{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNEDD8 is a ubiquitin‐like modifier that plays a pivotal role in regulating the activity of cullin–RING ligases (CRLs) by covalently attaching to cullin subunits. This modification triggers striking conformational rearrangements that destabilize inhibitory interactions (e.g. with CAND1) and re‐position key domains, thereby converting CRLs from inactive “closed” states into dynamic, catalytically competent assemblies capable of efficient polyubiquitination of substrates. Such conformational control not only facilitates substrate recruitment but also optimizes the spatial geometry required for E2 enzyme engagement and ubiquitin transfer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe NEDD8 conjugation cascade is initiated by a dedicated heterodimeric E1 enzyme that adenylates NEDD8 and transfers it via specific E2 and E3 enzymes. Structural and mutational studies have uncovered bipartite interfaces and selectivity determinants within these enzymes that not only ensure the preferential activation of NEDD8 over ubiquitin but also prevent cross‐reactivity between these pathways—guaranteeing fidelity during the conjugation process."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in CRL regulation, NEDD8 modifies a growing list of non‐cullin substrates, thereby influencing diverse signaling networks. For instance, NEDD8 conjugation has been shown to modulate the activity of transcription factors such as p53 (through FBXO11‐mediated neddylation), affect receptor sorting and turnover (e.g. EGFR and TGF‐β receptor), and control the stability of ribosomal proteins—all of which impact cellular proliferation, differentiation, and stress signaling. Moreover, NEDD8 modification can interplay with other post‐translational marks to fine‑tune the function and localization of key regulatory proteins."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUnder conditions of cellular stress—such as DNA damage, oxidative insult, or proteasome inhibition—the neddylation pathway is dynamically modulated to rewire multiple signaling cascades. NEDD8 influences the processing of NF‑κB precursors, stabilizes hypoxia‑inducible factors, and regulates the recruitment of cofactors (for example, through interactions with p97 complexes), as well as modulating chromatin states via histone modification. These adaptive changes have critical implications for tumor progression and responsiveness to therapeutic agents, and pharmacological inhibition of NEDD8‐activating enzymes is emerging as a promising anticancer strategy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have expanded our understanding of NEDD8’s multifaceted functions, revealing its deregulation in various cancers and its interplay with other ubiquitin‐like modifiers. These insights collectively underscore NEDD8’s role as a versatile regulator of protein stability, subcellular localization, and signal transduction, making it an attractive target for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jidong Liu, Manabu Furukawa, Tomohiro Matsumoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1097-2765(02)00783-9"}], "href": "https://doi.org/10.1016/s1097-2765(02"}, {"type": "t", "text": "00783-9) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12504025"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12504025"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kenneth Wu, Kosj Yamoah, Georgia Dolios, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DEN1 is a dual function protease capable of processing the C terminus of Nedd8 and deconjugating hyper-neddylated CUL1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M302888200"}], "href": "https://doi.org/10.1074/jbc.M302888200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12759363"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12759363"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "David M Duda, Laura A Borg, Daniel C Scott, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2008.07.022"}], "href": "https://doi.org/10.1016/j.cell.2008.07.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18805092"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18805092"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Anjanabha Saha, Raymond J Deshaies "}, {"type": "b", "children": [{"type": "t", "text": "Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2008.08.021"}], "href": "https://doi.org/10.1016/j.molcel.2008.08.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18851830"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18851830"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Alexander Y Kim, Claire C Bommeljé, Benjamin E Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SCCRO (DCUN1D1) is an essential component of the E3 complex for neddylation."}]}, {"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.M804440200"}], "href": "https://doi.org/10.1074/jbc.M804440200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18826954"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18826954"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Daniel C Scott, Vladislav O Sviderskiy, Julie K Monda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2014.04.037"}], "href": "https://doi.org/10.1016/j.cell.2014.04.037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24949976"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24949976"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sarah V Faull, Andy M C Lau, Chloe Martens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-019-11772-y"}], "href": "https://doi.org/10.1038/s41467-019-11772-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31444342"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31444342"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kheewoong Baek, David T Krist, J Rajan Prabu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-020-2000-y"}], "href": "https://doi.org/10.1038/s41586-020-2000-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32051583"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32051583"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ruthie E Amir, Kazuhiro Iwai, Aaron Ciechanover "}, {"type": "b", "children": [{"type": "t", "text": "The NEDD8 pathway is essential for SCF(beta -TrCP)-mediated ubiquitination and processing of the NF-kappa B precursor p105."