{"gene":"NDRG1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"Cap43/NDRG1 expression is specifically induced by Ni2+ compounds via elevation of free intracellular Ca2+; induction was attenuated by intracellular Ca2+ chelation and mimicked by calcium ionophores, establishing Ca2+ as the primary intracellular signal for nickel-mediated Cap43 induction.","method":"mRNA differential display, pharmacological manipulation (Ca2+ ionophores, BAPTA-AM chelator, okadaic acid), Northern blot in multiple human/rodent cell lines and rat organs","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal pharmacological approaches in single lab establishing the Ca2+ signaling mechanism","pmids":["9605764"],"is_preprint":false},{"year":1997,"finding":"TDD5/NDRG1 mRNA expression is differentially repressed by testosterone and dihydrotestosterone (DHT) at the mRNA level in androgen-responsive cells, with testosterone showing preferential repression over DHT.","method":"mRNA differential display PCR (DDPCR), Northern blot, in vivo animal DHT administration studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DDPCR and Northern blot with in vivo confirmation, single lab","pmids":["9144177"],"is_preprint":false},{"year":2004,"finding":"NDRG1 is a p53-regulated gene induced by DNA damage in a p53-dependent manner; the NDRG1 promoter contains a p53 binding site conferring p53-dependent transcriptional activation. NDRG1 is necessary but not sufficient for p53-mediated caspase activation and apoptosis.","method":"Promoter-reporter assay, RNA interference (RNAi), inducible gene expression, caspase activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (promoter assay, RNAi, inducible expression) in single rigorous study establishing p53-NDRG1 pathway","pmids":["15377670"],"is_preprint":false},{"year":2004,"finding":"Hypoxic induction of NDRG1 is predominantly dependent on the HIF-1 transcription factor, but HIF-1-independent pathways also contribute during chronic hypoxia. Nickel compounds likely induce NDRG1 by interacting with the oxygen-sensing pathway.","method":"Hypoxia mimetics treatment, HIF-1 knockout cells, Western blot, in vitro expression assays","journal":"BMC genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — HIF-1 KO cells and hypoxia mimetics, single lab, two orthogonal methods","pmids":["15341671"],"is_preprint":false},{"year":2004,"finding":"Nickel compounds induce HIF-1 transactivation and Cap43/NDRG1 protein expression through a PI3K/Akt-dependent and p70S6k-independent signaling pathway.","method":"Dominant-negative PI3K and Akt mutant overexpression, rapamycin inhibition, Western blot, HIF-1 transactivation assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — dominant-negative mutants plus pharmacological inhibition with multiple readouts in single rigorous study","pmids":["14729612"],"is_preprint":false},{"year":2001,"finding":"Ni(II) and Cu(II) bind to the C-terminal 10-amino acid repeat domain of Cap43/NDRG1 (sequence TRSRSHTSEG) via the imidazole nitrogen of histidine residues, forming octahedral and square planar complexes.","method":"pH-metric and spectroscopic analyses (UV-VIS, EPR, CD, NMR) of synthetic peptide","journal":"Journal of inorganic biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with multiple orthogonal spectroscopic methods defining metal-binding mode","pmids":["11330481"],"is_preprint":false},{"year":2004,"finding":"Ni(II) binds to two or three sites on the 20- and 30-amino acid C-terminal repeat fragments of Cap43/NDRG1 respectively, with each Ni(II) ion coordinated to the histidine imidazole of each 10-amino acid repeat unit.","method":"pH-metric titration, UV-visible spectroscopy, CD, NMR of synthetic peptide fragments","journal":"Journal of inorganic biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods on reconstituted peptide, extends prior metal-binding finding","pmids":["15149799"],"is_preprint":false},{"year":2003,"finding":"VHL tumor suppressor specifically downregulates Cap43/NDRG1 expression through an Sp1 site in the promoter region (−286 to −62 bp) of the Cap43 gene in renal cancer cells.","method":"VHL transfection into VHL-negative cells, Cap43 promoter deletion/mutation reporter assays, Western blot, Northern blot","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter mutagenesis plus VHL gain-of-function and multiple cell lines establishing VHL→Sp1→Cap43 pathway","pmids":["12767066"],"is_preprint":false},{"year":2013,"finding":"NDRG1 binds and stabilizes MGMT (O6-methylguanine-DNA methyltransferase), conferring resistance to alkylating chemotherapy. NDRG1 is an mTORC2/SGK1 pathway target induced by hypoxia, irradiation, corticosteroids, and alkylating agents.","method":"Co-immunoprecipitation (NDRG1-MGMT interaction), NDRG1 knockdown/overexpression, mTORC2/SGK1 pathway analysis, patient tissue analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing NDRG1-MGMT interaction, functional validation with KD, patient tissue correlation","pmids":["24367102"],"is_preprint":false},{"year":2009,"finding":"NDRG1/Cap43 suppresses NF-κB signaling by decreasing IKKβ expression, reducing IκBα phosphorylation, and blocking nuclear translocation of p65/p50, thereby attenuating expression of CXC chemokines (CXCL1, CXCL5, IL-8) and VEGF-A; exogenous IKKβ rescues these effects.","method":"Stable overexpression, IKKβ rescue transfection, NF-κB reporter assays, ChIP, immunoblot, xenograft mouse models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis by IKKβ rescue, ChIP, reporter assays and in vivo validation in single rigorous study","pmids":["19491262"],"is_preprint":false},{"year":2010,"finding":"Phosphorylation of NDRG1/Cap43 by SGK1 at both Ser330 and Thr346 (but not individually) in the C-terminal domain (aa 326–394) is required for suppression of NF-κB signaling and CXC chemokine (CXCL1, CXCL5) expression in pancreatic cancer cells.","method":"Deletion constructs, site-directed mutagenesis of Ser/Thr residues, stable expression, ELISA for chemokines, IκBα phosphorylation assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis of phosphorylation sites combined with functional chemokine suppression assays","pmids":["20416281"],"is_preprint":false},{"year":2011,"finding":"NDRG1 is phosphorylated by SGK1 and GSK3β in a cell-cycle-dependent manner; phosphorylated NDRG1 co-localizes with γ-tubulin at centromeres and at the cleavage furrow during cytokinesis, suggesting a role in mitosis.","method":"Cell cycle synchronization (aphidicolin, nocodazole), immunofluorescence co-localization with γ-tubulin, p53-proficient vs. deficient HCT116 cells, phospho-specific antibodies","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional implication, single lab, two orthogonal methods","pmids":["21708134"],"is_preprint":false},{"year":2013,"finding":"NDRG1 silencing in epithelial cells reduces LDL receptor (LDLR) abundance at the plasma membrane by causing LDLR accumulation in enlarged EEA1-positive endosomes with increased LDLR ubiquitylation; co-depletion of IDOL (E3 ligase) rescues LDLR at the plasma membrane, identifying NDRG1 as a regulator of multivesicular body formation and endosomal LDLR trafficking.","method":"siRNA silencing, confocal microscopy, LDLR ubiquitylation assays, co-depletion (NDRG1 + IDOL), LDL uptake assays, murine oligodendrocyte studies","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-depletion epistasis with mechanistic readouts (ubiquitylation, endosome morphology, LDL uptake) across multiple cell types","pmids":["23813961"],"is_preprint":false},{"year":2005,"finding":"NDRG1 physically interacts with apolipoproteins A-I and A-II (confirmed by yeast two-hybrid and mammalian cell co-immunoprecipitation), suggesting a role in Schwann cell lipid/cholesterol trafficking; the HMSNL founder mutation R148X is associated with decreased HDL-C levels.","method":"Yeast two-hybrid screening, reciprocal co-immunoprecipitation in mammalian cells, biochemical lipid analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus mammalian Co-IP confirming interaction, single lab","pmids":["15922294"],"is_preprint":false},{"year":2011,"finding":"NDRG1 promotes metastasis suppression through the ATF3/NF-κB/KAI1 transcriptional cascade: NDRG1 expression suppresses ATF3, which normally represses KAI1 through ATF3-NFκB co-repressor complex. Knockdown of KAI1 abrogates NDRG1-mediated metastasis suppression in vitro and in vivo.","method":"ChIP analysis of ATF3 binding to KAI1 promoter, stable NDRG1 overexpression/silencing, KAI1 promoter reporter assays, in vivo spontaneous metastasis animal model, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, reporter assays, in vivo epistasis with multiple orthogonal methods in single study","pmids":["21454613"],"is_preprint":false},{"year":2015,"finding":"NDRG1 physically associates with γ-tubulin (centrosome component) and regulates centrosome number and amplification downstream of p53 in low-proliferative states; NDRG1 loss leads to centrosome amplification and genomic instability.","method":"Co-immunoprecipitation (NDRG1-γ-tubulin), RNAi and overexpression in isogenic TP53 WT/null/mutant cells, centrosome counting, genomic analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of NDRG1-γ-tubulin, isogenic cell lines, multiple orthogonal readouts","pmids":["26324937"],"is_preprint":false},{"year":2015,"finding":"NDRG1 is post-translationally modified by SUMO-2 predominantly at Lys14; SUMO-2 modification influences NDRG1 protein stability (a SUMO-2 fused NDRG1 K14R mutant shows dramatically decreased stability) without affecting subcellular distribution. SUMO-2-fused NDRG1 K14R also downregulates p21 expression.","method":"SUMO modification assays, NDRG1 mutant (K14R) construction, protein stability assays, subcellular fractionation, Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct SUMO modification with mutagenesis and stability assays, single lab","pmids":["25712528"],"is_preprint":false},{"year":2015,"finding":"Ndrg1 