/10.1074/jbc.M603517200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16867982"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16867982"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Elena Maspero, Eleonora Valentini, Sara Mari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb.2566"}], "href": "https://doi.org/10.1038/nsmb.2566"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23644597"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23644597"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Youngshil Pak, Wioletta K Glowacka, M Christine Bruce, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transport of LAPTM5 to lysosomes requires association with the ubiquitin ligase Nedd4, but not LAPTM5 ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200603001"}], "href": "https://doi.org/10.1083/jcb.200603001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17116753"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17116753"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Zan Chen, Hanjie Jiang, Wei Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Tunable Brake for HECT Ubiquitin Ligases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2017.03.020"}], "href": "https://doi.org/10.1016/j.molcel.2017.03.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28475870"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28475870"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Zhi-Wei Wang, Xiaoli Hu, Miaomiao Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDD4 E3 ligase: Functions and mechanism in human cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Semin Cancer Biol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.semcancer.2020.03.006"}], "href": "https://doi.org/10.1016/j.semcancer.2020.03.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32171886"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32171886"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Sara Mari, Natalia Ruetalo, Elena Maspero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural and functional framework for the autoinhibition of Nedd4-family ubiquitin ligases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2014.09.006"}], "href": "https://doi.org/10.1016/j.str.2014.09.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25438670"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25438670"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Laura Novellasdemunt, Anna Kucharska, Cara Jamieson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.2019102771"}], "href": "https://doi.org/10.15252/embj.2019102771"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31867777"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31867777"}]}]}]}