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M200967200"}], "href": "https://doi.org/10.1074/jbc.M200967200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11953428"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11953428"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Helen Walden, Michael S Podgorski, Brenda A Schulman "}, {"type": "b", "children": [{"type": "t", "text": "Insights into the ubiquitin transfer cascade from the structure of the activating enzyme for NEDD8."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature01456"}], "href": "https://doi.org/10.1038/nature01456"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12646924"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12646924"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Helen Walden, Michael S Podgorski, Danny T Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1097-2765(03)00452-0"}], "href": "https://doi.org/10.1016/s1097-2765(03"}, {"type": "t", "text": "00452-0) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14690597"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14690597"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Danny T Huang, Amir Paydar, Min Zhuang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for recruitment of Ubc12 by an E2 binding domain in NEDD8's E1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2004.12.020"}], "href": "https://doi.org/10.1016/j.molcel.2004.12.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15694336"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15694336"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yu Ye, Masato Akutsu, Francisca Reyes-Turcu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polyubiquitin binding and cross-reactivity in the USP domain deubiquitinase USP21."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/embor.2011.17"}], "href": "https://doi.org/10.1038/embor.2011.17"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21399617"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21399617"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Keita Noguchi, Fumihiko Okumura, Norihiko Takahashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM40 promotes neddylation of IKKγ and is downregulated in gastrointestinal cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Carcinogenesis (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/carcin/bgr068"}], "href": "https://doi.org/10.1093/carcin/bgr068"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21474709"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21474709"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Shlomo Oved, Yaron Mosesson, Yaara Zwang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases."}]}, {"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.M513034200"}], "href": "https://doi.org/10.1074/jbc.M513034200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16735510"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16735510"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Gil Bornstein, Dvora Ganoth, Avram Hershko "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of neddylation and deneddylation of cullin1 in SCFSkp2 ubiquitin ligase by F-box protein and substrate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0603921103"}], "href": "https://doi.org/10.1073/pnas.0603921103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16861300"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16861300"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Wassim M Abida, Anatoly Nikolaev, Wenhui Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M609001200"}], "href": "https://doi.org/10.1074/jbc.M609001200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17098746"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17098746"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Anabela Ferro, Ana Luísa Carvalho, Andreia Teixeira-Castro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDD8: a new ataxin-3 interactor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2007.07.012"}], "href": "https://doi.org/10.1016/j.bbamcr.2007.07.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17935801"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17935801"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Dimitris P Xirodimas, Anders Sundqvist, Akihiro Nakamura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ribosomal proteins are targets for the NEDD8 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/embor.2008.10"}], "href": "https://doi.org/10.1038/embor.2008.10"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18274552"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18274552"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Anders Sundqvist, Geng Liu, Antonis Mirsaliotis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of nucleolar signalling to p53 through NEDDylation of L11."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/embor.2009.178"}], "href": "https://doi.org/10.1038/embor.2009.178"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19713960"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19713960"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "I R Watson, B K Li, O Roche, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chemotherapy induces NEDP1-mediated destabilization of MDM2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2009.314"}], "href": "https://doi.org/10.1038/onc.2009.314"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19784069"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19784069"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Ji-Hye Ryu, Shan-Hua Li, Hyoung-Sook Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hypoxia-inducible factor α subunit stabilization by NEDD8 conjugation is reactive oxygen species-dependent."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.188706"}], "href": "https://doi.org/10.1074/jbc.M110.188706"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21193393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21193393"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Ian R Watson, Meredith S Irwin, Michael Ohh "}, {"type": "b", "children": [{"type": "t", "text": "NEDD8 pathways in cancer, Sine Quibus Non."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccr.2011.01.002"}], "href": "https://doi.org/10.1016/j.ccr.2011.01.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21316600"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21316600"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "B Mahata, A Sundqvist, D P Xirodimas "}, {"type": "b", "children": [{"type": "t", "text": "Recruitment of RPL11 at promoter sites of p53-regulated genes upon nucleolar stress through NEDD8 and in an Mdm2-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2011.482"}], "href": "https://doi.org/10.1038/onc.2011.482"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22081073"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22081073"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Wei Zuo, Fei Huang, Y Jeffrey Chiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-β type II receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2012.12.002"}], "href": "https://doi.org/10.1016/j.molcel.2012.12.