is an anergy factor in T cells induced by the transcription factor Egr2; Ndrg1 is phosphorylated and degraded via the proteasome upon CD28 costimulation and IL-2 treatment; Ndrg1-deficient T cells fail to become anergic and show hyperresponsiveness.","method":"Ndrg1 knockout mice, Ndrg1 overexpression, proteasome inhibitor treatment, T-cell anergy induction assays, autoimmune inflammation models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus overexpression with multiple functional readouts and mechanistic proteasome-dependent degradation established","pmids":["26507712"],"is_preprint":false},{"year":2007,"finding":"NDRG1 deficiency in mice impairs mast cell maturation and degranulation: Ndrg1-knockout mast cells show defective exocytosis (degranulation) after FcεRI crosslinking under CTMC-like maturation conditions, while leukotriene and cytokine production are unaffected.","method":"Ndrg1 knockout mouse, ex vivo bone marrow-derived mast cell (BMMC) co-culture with fibroblasts, FcεRI crosslinking assay, IgE-mediated anaphylaxis models","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined in vivo and ex vivo phenotypes and mechanistic specificity (degranulation vs. cytokine production)","pmids":["17513753"],"is_preprint":false},{"year":2006,"finding":"17β-estradiol (E2) decreases Cap43/NDRG1 expression dose-dependently through an estrogen receptor-α (ERα)-dependent pathway; overexpression of ERα in ER-negative cell lines is sufficient to downregulate Cap43, and anti-estrogens reverse this effect.","method":"Real-time PCR, immunoblotting, ERα cDNA transfection in ER-negative lines, anti-estrogen (tamoxifen, ICI 182780) treatment","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function ERα plus pharmacological reversal, single lab, two orthogonal methods","pmids":["16707596"],"is_preprint":false},{"year":2007,"finding":"p53-dependent NDRG1 expression (induced by polyamine depletion) inhibits intestinal epithelial cell proliferation (DNA synthesis and cell number) without inducing apoptosis; NDRG1 overexpression inhibits growth regardless of endogenous p53, and p53-binding sites in the NDRG1 proximal promoter mediate this induction.","method":"p53 siRNA, p53 knockout cells, NDRG1 promoter deletion analysis, ectopic ODC overexpression, DNA synthesis assay, flow cytometry, TNF-α/cycloheximide apoptosis assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter mutagenesis, genetic KO, and overexpression with multiple orthogonal readouts in single study","pmids":["17442733"],"is_preprint":false},{"year":2013,"finding":"HIF-1α binds directly to the NDRG1 promoter (critical region −1202 to −450) to activate NDRG1 expression, and NDRG1 overexpression promotes proliferation and reduces apoptosis in A549 lung cancer cells.","method":"Promoter cloning and reporter assay, HIF-1α CDS overexpression, stable NDRG1 transfection, MTT assay, colony formation, flow cytometry","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — promoter reporter with defined binding region, single lab","pmids":["23526365"],"is_preprint":false},{"year":2013,"finding":"SGK1 phosphorylates NDRG1 at serine/threonine sites; phospho-NDRG1 is increased in Alzheimer's disease brain tissue (~2-fold), suggesting augmented SGK1 activity targeting NDRG1 in AD.","method":"Immunoblot with phospho-specific NDRG1 antibody (SGK1-specific target), human post-mortem brain tissue analysis","journal":"Neuropathology and applied neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (phospho-immunoblot in tissue), no direct kinase assay performed in this paper","pmids":["23363009"],"is_preprint":false},{"year":2017,"finding":"NDRG1 inhibits EGFR/HER2 and HER2/HER3 heterodimer formation and promotes EGFR degradation, thereby attenuating ErbB oncogenic signaling.","method":"Co-immunoprecipitation, NDRG1 overexpression/knockdown, receptor dimerization assays, Western blot for receptor degradation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of receptor dimers plus functional degradation assay, single lab","pmids":["28615452"],"is_preprint":false},{"year":2019,"finding":"GSK3β phosphorylates serine and threonine residues in the C-terminal domain of NDRG1 and reduces NDRG1 protein stability. Conversely, NDRG1 overexpression decreases GSK3β levels via proteasomal degradation and suppresses AKT/S6 and cell-cycle signaling, revealing a bidirectional regulatory loop.","method":"GSK3β inhibitor treatment, NDRG1 overexpression/knockdown, proteasome inhibitor assays, Western blot for pathway targets, in vivo xenograft models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional epistasis with pharmacological and genetic tools, single lab","pmids":["31723002"],"is_preprint":false},{"year":2021,"finding":"NDRG1 promotes interaction of the androgen receptor (AR) with chaperone HSP90, stabilizing AR while decreasing its androgen-mediated activation; NDRG1 also suppresses AR transcriptional activity partly by inhibiting c-Jun-AR interaction via reduced c-Jun phosphorylation. The CAP domain of NDRG1 is identified as vital for inhibition of AR activity.","method":"Co-immunoprecipitation (AR-HSP90), NDRG1 overexpression/knockdown, CAP-domain deletion mutants, AR transcriptional reporter assay, PSA expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, functional reporter assay, and patient specimen correlation","pmids":["34785213"],"is_preprint":false},{"year":2021,"finding":"Crystal structure of the α/β hydrolase domain of human NDRG1 was determined (PDB: 6ZMM); full-length NDRG1 has a flexible N- and C-terminal region; NDRG1 binds to lipid vesicles with conformational changes in the C-terminal region; NDRG1 interacts with metal ions (e.g., nickel) but aggregates in their presence.","method":"X-ray crystallography (PDB 6ZMM), small-angle X-ray scattering (SAXS), CD spectroscopy, lipid vesicle binding assays","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus SAXS and functional lipid-binding assays with multiple orthogonal methods","pmids":["33305529"],"is_preprint":false},{"year":2017,"finding":"NDRG1 loss disrupts the binding between RhoGDIα and CDC42, triggering CDC42 activation and downstream PAK1/Cofilin signaling, promoting filopodia formation and colorectal cancer invasiveness.","method":"NDRG1 silencing/overexpression, CDC42 activity assay (pull-down), Co-IP (RhoGDIα-CDC42), Western blot for PAK1/Cofilin, in vivo metastasis model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and activity assay establishing mechanism, single lab","pmids":["33994856"],"is_preprint":false},{"year":2017,"finding":"NDRG1 deficiency reduces active RhoA and Rac1 GTPases while upregulating active Cdc42; NDRG1-deficient prostate cancer cells have restricted actin dynamics (measured by fluorescent polymerized-actin sensor), reduced integrin expression and adhesion, increased EMMPRIN expression with altered glycosylation, increased matrix metalloproteases, and collective invasion phenotype.","method":"NDRG1 KD, Rho GTPase activity assays, live-cell fluorescent actin imaging (FRAP), EMMPRIN glycosylation analysis, 3D invasion assay, in vivo xenograft metastasis assay","journal":"Molecular oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell imaging plus GTPase activity assays plus in vivo validation with multiple mechanistic readouts","pmids":["28371345"],"is_preprint":false},{"year":2021,"finding":"NDRG1 enhances cetuximab (EGFR antibody) sensitivity in colorectal cancer by reducing EGFR expression, blocking EGFR phosphorylation, reducing EGFR at the cell membrane, and attenuating endocytosis/degradation of EGFR induced by caveolin-1 (Cav1).","method":"NDRG1 overexpression/knockdown, EGFR distribution analysis (membrane/cytoplasm/nuclear fractions), caveolin-1 co-immunoprecipitation, in vivo xenograft and patient tissue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation and Co-IP with in vivo validation, single lab","pmids":["34385595"],"is_preprint":false},{"year":2020,"finding":"NDRG1 forms a complex with PLCγ1 through its phosphorylation sites and is required for VEGF-A-induced PLCγ1 and ERK1/2 activation in endothelial cells; Ndrg1-knockout mice display impaired VEGF-A-induced corneal angiogenesis and reduced aortic sprouting.","method":"Co-immunoprecipitation (NDRG1-PLCγ1), Ndrg1 knockout mice, corneal angiogenesis assay, aortic ring sprouting assay, Western blot for PLCγ1/ERK activation, dorsal air sac assay","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of NDRG1-PLCγ1 complex, genetic KO with multiple in vivo angiogenesis assays","pmids":["32144393"],"is_preprint":false},{"year":2022,"finding":"NDRG1 interacts with the orphan nuclear receptor Nur77 and functionally inhibits Nur77 transcriptional activity and NF-κB activity in endothelial cells; NDRG1 knockdown attenuates cytokine-induced MAPK activation, c-Jun phosphorylation, and AP-1 transcriptional activity. Endothelial cell-specific NDRG1 knockout mice show reduced neointima formation, atherosclerosis, and arterial thrombosis.","method":"Co-immunoprecipitation (NDRG1-Nur77), lentiviral shRNA knockdown, endothelial-specific NDRG1 KO mice, carotid artery ligation model, Nur77/NF-κB reporter assays, Western blot","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of NDRG1-Nur77, genetic KO with multiple in vivo vascular models, reporter assays","pmids":["36562299"],"is_preprint":false},{"year":2023,"finding":"Fasting or lipid availability activates mTORC2, which phosphorylates NDRG1 at Ser336; phosphorylated NDRG1 engages mitochondria and facilitates mitochondrial fission by cooperating with CDC42 and its effectors/regulators. The phosphorylation-deficient NDRG1-Ser336Ala mutant fails to support fission.","method":"Time-lapse imaging of NDRG1-mitochondria interaction, phospho-deficient mutant (NDRG1-S336A), siRNA screen, epistasis with DRP1-KO cells, proteomics, CDC42 co-immunoprecipitation, RictorKO and Cdc42-KO phenotyping","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — phospho-deficient mutant, live imaging, epistasis experiments, proteomics and multiple KO models in one rigorous study","pmids":["37386153"],"is_preprint":false},{"year":2019,"finding":"NDRG1 directly interacts with MIG6 (a tumor suppressor/EGFR regulator) and regulates c-Cbl E3 ligase activity as part of its mechanism for inhibiting receptor tyrosine kinases.","method":"Co-immunoprecipitation (NDRG1-MIG6), NDRG1 overexpression studies","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP reported in review context, limited mechanistic follow-up described in abstract","pmids":["34572031"],"is_preprint":false},{"year":2017,"finding":"MNK1 (but not MNK2) signaling regulates NDRG1 phosphorylation; however, MNK1 cannot directly phosphorylate NDRG1 in vitro, indicating an indirect mechanism. MNK inhibition increases NDRG1 protein and mRNA expression. SGK1 phosphorylates MNK1 at a conserved site to repress its activity.","method":"MNK1/2 knockout cells, in vitro kinase assay (MNK1 vs. NDRG1), MNK inhibitors, SGK1 kinase assay on MNK1, Western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay (yielding negative direct result) plus genetic KO cells and SGK1 phosphorylation of MNK1 established","pmids":["28545025"],"is_preprint":false},{"year":2019,"finding":"NDRG1 regulates all three main arms of the ER stress response: increases ER chaperone expression (BiP, calreticulin, calnexin), suppresses PERK and IRE1α arms, and increases ATF6 cleavage. In the presence of anti-cancer agent Dp44mT, NDRG1 markedly increases eIF2α activation, maintains ATF4, elevates cytosolic Ca2+, and increases pro-apoptotic CHOP.","method":"NDRG1 overexpression/knockdown in pancreatic and colon cancer cells, Western blot for ER stress markers, Ca2+ measurement, confocal microscopy","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple ER stress arm readouts with NDRG1 gain/loss of function, single lab","pmids":["30981813"],"is_preprint":false},{"year":2019,"finding":"NDRG1 facilitates KSHV genome replication and episome persistence by interacting directly with PCNA (proliferating cell nuclear antigen) and forming a ternary complex with LANA (viral latent protein) and PCNA, bridging LANA to PCNA at viral terminal repeats (TRs) to facilitate viral DNA replication.","method":"Co-immunoprecipitation (NDRG1-PCNA, LANA-NDRG1-PCNA complex), NDRG1 knockdown in KSHV-infected cells, viral genome copy number assay, chromatin immunoprecipitation of PCNA at viral TRs","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of ternary complex, ChIP at viral TRs, KD with viral genome copy number readout","pmids":["30811506"],"is_preprint":false},{"year":2020,"finding":"NDRG1 suppresses autophagy at both the initiation stage and autolysosome formation (reducing LC3-LAMP2 co-localization, increasing p62); NDRG1 expression decreases cholesterol levels (independent of AMPK), sensitizing lysosomes to membrane permeabilization.","method":"NDRG1 overexpression/knockdown, confocal microscopy (LC3/LAMP2 co-localization), p62 Western blot, cholesterol determination, acridine orange staining for LMP, AMPK phosphorylation assays","journal":"Biochimica et biophysica acta. General subjects","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal readouts for autophagy stages, single lab","pmids":["32335136"],"is_preprint":false},{"year":2018,"finding":"NDRG1 regulates neutral lipid metabolism and lipid droplet formation in breast cancer cells; NDRG1 silencing increases fatty acid incorporation into neutral lipids and lipid droplets, while NDRG1 expression minimizes lipid droplet formation under both nutrient-replete and starvation conditions.","method":"NDRG1 silencing/overexpression, comprehensive lipidomics mass spectrometry, labeled fatty acid tracking, high-throughput quantitative microscopy, multiple breast cancer cell lines","journal":"Breast cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive lipidomics plus labeled fatty acid tracking plus quantitative microscopy in multiple cell lines","pmids":["29898756"],"is_preprint":false},{"year":2017,"finding":"Ndrg1 promotes adipocyte differentiation by inducing PPARγ expression and is required for C/EBPα phosphorylation; SGK1-dependent phosphorylation of Ndrg1 is induced during adipogenesis and promotes adipocyte formation.","method":"Ndrg1 knockdown/overexpression in adipocyte precursor cells, PPARγ and C/EBPα Western blot, adipogenesis differentiation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss of function with mechanistic downstream targets, single lab","pmids":["28775290"],"is_preprint":false},{"year":2024,"finding":"NSUN6-mediated m5C methylation of NDRG1 mRNA enhances its stability via the m5C reader ALYREF; elevated NDRG1 expression promotes homologous recombination-mediated DNA repair, contributing to radioresistance in cervical cancer.","method":"Integrated m5C sequencing, mRNA sequencing, RNA immunoprecipitation, NSUN6 overexpression/silencing, CDX and 3D PDO models, in vivo xenograft","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — integrated m5C-seq with RIP and functional validation in organoid and in vivo models","pmids":["38970106"],"is_preprint":false},{"year":2021,"finding":"c-Jun, AR (androgen receptor), and DNMT1 form a complex at TRE regions of the NDRG1 promoter and suppress NDRG1 transcription through DNA hypermethylation; N-cadherin promotes c-Jun expression to suppress NDRG1, establishing an N-cadherin/c-Jun/NDRG1 axis in prostate cancer progression.","method":"Co-immunoprecipitation (c-Jun/AR/DNMT1 complex), ChIP at NDRG1 promoter TRE region, bisulfite sequencing for promoter methylation, NDRG1 knockdown/overexpression, in vivo xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and methylation analysis in single study, single lab","pmids":["34512147"],"is_preprint":false},{"year":2022,"finding":"KDM1A (LSD1) histone demethylase represses NDRG1 expression; de-repression of NDRG1 by KDM1A inhibition causes inhibition of Wnt signaling and G1 cell cycle arrest in gastric cancer patient-derived organoids.","method":"CRISPR/Cas9 viability screen in patient-derived organoids, KDM1A genetic and pharmacological inhibition, NDRG1 expression measurement, cell cycle analysis, Wnt signaling assays","journal":"Small methods","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus pharmacological validation in PDOs with pathway readouts, single lab","pmids":["36908010"],"is_preprint":false},{"year":2022,"finding":"Ndrg1a in zebrafish binds to the sodium-potassium ATPase (NKA) pump under anoxia and is required for NKA degradation, preserving ATP in kidney and ionocytes during hypoxia; sodium azide (which increases lactate) triggers NKA degradation in an Ndrg1a-dependent manner.","method":"Ndrg1a knockout zebrafish, co-immunoprecipitation (Ndrg1a-NKA), sodium azide treatment, anoxia survival assays, kidney function assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with Co-IP and mechanistic rescue in zebrafish, ortholog of mammalian NDRG1","pmids":["36214665"],"is_preprint":false},{"year":2023,"finding":"MAOA interacts with NDRG1 and together they regulate glycolysis (Warburg effect) through suppression of the PI3K/AKT/mTOR pathway in gastric cancer.","method":"Co-immunoprecipitation (MAOA-NDRG1), Seahorse assay for glycolysis, Western blot for PI3K/AKT/mTOR pathway, overexpression/knockdown studies","journal":"Cellular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up described in abstract, single lab","pmids":["37249744"],"is_preprint":false},{"year":2018,"finding":"HER4 interacts with NDRG1 in osteosarcoma cells; NDRG1 overexpression antagonizes HER4 knockdown-mediated cell growth inhibition and apoptosis under stress conditions.","method":"Co-immunoprecipitation (HER4-NDRG1), shRNA knockdown of HER4, NDRG1 overexpression rescue assay, immunohistochemistry","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with functional rescue, single lab, limited mechanistic detail","pmids":["29524631"],"is_preprint":false},{"year":2024,"finding":"NDRG1 inhibits ATG9A-dependent lysosomal-autophagy degradation of MHC class I (MHC-1) in pancreatic ductal adenocarcinoma cells, maintaining MHC-1 surface expression; elevated NDRG1 promotes CD8+ T cell infiltration and overcomes immune checkpoint blockade resistance.","method":"NDRG1 knockdown/overexpression, autophagy inhibitor studies, co-immunoprecipitation (NDRG1-ATG9A pathway), flow cytometry for MHC-1 and T cells, in vivo orthotopic mouse models, multiplex immunofluorescence","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation, inhibitor epistasis and in vivo validation, single lab","pmids":["38228036"],"is_preprint":false},{"year":2025,"finding":"NDRG1 stabilizes LDHA by inhibiting its ubiquitination, thereby enhancing glycolysis and promoting lactate accumulation in lung adenocarcinoma; histone H2B K58 lactylation at the NDRG1 locus (mediated by LDHA-generated lactate) represents an epigenetic feedback mechanism.","method":"NDRG1 knockdown/overexpression, ubiquitination assay (LDHA ubiquitylation), Seahorse glycolysis assay, lactate measurement, histone lactylation ChIP","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and functional metabolic readouts, single lab","pmids":["40539245"],"is_preprint":false},{"year":2016,"finding":"NDRG1 physically associates with TLE2 and β-catenin to activate Wnt/β-catenin signaling in esophageal squamous cell carcinoma, promoting EMT; TLE2 overexpression prevents NDRG1-driven Wnt pathway activation.","method":"Co-immunoprecipitation (NDRG1-TLE2, NDRG1-β-catenin), stable lentiviral overexpression, RNAi, TLE2 overexpression epistasis, Western blot for EMT markers","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP with limited mutational/structural follow-up, single lab","pmids":["27414086"],"is_preprint":false},{"year":2020,"finding":"NDRG1 binds directly to PI3K (co-immunoprecipitation) in placental JEG-3 cells; NDRG1 knockdown upregulates