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23290524"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23290524"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Aravinth Kumar Jayabalan, Anthony Sanchez, Ra Young Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDDylation promotes stress granule assembly."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms12125"}], "href": "https://doi.org/10.1038/ncomms12125"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27381497"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27381497"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Ruthie E Amir, Hans Haecker, Michael Karin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanism of processing of the NF-kappa B2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF(beta-TrCP) ubiquitin ligase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1207366"}], "href": "https://doi.org/10.1038/sj.onc.1207366"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14676825"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14676825"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Jixin Cui, Qing Yao, Shan Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1193844"}], "href": "https://doi.org/10.1126/science.1193844"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20688984"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20688984"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Willem den Besten, Rati Verma, Gary Kleiger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb.2269"}], "href": "https://doi.org/10.1038/nsmb.2269"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22466964"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22466964"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Ethan D Emberley, Ruzbeh Mosadeghi, Raymond J Deshaies "}, {"type": "b", "children": [{"type": "t", "text": "Deconjugation of Nedd8 from Cul1 is directly regulated by Skp1-F-box and substrate, and the COP9 signalosome inhibits deneddylated SCF by a noncatalytic mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.352484"}], "href": "https://doi.org/10.1074/jbc.M112.352484"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22767593"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22767593"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Teng Ma, Yibin Chen, Feng Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNF111-dependent neddylation activates DNA damage-induced ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2013.01.006"}], "href": "https://doi.org/10.1016/j.molcel.2013.01.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23394999"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23394999"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Qiang Gao, Guang-Yang Yu, Jie-Yi Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neddylation pathway is up-regulated in human intrahepatic cholangiocarcinoma and serves as a potential therapeutic target."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.2309"}], "href": "https://doi.org/10.18632/oncotarget.2309"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25229838"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25229838"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Yanchun Wang, Zhongguang Luo, Yongfu Pan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting protein neddylation with an NEDD8-activating enzyme inhibitor MLN4924 induced apoptosis or senescence in human lymphoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15384047.2014.1003003"}], "href": "https://doi.org/10.1080/15384047.2014.1003003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25782162"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25782162"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Ping Xie, Jun-Ping Yang, Yun Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Promoting tumorigenesis in nasopharyngeal carcinoma, NEDD8 serves as a potential theranostic target."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2017.195"}], "href": "https://doi.org/10.1038/cddis.2017.195"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28569775"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28569775"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Lisha Zhou, Yanyu Jiang, Xiaojun Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Promotion of tumor-associated macrophages infiltration by elevated neddylation pathway via NF-κB-CCL2 signaling in lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-019-0840-4"}], "href": "https://doi.org/10.1038/s41388-019-0840-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31243299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31243299"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Meiyun Fan, Robert M Bigsby, Kenneth P Nephew "}, {"type": "b", "children": [{"type": "t", "text": "The NEDD8 pathway is required for proteasome-mediated degradation of human estrogen receptor (ER)-alpha and essential for the antiproliferative activity of ICI 182,780 in ERalpha-positive breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2002-0323"}], "href": "https://doi.org/10.1210/me.2002-0323"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12554766"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12554766"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Zeynep Tokgöz, Thomas J Siepmann, Frederick Streich, et al. "}, {"type": "b", "children": [{"type": "t", "text": "E1-E2 interactions in ubiquitin and Nedd8 ligation pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.294975"}], "href": "https://doi.org/10.1074/jbc.M111.294975"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22069333"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22069333"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "J Zhang, D Bai, X Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "hCINAP is a novel regulator of ribosomal protein-HDM2-p53 pathway by controlling NEDDylation of ribosomal protein S14."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2012.560"}], "href": "https://doi.org/10.1038/onc.2012.560"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23246961"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23246961"}]}]}]}