PI3K and AKT expression, identifying PI3K/AKT as a downstream mechanism of NDRG1-mediated suppression of angiogenesis.","method":"Co-immunoprecipitation (NDRG1-PI3K), lentiviral NDRG1 overexpression/knockdown, ELISA for PLGF/sFlt-1, Western blot for PI3K/AKT/VEGF, tube formation assay","journal":"Pregnancy hypertension","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP without mutagenesis or structural validation, single lab","pmids":["32470876"],"is_preprint":false},{"year":2022,"finding":"In triple-negative breast cancer, YAP1 positively regulates NDRG1 transcription by binding the NDRG1 promoter; HJURP affects YAP1 ubiquitination and degradation, thereby modulating NDRG1 expression via the HJURP/YAP1/NDRG1 axis.","method":"YAP1 ChIP at NDRG1 promoter, ubiquitination assay (YAP1), HJURP knockdown/overexpression, Western blot, cell proliferation and chemosensitivity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and ubiquitination assay, single lab","pmids":["35459269"],"is_preprint":false},{"year":2011,"finding":"NDRG1/Cap43 overexpression in hepatocellular carcinoma cells induces G0/G1 cell cycle arrest accompanied by increased p21 and decreased CDK4 expression both in vitro and in vivo.","method":"Stable NDRG1 transfection, cell cycle analysis (flow cytometry), Western blot for p21/CDK4, in vivo xenograft tumor growth, mimosine-induced G0/G1 block","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable overexpression with cell cycle, molecular markers, and in vivo validation in two HCC lines","pmids":["21775055"],"is_preprint":false},{"year":2009,"finding":"NDRG1 regulates endothelial cell migration under intermittent hypoxia: siRNA silencing of NDRG1 decreases endothelial cell migration under intermittent hypoxia (as identified by 2D-DIGE proteomics and confirmed by siRNA).","method":"2D-DIGE proteomics, mass spectrometry protein identification, siRNA knockdown, endothelial cell migration assay","journal":"Angiogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA knockdown with single migration assay readout, single lab","pmids":["19760510"],"is_preprint":false},{"year":2022,"finding":"PTK7 (a membrane-localized pseudokinase) interacts with and stabilizes NDRG1 adjacent to adherens junctions; downregulation of either PTK7 or NDRG1 eliminates AZD9291 resistance in NSCLC cells.","method":"BioID proximal labeling (BirA*-PTK7), Co-immunoprecipitation (PTK7-NDRG1), knockdown/overexpression, phospho- and proximal proteomics","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID proximity labeling plus Co-IP establishing PTK7-NDRG1 interaction, single lab","pmids":["36205702"],"is_preprint":false}],"current_model":"NDRG1 is a stress-responsive, iron-regulated metastasis suppressor that functions as a multi-pathway signaling disruptor: it is transcriptionally induced by p53, HIF-1α, and hypoxia (among other stimuli) and post-translationally regulated by SGK1/mTORC2-mediated phosphorylation (at C-terminal Ser/Thr residues), SUMO-2 modification (at Lys14), proteasomal degradation (downstream of CD28/IL-2 in T cells), and NSUN6-mediated m5C mRNA methylation; structurally, it possesses an α/β hydrolase fold domain with a disordered C-terminus containing three 10-amino acid metal-binding repeats that bind Ni(II)/Cu(II) via histidine imidazole coordination; mechanistically, NDRG1 directly binds PLCγ1 to support VEGF-A-induced angiogenesis, associates with PCNA and LANA to support viral DNA replication, interacts with γ-tubulin to maintain centrosome homeostasis, stabilizes HSP90-AR complexes to dampen androgen receptor signaling, binds apolipoproteins A-I/A-II to regulate lipid trafficking, attenuates NF-κB signaling by reducing IKKβ expression (requiring phosphorylation at both Ser330 and Thr346), stabilizes MGMT to confer alkylating drug resistance, inhibits EGFR/HER2/HER3 dimerization and degradation, disrupts RhoGDIα-CDC42 binding to control actin dynamics, and—upon mTORC2-mediated phosphorylation at Ser336—cooperates with CDC42 to orchestrate mitochondrial fission during fasting."},"narrative":{"mechanistic_narrative":"NDRG1 is a stress- and metal-responsive signaling scaffold that integrates transcriptional and post-translational inputs to suppress oncogenic signaling, regulate metabolism, and maintain cellular homeostasis [PMID:15377670, PMID:11330481, PMID:28371345]. It is transcriptionally induced through multiple stress-sensing axes: p53 binds the proximal promoter to drive expression upon DNA damage and growth arrest [PMID:15377670, PMID:17442733], HIF-1 mediates hypoxic induction via a defined promoter element [PMID:15341671, PMID:23526365], and Ni(II) acts through a Ca2+/PI3K-Akt-HIF route [PMID:9605764, PMID:14729612], while VHL, ERα, androgen, and KDM1A repress it [PMID:12767066, PMID:16707596, PMID:34512147, PMID:36908010]. Structurally, NDRG1 adopts an α/β hydrolase fold with flexible N- and C-terminal regions that bind lipid vesicles, and a C-terminal 10-residue repeat domain coordinates Ni(II)/Cu(II) through histidine imidazole nitrogens [PMID:11330481, PMID:15149799, PMID:33305529]. Its activity is gated by C-terminal Ser/Thr phosphorylation: SGK1 (and GSK3β) phosphorylation at Ser330/Thr346 is required to attenuate NF-κB signaling by lowering IKKβ and blocking p65/p50 nuclear translocation [PMID:19491262, PMID:20416281, PMID:31723002], and mTORC2-dependent Ser336 phosphorylation directs NDRG1 to mitochondria where it cooperates with CDC42 to drive fission during fasting [PMID:37386153]. As a metastasis suppressor it acts through an ATF3/NF-κB/KAI1 cascade and restrains cytoskeletal remodeling by preserving RhoGDIα–CDC42 binding to limit CDC42/PAK1/Cofilin-driven invasion [PMID:21454613, PMID:33994856, PMID:28371345]. NDRG1 also dampens receptor tyrosine kinase signaling by inhibiting EGFR/HER2/HER3 dimerization and promoting EGFR degradation [PMID:28615452, PMID:34385595], stabilizes the AR–HSP90 complex to suppress androgen receptor transactivation [PMID:34785213], binds PLCγ1 to support VEGF-A-induced angiogenesis [PMID:32144393], and controls lipid handling through endosomal LDLR trafficking, lipid-droplet limitation, and apolipoprotein A-I/A-II association [PMID:23813961, PMID:15922294, PMID:29898756]. Additional roles span DNA-repair-linked drug resistance via MGMT stabilization and NSUN6/ALYREF-controlled mRNA stability promoting homologous recombination [PMID:24367102, PMID:38970106], centrosome homeostasis through γ-tubulin association [PMID:21708134, PMID:26324937], immune regulation as an Egr2-induced T-cell anergy factor and a determinant of mast-cell degranulation [PMID:26507712, PMID:17513753], and ER-stress and autophagy modulation [PMID:30981813, PMID:32335136, PMID:38228036]. Apolipoprotein binding links NDRG1 to Schwann-cell lipid trafficking, consistent with the HMSNL-associated R148X founder mutation [PMID:15922294].","teleology":[{"year":1998,"claim":"Established the upstream signal that drives NDRG1 induction, showing it is a metal- and Ca2+-responsive gene rather than constitutively expressed.","evidence":"mRNA differential display with Ca2+ ionophores and chelators across human/rodent cells","pmids":["9605764"],"confidence":"Medium","gaps":["Did not connect Ca2+ signal to a specific transcription factor","Functional consequence of induction not addressed"]},{"year":2004,"claim":"Placed NDRG1 transcription under defined stress transcription factors, linking it to the p53 DNA-damage program and the HIF-1/oxygen-sensing pathway.","evidence":"Promoter-reporter, RNAi, inducible expression, HIF-1 knockout cells, and dominant-negative PI3K/Akt in cancer cell lines","pmids":["15377670","15341671","14729612","12767066"],"confidence":"High","gaps":["How p53 vs HIF inputs are integrated at a single promoter is unresolved","VHL→Sp1 repression mechanism not linked to protein function"]},{"year":2001,"claim":"Defined the structural basis of NDRG1 metal binding, showing histidine imidazole coordination of Ni(II)/Cu(II) in the C-terminal repeats.","evidence":"pH-metric and spectroscopic (UV-VIS, EPR, CD, NMR) analysis of synthetic repeat peptides","pmids":["11330481","15149799"],"confidence":"High","gaps":["Physiological role of metal binding by full-length protein unclear","Peptide studies do not capture intact-protein context"]},{"year":2009,"claim":"Identified the core anti-inflammatory/anti-metastatic mechanism: NDRG1 suppresses NF-κB by reducing IKKβ and requires dual C-terminal phosphorylation by SGK1.","evidence":"Overexpression with IKKβ rescue, site-directed Ser330/Thr346 mutagenesis, reporter/ChIP assays and xenografts","pmids":["19491262","20416281"],"confidence":"High","gaps":["Direct mechanism by which NDRG1 lowers IKKβ expression not defined","Whether phosphorylation creates a binding surface unknown"]},{"year":2011,"claim":"Linked NDRG1 to mitosis and genome stability through phosphorylation-dependent centrosome localization and γ-tubulin association.","evidence":"Cell-cycle synchronization with γ-tubulin co-localization and Co-IP in isogenic TP53 cells","pmids":["21708134","26324937"],"confidence":"High","gaps":["Molecular function of NDRG1 at the centrosome undefined","Direct vs indirect γ-tubulin interaction not resolved"]},{"year":2011,"claim":"Established the transcriptional output of NDRG1-mediated metastasis suppression via the ATF3/NF-κB/KAI1 axis.","evidence":"ChIP of ATF3 at KAI1 promoter, reporter assays, KAI1 knockdown epistasis, in vivo metastasis models","pmids":["21454613"],"confidence":"High","gaps":["How NDRG1 suppresses ATF3 mechanistically is unclear"]},{"year":2017,"claim":"Defined NDRG1 control of cytoskeletal dynamics, showing it preserves RhoGDIα–CDC42 binding to restrain invasive actin remodeling.","evidence":"CDC42 pull-down, RhoGDIα-CDC42 Co-IP, live-cell actin imaging and in vivo metastasis assays","pmids":["33994856","28371345"],"confidence":"High","gaps":["Direct binding partner of NDRG1 within the RhoGDIα-CDC42 complex not identified"]},{"year":2017,"claim":"Extended NDRG1 to immune regulation as an Egr2-induced, proteasome-degraded T-cell anergy factor and a mast-cell degranulation determinant.","evidence":"Ndrg1 knockout mice, proteasome inhibition, anergy and FcεRI degranulation assays","pmids":["26507712","17513753"],"confidence":"High","gaps":["Molecular targets of NDRG1 enforcing anergy unknown","Degranulation defect mechanism not defined"]},{"year":2013,"claim":"Connected NDRG1 to therapy resistance and lipid trafficking, stabilizing MGMT and regulating endosomal LDLR sorting.","evidence":"Reciprocal Co-IP (NDRG1-MGMT), IDOL co-depletion epistasis, LDLR ubiquitylation and uptake assays","pmids":["24367102","23813961"],"confidence":"High","gaps":["How NDRG1 mechanistically promotes MVB formation unclear","Whether MGMT stabilization is direct not fully resolved"]},{"year":2020,"claim":"Established NDRG1 as an angiogenic signaling adaptor by direct PLCγ1 binding required for VEGF-A responses.","evidence":"NDRG1-PLCγ1 Co-IP, Ndrg1 knockout mice, corneal/aortic angiogenesis assays","pmids":["32144393"],"confidence":"High","gaps":["Phosphosite-dependence of the PLCγ1 interaction not mapped"]},{"year":2021,"claim":"Defined NDRG1 suppression of androgen receptor signaling via AR–HSP90 stabilization and CAP-domain dependence.","evidence":"AR-HSP90 Co-IP, CAP-domain deletion mutants, AR reporter and PSA assays","pmids":["34785213"],"confidence":"High","gaps":["Structural basis of CAP domain action on AR unknown"]},{"year":2021,"claim":"Provided the structural model of NDRG1, defining the α/β hydrolase fold and lipid-binding flexible termini.","evidence":"X-ray crystallography (PDB 6ZMM), SAXS, CD and lipid vesicle binding","pmids":["33305529"],"confidence":"High","gaps":["Catalytic activity of the hydrolase fold, if any, not demonstrated","Aggregation with metals leaves physiological metal role unresolved"]},{"year":2023,"claim":"Revealed a metabolic membrane-remodeling function: mTORC2 phosphorylates NDRG1 at Ser336 to drive CDC42-dependent mitochondrial fission during fasting.","evidence":"Live imaging, S336A mutant, DRP1/Rictor/Cdc42 KO epistasis, proteomics and CDC42 Co-IP","pmids":["37386153"],"confidence":"High","gaps":["How phospho-NDRG1 physically engages the fission machinery is not fully defined"]},{"year":2024,"claim":"Linked NDRG1 mRNA stability to DNA repair and immune evasion through NSUN6/ALYREF m5C methylation and ATG9A-dependent MHC-I control.","evidence":"m5C-seq with RIP and HR repair assays; autophagy inhibitor epistasis with MHC-I/T-cell readouts in vivo","pmids":["38970106","38228036"],"confidence":"High","gaps":["Direct HR repair role of NDRG1 protein vs transcriptional consequence not separated","Mechanism of ATG9A pathway inhibition incomplete"]},{"year":null,"claim":"The biochemical activity of the conserved α/β hydrolase fold and the unifying mechanism by which a single scaffold coordinates NF-κB, RTK, cytoskeletal, metabolic and trafficking outputs remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No catalytic substrate identified for the hydrolase fold","No structure of full-length phosphorylated NDRG1 with a partner","Whether the many reported interactions share a common binding determinant is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[30,25,36,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,23,27,25]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[26,38,13]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[32,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[12]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[32]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[11,15]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[36,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,30,23,27]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,8,40]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[38,32,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,18,46]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,35,43]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[12,37]}],"complexes":[],"partners":["MGMT","PLCG1","AR","HSP90","PCNA","TUBG1","CDC42","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92597","full_name":"Protein NDRG1","aliases":["Differentiation-related gene 1 protein","DRG-1","N-myc downstream-regulated gene 1 protein","Nickel-specific induction protein Cap43","Reducing agents and tunicamycin-responsive protein","RTP","Rit42"],"length_aa":394,"mass_kda":42.8,"function":"Stress-responsive protein involved in hormone responses, cell growth, and differentiation. Acts as a tumor suppressor in many cell types. Necessary but not sufficient for p53/TP53-mediated caspase activation and apoptosis. Has a role in cell trafficking, notably of the Schwann cell, and is necessary for the maintenance and development of the peripheral nerve myelin sheath. Required for vesicular recycling of CDH1 and TF. May also function in lipid trafficking. Protects cells from spindle disruption damage. Functions in p53/TP53-dependent mitotic spindle checkpoint. Regulates microtubule dynamics and maintains euploidy","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Nucleus; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q92597/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NDRG1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"DRG1","ensg_id":"ENSG00000185721","cell_line_id":"CID001617","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"SLC7A5","stoichiometry":10.0},{"gene":"ATP1A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001617","total_profiled":1310},"omim":[{"mim_id":"614463","title":"NMYC DOWNSTREAM-REGULATED GENE 4; NDRG4","url":"https://www.omim.org/entry/614463"},{"mim_id":"605273","title":"NMYC DOWNSTREAM-REGULATED GENE 3; NDRG3","url":"https://www.omim.org/entry/605273"},{"mim_id":"605272","title":"NMYC DOWNSTREAM-REGULATED GENE 2; NDRG2","url":"https://www.omim.org/entry/605272"},{"mim_id":"605262","title":"NMYC DOWNSTREAM-REGULATED GENE 1; NDRG1","url":"https://www.omim.org/entry/605262"},{"mim_id":"601455","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4D; CMT4D","url":"https://www.omim.org/entry/601455"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Connecting piece","reliability":"Supported"},{"location":"Mid piece","reliability":"Supported"},{"location":"Principal piece","reliability":"Supported"},{"location":"End piece","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NDRG1"},"hgnc":{"alias_symbol":["DRG1","RTP","TDD5","NDR1"],"prev_symbol":["CAP43"]},"alphafold":{"accession":"Q92597","domains":[{"cath_id":"3.40.50.1820","chopping":"33-313","consensus_level":"high","plddt":92.4352,"start":33,"end":313}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92597","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92597-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92597-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NDRG1","jax_strain_url":"https://www.jax.org/strain/search?query=NDRG1"},"sequence":{"accession":"Q92597","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92597.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92597/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92597"}},"corpus_meta":[{"pmid":"9605764","id":"PMC_9605764","title":"Cap43, a novel gene specifically induced by Ni2+ compounds.","date":"1998","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9605764","citation_count":212,"is_preprint":false},{"pmid":"15377670","id":"PMC_15377670","title":"NDRG1 is necessary for p53-dependent apoptosis.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15377670","citation_count":187,"is_preprint":false},{"pmid":"12432451","id":"PMC_12432451","title":"Expression of NDRG1, a differentiation-related gene, in human tissues.","date":"2002","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12432451","citation_count":173,"is_preprint":false},{"pmid":"16920733","id":"PMC_16920733","title":"The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer.","date":"2006","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/16920733","citation_count":171,"is_preprint":false},{"pmid":"24367102","id":"PMC_24367102","title":"mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24367102","citation_count":154,"is_preprint":false},{"pmid":"15341671","id":"PMC_15341671","title":"Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers.","date":"2004","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15341671","citation_count":154,"is_preprint":false},{"pmid":"16778198","id":"PMC_16778198","title":"Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis.","date":"2006","source":"Cancer 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NDRG1 is necessary but not sufficient for p53-mediated caspase activation and apoptosis.\",\n      \"method\": \"Promoter-reporter assay, RNA interference (RNAi), inducible gene expression, caspase activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (promoter assay, RNAi, inducible expression) in single rigorous study establishing p53-NDRG1 pathway\",\n      \"pmids\": [\"15377670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Hypoxic induction of NDRG1 is predominantly dependent on the HIF-1 transcription factor, but HIF-1-independent pathways also contribute during chronic hypoxia. Nickel compounds likely induce NDRG1 by interacting with the oxygen-sensing pathway.\",\n      \"method\": \"Hypoxia mimetics treatment, HIF-1 knockout cells, Western blot, in vitro expression assays\",\n      \"journal\": \"BMC genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — HIF-1 KO cells and hypoxia mimetics, single lab, two orthogonal methods\",\n      \"pmids\": [\"15341671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nickel compounds induce HIF-1 transactivation and Cap43/NDRG1 protein expression through a PI3K/Akt-dependent and p70S6k-independent signaling pathway.\",\n      \"method\": \"Dominant-negative PI3K and Akt mutant overexpression, rapamycin inhibition, Western blot, HIF-1 transactivation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — dominant-negative mutants plus pharmacological inhibition with multiple readouts in single rigorous study\",\n      \"pmids\": [\"14729612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Ni(II) and Cu(II) bind to the C-terminal 10-amino acid repeat domain of Cap43/NDRG1 (sequence TRSRSHTSEG) via the imidazole nitrogen of histidine residues, forming octahedral and square planar complexes.\",\n      \"method\": \"pH-metric and spectroscopic analyses (UV-VIS, EPR, CD, NMR) of synthetic peptide\",\n      \"journal\": \"Journal of inorganic biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with multiple orthogonal spectroscopic methods defining metal-binding mode\",\n      \"pmids\": [\"11330481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ni(II) binds to two or three sites on the 20- and 30-amino acid C-terminal repeat fragments of Cap43/NDRG1 respectively, with each Ni(II) ion coordinated to the histidine imidazole of each 10-amino acid repeat unit.\",\n      \"method\": \"pH-metric titration, UV-visible spectroscopy, CD, NMR of synthetic peptide fragments\",\n      \"journal\": \"Journal of inorganic biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods on reconstituted peptide, extends prior metal-binding finding\",\n      \"pmids\": [\"15149799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"VHL tumor suppressor specifically downregulates Cap43/NDRG1 expression through an Sp1 site in the promoter region (−286 to −62 bp) of the Cap43 gene in renal cancer cells.\",\n      \"method\": \"VHL transfection into VHL-negative cells, Cap43 promoter deletion/mutation reporter assays, Western blot, Northern blot\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter mutagenesis plus VHL gain-of-function and multiple cell lines establishing VHL→Sp1→Cap43 pathway\",\n      \"pmids\": [\"12767066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NDRG1 binds and stabilizes MGMT (O6-methylguanine-DNA methyltransferase), conferring resistance to alkylating chemotherapy. NDRG1 is an mTORC2/SGK1 pathway target induced by hypoxia, irradiation, corticosteroids, and alkylating agents.\",\n      \"method\": \"Co-immunoprecipitation (NDRG1-MGMT interaction), NDRG1 knockdown/overexpression, mTORC2/SGK1 pathway analysis, patient tissue analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing NDRG1-MGMT interaction, functional validation with KD, patient tissue correlation\",\n      \"pmids\": [\"24367102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NDRG1/Cap43 suppresses NF-κB signaling by decreasing IKKβ expression, reducing IκBα phosphorylation, and blocking nuclear translocation of p65/p50, thereby attenuating expression of CXC chemokines (CXCL1, CXCL5, IL-8) and VEGF-A; exogenous IKKβ rescues these effects.\",\n      \"method\": \"Stable overexpression, IKKβ rescue transfection, NF-κB reporter assays, ChIP, immunoblot, xenograft mouse models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis by IKKβ rescue, ChIP, reporter assays and in vivo validation in single rigorous study\",\n      \"pmids\": [\"19491262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Phosphorylation of NDRG1/Cap43 by SGK1 at both Ser330 and Thr346 (but not individually) in the C-terminal domain (aa 326–394) is required for suppression of NF-κB signaling and CXC chemokine (CXCL1, CXCL5) expression in pancreatic cancer cells.\",\n      \"method\": \"Deletion constructs, site-directed mutagenesis of Ser/Thr residues, stable expression, ELISA for chemokines, IκBα phosphorylation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis of phosphorylation sites combined with functional chemokine suppression assays\",\n      \"pmids\": [\"20416281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NDRG1 is phosphorylated by SGK1 and GSK3β in a cell-cycle-dependent manner; phosphorylated NDRG1 co-localizes with γ-tubulin at centromeres and at the cleavage furrow during cytokinesis, suggesting a role in mitosis.\",\n      \"method\": \"Cell cycle synchronization (aphidicolin, nocodazole), immunofluorescence co-localization with γ-tubulin, p53-proficient vs. deficient HCT116 cells, phospho-specific antibodies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional implication, single lab, two orthogonal methods\",\n      \"pmids\": [\"21708134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NDRG1 silencing in epithelial cells reduces LDL receptor (LDLR) abundance at the plasma membrane by causing LDLR accumulation in enlarged EEA1-positive endosomes with increased LDLR ubiquitylation; co-depletion of IDOL (E3 ligase) rescues LDLR at the plasma membrane, identifying NDRG1 as a regulator of multivesicular body formation and endosomal LDLR trafficking.\",\n      \"method\": \"siRNA silencing, confocal microscopy, LDLR ubiquitylation assays, co-depletion (NDRG1 + IDOL), LDL uptake assays, murine oligodendrocyte studies\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-depletion epistasis with mechanistic readouts (ubiquitylation, endosome morphology, LDL uptake) across multiple cell types\",\n      \"pmids\": [\"23813961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NDRG1 physically interacts with apolipoproteins A-I and A-II (confirmed by yeast two-hybrid and mammalian cell co-immunoprecipitation), suggesting a role in Schwann cell lipid/cholesterol trafficking; the HMSNL founder mutation R148X is associated with decreased HDL-C levels.\",\n      \"method\": \"Yeast two-hybrid screening, reciprocal co-immunoprecipitation in mammalian cells, biochemical lipid analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus mammalian Co-IP confirming interaction, single lab\",\n      \"pmids\": [\"15922294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NDRG1 promotes metastasis suppression through the ATF3/NF-κB/KAI1 transcriptional cascade: NDRG1 expression suppresses ATF3, which normally represses KAI1 through ATF3-NFκB co-repressor complex. Knockdown of KAI1 abrogates NDRG1-mediated metastasis suppression in vitro and in vivo.\",\n      \"method\": \"ChIP analysis of ATF3 binding to KAI1 promoter, stable NDRG1 overexpression/silencing, KAI1 promoter reporter assays, in vivo spontaneous metastasis animal model, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, reporter assays, in vivo epistasis with multiple orthogonal methods in single study\",\n      \"pmids\": [\"21454613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NDRG1 physically associates with γ-tubulin (centrosome component) and regulates centrosome number and amplification downstream of p53 in low-proliferative states; NDRG1 loss leads to centrosome amplification and genomic instability.\",\n      \"method\": \"Co-immunoprecipitation (NDRG1-γ-tubulin), RNAi and overexpression in isogenic TP53 WT/null/mutant cells, centrosome counting, genomic analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of NDRG1-γ-tubulin, isogenic cell lines, multiple orthogonal readouts\",\n      \"pmids\": [\"26324937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NDRG1 is post-translationally modified by SUMO-2 predominantly at Lys14; SUMO-2 modification influences NDRG1 protein stability (a SUMO-2 fused NDRG1 K14R mutant shows dramatically decreased stability) without affecting subcellular distribution. SUMO-2-fused NDRG1 K14R also downregulates p21 expression.\",\n      \"method\": \"SUMO modification assays, NDRG1 mutant (K14R) construction, protein stability assays, subcellular fractionation, Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct SUMO modification with mutagenesis and stability assays, single lab\",\n      \"pmids\": [\"25712528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ndrg1 is an anergy factor in T cells induced by the transcription factor Egr2; Ndrg1 is phosphorylated and degraded via the proteasome upon CD28 costimulation and IL-2 treatment; Ndrg1-deficient T cells fail to become anergic and show hyperresponsiveness.\",\n      \"method\": \"Ndrg1 knockout mice, Ndrg1 overexpression, proteasome inhibitor treatment, T-cell anergy induction assays, autoimmune inflammation models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus overexpression with multiple functional readouts and mechanistic proteasome-dependent degradation established\",\n      \"pmids\": [\"26507712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NDRG1 deficiency in mice impairs mast cell maturation and degranulation: Ndrg1-knockout mast cells show defective exocytosis (degranulation) after FcεRI crosslinking under CTMC-like maturation conditions, while leukotriene and cytokine production are unaffected.\",\n      \"method\": \"Ndrg1 knockout mouse, ex vivo bone marrow-derived mast cell (BMMC) co-culture with fibroblasts, FcεRI crosslinking assay, IgE-mediated anaphylaxis models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined in vivo and ex vivo phenotypes and mechanistic specificity (degranulation vs. cytokine production)\",\n      \"pmids\": [\"17513753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"17β-estradiol (E2) decreases Cap43/NDRG1 expression dose-dependently through an estrogen receptor-α (ERα)-dependent pathway; overexpression of ERα in ER-negative cell lines is sufficient to downregulate Cap43, and anti-estrogens reverse this effect.\",\n      \"method\": \"Real-time PCR, immunoblotting, ERα cDNA transfection in ER-negative lines, anti-estrogen (tamoxifen, ICI 182780) treatment\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function ERα plus pharmacological reversal, single lab, two orthogonal methods\",\n      \"pmids\": [\"16707596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p53-dependent NDRG1 expression (induced by polyamine depletion) inhibits intestinal epithelial cell proliferation (DNA synthesis and cell number) without inducing apoptosis; NDRG1 overexpression inhibits growth regardless of endogenous p53, and p53-binding sites in the NDRG1 proximal promoter mediate this induction.\",\n      \"method\": \"p53 siRNA, p53 knockout cells, NDRG1 promoter deletion analysis, ectopic ODC overexpression, DNA synthesis assay, flow cytometry, TNF-α/cycloheximide apoptosis assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter mutagenesis, genetic KO, and overexpression with multiple orthogonal readouts in single study\",\n      \"pmids\": [\"17442733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HIF-1α binds directly to the NDRG1 promoter (critical region −1202 to −450) to activate NDRG1 expression, and NDRG1 overexpression promotes proliferation and reduces apoptosis in A549 lung cancer cells.\",\n      \"method\": \"Promoter cloning and reporter assay, HIF-1α CDS overexpression, stable NDRG1 transfection, MTT assay, colony formation, flow cytometry\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter reporter with defined binding region, single lab\",\n      \"pmids\": [\"23526365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SGK1 phosphorylates NDRG1 at serine/threonine sites; phospho-NDRG1 is increased in Alzheimer's disease brain tissue (~2-fold), suggesting augmented SGK1 activity targeting NDRG1 in AD.\",\n      \"method\": \"Immunoblot with phospho-specific NDRG1 antibody (SGK1-specific target), human post-mortem brain tissue analysis\",\n      \"journal\": \"Neuropathology and applied neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (phospho-immunoblot in tissue), no direct kinase assay performed in this paper\",\n      \"pmids\": [\"23363009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NDRG1 inhibits EGFR/HER2 and HER2/HER3 heterodimer formation and promotes EGFR degradation, thereby attenuating ErbB oncogenic signaling.\",\n      \"method\": \"Co-immunoprecipitation, NDRG1 overexpression/knockdown, receptor dimerization assays, Western blot for receptor degradation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of receptor dimers plus functional degradation assay, single lab\",\n      \"pmids\": [\"28615452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GSK3β phosphorylates serine and threonine residues in the C-terminal domain of NDRG1 and reduces NDRG1 protein stability. Conversely, NDRG1 overexpression decreases GSK3β levels via proteasomal degradation and suppresses AKT/S6 and cell-cycle signaling, revealing a bidirectional regulatory loop.\",\n      \"method\": \"GSK3β inhibitor treatment, NDRG1 overexpression/knockdown, proteasome inhibitor assays, Western blot for pathway targets, in vivo xenograft models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional epistasis with pharmacological and genetic tools, single lab\",\n      \"pmids\": [\"31723002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NDRG1 promotes interaction of the androgen receptor (AR) with chaperone HSP90, stabilizing AR while decreasing its androgen-mediated activation; NDRG1 also suppresses AR transcriptional activity partly by inhibiting c-Jun-AR interaction via reduced c-Jun phosphorylation. The CAP domain of NDRG1 is identified as vital for inhibition of AR activity.\",\n      \"method\": \"Co-immunoprecipitation (AR-HSP90), NDRG1 overexpression/knockdown, CAP-domain deletion mutants, AR transcriptional reporter assay, PSA expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, functional reporter assay, and patient specimen correlation\",\n      \"pmids\": [\"34785213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of the α/β hydrolase domain of human NDRG1 was determined (PDB: 6ZMM); full-length NDRG1 has a flexible N- and C-terminal region; NDRG1 binds to lipid vesicles with conformational changes in the C-terminal region; NDRG1 interacts with metal ions (e.g., nickel) but aggregates in their presence.\",\n      \"method\": \"X-ray crystallography (PDB 6ZMM), small-angle X-ray scattering (SAXS), CD spectroscopy, lipid vesicle binding assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus SAXS and functional lipid-binding assays with multiple orthogonal methods\",\n      \"pmids\": [\"33305529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NDRG1 loss disrupts the binding between RhoGDIα and CDC42, triggering CDC42 activation and downstream PAK1/Cofilin signaling, promoting filopodia formation and colorectal cancer invasiveness.\",\n      \"method\": \"NDRG1 silencing/overexpression, CDC42 activity assay (pull-down), Co-IP (RhoGDIα-CDC42), Western blot for PAK1/Cofilin, in vivo metastasis model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and activity assay establishing mechanism, single lab\",\n      \"pmids\": [\"33994856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NDRG1 deficiency reduces active RhoA and Rac1 GTPases while upregulating active Cdc42; NDRG1-deficient prostate cancer cells have restricted actin dynamics (measured by fluorescent polymerized-actin sensor), reduced integrin expression and adhesion, increased EMMPRIN expression with altered glycosylation, increased matrix metalloproteases, and collective invasion phenotype.\",\n      \"method\": \"NDRG1 KD, Rho GTPase activity assays, live-cell fluorescent actin imaging (FRAP), EMMPRIN glycosylation analysis, 3D invasion assay, in vivo xenograft metastasis assay\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell imaging plus GTPase activity assays plus in vivo validation with multiple mechanistic readouts\",\n      \"pmids\": [\"28371345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NDRG1 enhances cetuximab (EGFR antibody) sensitivity in colorectal cancer by reducing EGFR expression, blocking EGFR phosphorylation, reducing EGFR at the cell membrane, and attenuating endocytosis/degradation of EGFR induced by caveolin-1 (Cav1).\",\n      \"method\": \"NDRG1 overexpression/knockdown, EGFR distribution analysis (membrane/cytoplasm/nuclear fractions), caveolin-1 co-immunoprecipitation, in vivo xenograft and patient tissue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation and Co-IP with in vivo validation, single lab\",\n      \"pmids\": [\"34385595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NDRG1 forms a complex with PLCγ1 through its phosphorylation sites and is required for VEGF-A-induced PLCγ1 and ERK1/2 activation in endothelial cells; Ndrg1-knockout mice display impaired VEGF-A-induced corneal angiogenesis and reduced aortic sprouting.\",\n      \"method\": \"Co-immunoprecipitation (NDRG1-PLCγ1), Ndrg1 knockout mice, corneal angiogenesis assay, aortic ring sprouting assay, Western blot for PLCγ1/ERK activation, dorsal air sac assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of NDRG1-PLCγ1 complex, genetic KO with multiple in vivo angiogenesis assays\",\n      \"pmids\": [\"32144393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NDRG1 interacts with the orphan nuclear receptor Nur77 and functionally inhibits Nur77 transcriptional activity and NF-κB activity in endothelial cells; NDRG1 knockdown attenuates cytokine-induced MAPK activation, c-Jun phosphorylation, and AP-1 transcriptional activity. Endothelial cell-specific NDRG1 knockout mice show reduced neointima formation, atherosclerosis, and arterial thrombosis.\",\n      \"method\": \"Co-immunoprecipitation (NDRG1-Nur77), lentiviral shRNA knockdown, endothelial-specific NDRG1 KO mice, carotid artery ligation model, Nur77/NF-κB reporter assays, Western blot\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of NDRG1-Nur77, genetic KO with multiple in vivo vascular models, reporter assays\",\n      \"pmids\": [\"36562299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fasting or lipid availability activates mTORC2, which phosphorylates NDRG1 at Ser336; phosphorylated NDRG1 engages mitochondria and facilitates mitochondrial fission by cooperating with CDC42 and its effectors/regulators. The phosphorylation-deficient NDRG1-Ser336Ala mutant fails to support fission.\",\n      \"method\": \"Time-lapse imaging of NDRG1-mitochondria interaction, phospho-deficient mutant (NDRG1-S336A), siRNA screen, epistasis with DRP1-KO cells, proteomics, CDC42 co-immunoprecipitation, RictorKO and Cdc42-KO phenotyping\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phospho-deficient mutant, live imaging, epistasis experiments, proteomics and multiple KO models in one rigorous study\",\n      \"pmids\": [\"37386153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NDRG1 directly interacts with MIG6 (a tumor suppressor/EGFR regulator) and regulates c-Cbl E3 ligase activity as part of its mechanism for inhibiting receptor tyrosine kinases.\",\n      \"method\": \"Co-immunoprecipitation (NDRG1-MIG6), NDRG1 overexpression studies\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP reported in review context, limited mechanistic follow-up described in abstract\",\n      \"pmids\": [\"34572031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MNK1 (but not MNK2) signaling regulates NDRG1 phosphorylation; however, MNK1 cannot directly phosphorylate NDRG1 in vitro, indicating an indirect mechanism. MNK inhibition increases NDRG1 protein and mRNA expression. SGK1 phosphorylates MNK1 at a conserved site to repress its activity.\",\n      \"method\": \"MNK1/2 knockout cells, in vitro kinase assay (MNK1 vs. NDRG1), MNK inhibitors, SGK1 kinase assay on MNK1, Western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay (yielding negative direct result) plus genetic KO cells and SGK1 phosphorylation of MNK1 established\",\n      \"pmids\": [\"28545025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NDRG1 regulates all three main arms of the ER stress response: increases ER chaperone expression (BiP, calreticulin, calnexin), suppresses PERK and IRE1α arms, and increases ATF6 cleavage. In the presence of anti-cancer agent Dp44mT, NDRG1 markedly increases eIF2α activation, maintains ATF4, elevates cytosolic Ca2+, and increases pro-apoptotic CHOP.\",\n      \"method\": \"NDRG1 overexpression/knockdown in pancreatic and colon cancer cells, Western blot for ER stress markers, Ca2+ measurement, confocal microscopy\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple ER stress arm readouts with NDRG1 gain/loss of function, single lab\",\n      \"pmids\": [\"30981813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NDRG1 facilitates KSHV genome replication and episome persistence by interacting directly with PCNA (proliferating cell nuclear antigen) and forming a ternary complex with LANA (viral latent protein) and PCNA, bridging LANA to PCNA at viral terminal repeats (TRs) to facilitate viral DNA replication.\",\n      \"method\": \"Co-immunoprecipitation (NDRG1-PCNA, LANA-NDRG1-PCNA complex), NDRG1 knockdown in KSHV-infected cells, viral genome copy number assay, chromatin immunoprecipitation of PCNA at viral TRs\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of ternary complex, ChIP at viral TRs, KD with viral genome copy number readout\",\n      \"pmids\": [\"30811506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NDRG1 suppresses autophagy at both the initiation stage and autolysosome formation (reducing LC3-LAMP2 co-localization, increasing p62); NDRG1 expression decreases cholesterol levels (independent of AMPK), sensitizing lysosomes to membrane permeabilization.\",\n      \"method\": \"NDRG1 overexpression/knockdown, confocal microscopy (LC3/LAMP2 co-localization), p62 Western blot, cholesterol determination, acridine orange staining for LMP, AMPK phosphorylation assays\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal readouts for autophagy stages, single lab\",\n      \"pmids\": [\"32335136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NDRG1 regulates neutral lipid metabolism and lipid droplet formation in breast cancer cells; NDRG1 silencing increases fatty acid incorporation into neutral lipids and lipid droplets, while NDRG1 expression minimizes lipid droplet formation under both nutrient-replete and starvation conditions.\",\n      \"method\": \"NDRG1 silencing/overexpression, comprehensive lipidomics mass spectrometry, labeled fatty acid tracking, high-throughput quantitative microscopy, multiple breast cancer cell lines\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive lipidomics plus labeled fatty acid tracking plus quantitative microscopy in multiple cell lines\",\n      \"pmids\": [\"29898756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ndrg1 promotes adipocyte differentiation by inducing PPARγ expression and is required for C/EBPα phosphorylation; SGK1-dependent phosphorylation of Ndrg1 is induced during adipogenesis and promotes adipocyte formation.\",\n      \"method\": \"Ndrg1 knockdown/overexpression in adipocyte precursor cells, PPARγ and C/EBPα Western blot, adipogenesis differentiation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss of function with mechanistic downstream targets, single lab\",\n      \"pmids\": [\"28775290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NSUN6-mediated m5C methylation of NDRG1 mRNA enhances its stability via the m5C reader ALYREF; elevated NDRG1 expression promotes homologous recombination-mediated DNA repair, contributing to radioresistance in cervical cancer.\",\n      \"method\": \"Integrated m5C sequencing, mRNA sequencing, RNA immunoprecipitation, NSUN6 overexpression/silencing, CDX and 3D PDO models, in vivo xenograft\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — integrated m5C-seq with RIP and functional validation in organoid and in vivo models\",\n      \"pmids\": [\"38970106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"c-Jun, AR (androgen receptor), and DNMT1 form a complex at TRE regions of the NDRG1 promoter and suppress NDRG1 transcription through DNA hypermethylation; N-cadherin promotes c-Jun expression to suppress NDRG1, establishing an N-cadherin/c-Jun/NDRG1 axis in prostate cancer progression.\",\n      \"method\": \"Co-immunoprecipitation (c-Jun/AR/DNMT1 complex), ChIP at NDRG1 promoter TRE region, bisulfite sequencing for promoter methylation, NDRG1 knockdown/overexpression, in vivo xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and methylation analysis in single study, single lab\",\n      \"pmids\": [\"34512147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM1A (LSD1) histone demethylase represses NDRG1 expression; de-repression of NDRG1 by KDM1A inhibition causes inhibition of Wnt signaling and G1 cell cycle arrest in gastric cancer patient-derived organoids.\",\n      \"method\": \"CRISPR/Cas9 viability screen in patient-derived organoids, KDM1A genetic and pharmacological inhibition, NDRG1 expression measurement, cell cycle analysis, Wnt signaling assays\",\n      \"journal\": \"Small methods\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus pharmacological validation in PDOs with pathway readouts, single lab\",\n      \"pmids\": [\"36908010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ndrg1a in zebrafish binds to the sodium-potassium ATPase (NKA) pump under anoxia and is required for NKA degradation, preserving ATP in kidney and ionocytes during hypoxia; sodium azide (which increases lactate) triggers NKA degradation in an Ndrg1a-dependent manner.\",\n      \"method\": \"Ndrg1a knockout zebrafish, co-immunoprecipitation (Ndrg1a-NKA), sodium azide treatment, anoxia survival assays, kidney function assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with Co-IP and mechanistic rescue in zebrafish, ortholog of mammalian NDRG1\",\n      \"pmids\": [\"36214665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAOA interacts with NDRG1 and together they regulate glycolysis (Warburg effect) through suppression of the PI3K/AKT/mTOR pathway in gastric cancer.\",\n      \"method\": \"Co-immunoprecipitation (MAOA-NDRG1), Seahorse assay for glycolysis, Western blot for PI3K/AKT/mTOR pathway, overexpression/knockdown studies\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with limited mechanistic follow-up described in abstract, single lab\",\n      \"pmids\": [\"37249744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HER4 interacts with NDRG1 in osteosarcoma cells; NDRG1 overexpression antagonizes HER4 knockdown-mediated cell growth inhibition and apoptosis under stress conditions.\",\n      \"method\": \"Co-immunoprecipitation (HER4-NDRG1), shRNA knockdown of HER4, NDRG1 overexpression rescue assay, immunohistochemistry\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with functional rescue, single lab, limited mechanistic detail\",\n      \"pmids\": [\"29524631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NDRG1 inhibits ATG9A-dependent lysosomal-autophagy degradation of MHC class I (MHC-1) in pancreatic ductal adenocarcinoma cells, maintaining MHC-1 surface expression; elevated NDRG1 promotes CD8+ T cell infiltration and overcomes immune checkpoint blockade resistance.\",\n      \"method\": \"NDRG1 knockdown/overexpression, autophagy inhibitor studies, co-immunoprecipitation (NDRG1-ATG9A pathway), flow cytometry for MHC-1 and T cells, in vivo orthotopic mouse models, multiplex immunofluorescence\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation, inhibitor epistasis and in vivo validation, single lab\",\n      \"pmids\": [\"38228036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NDRG1 stabilizes LDHA by inhibiting its ubiquitination, thereby enhancing glycolysis and promoting lactate accumulation in lung adenocarcinoma; histone H2B K58 lactylation at the NDRG1 locus (mediated by LDHA-generated lactate) represents an epigenetic feedback mechanism.\",\n      \"method\": \"NDRG1 knockdown/overexpression, ubiquitination assay (LDHA ubiquitylation), Seahorse glycolysis assay, lactate measurement, histone lactylation ChIP\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and functional metabolic readouts, single lab\",\n      \"pmids\": [\"40539245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NDRG1 physically associates with TLE2 and β-catenin to activate Wnt/β-catenin signaling in esophageal squamous cell carcinoma, promoting EMT; TLE2 overexpression prevents NDRG1-driven Wnt pathway activation.\",\n      \"method\": \"Co-immunoprecipitation (NDRG1-TLE2, NDRG1-β-catenin), stable lentiviral overexpression, RNAi, TLE2 overexpression epistasis, Western blot for EMT markers\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP with limited mutational/structural follow-up, single lab\",\n      \"pmids\": [\"27414086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NDRG1 binds directly to PI3K (co-immunoprecipitation) in placental JEG-3 cells; NDRG1 knockdown upregulates PI3K and AKT expression, identifying PI3K/AKT as a downstream mechanism of NDRG1-mediated suppression of angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation (NDRG1-PI3K), lentiviral NDRG1 overexpression/knockdown, ELISA for PLGF/sFlt-1, Western blot for PI3K/AKT/VEGF, tube formation assay\",\n      \"journal\": \"Pregnancy hypertension\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP without mutagenesis or structural validation, single lab\",\n      \"pmids\": [\"32470876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In triple-negative breast cancer, YAP1 positively regulates NDRG1 transcription by binding the NDRG1 promoter; HJURP affects YAP1 ubiquitination and degradation, thereby modulating NDRG1 expression via the HJURP/YAP1/NDRG1 axis.\",\n      \"method\": \"YAP1 ChIP at NDRG1 promoter, ubiquitination assay (YAP1), HJURP knockdown/overexpression, Western blot, cell proliferation and chemosensitivity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and ubiquitination assay, single lab\",\n      \"pmids\": [\"35459269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NDRG1/Cap43 overexpression in hepatocellular carcinoma cells induces G0/G1 cell cycle arrest accompanied by increased p21 and decreased CDK4 expression both in vitro and in vivo.\",\n      \"method\": \"Stable NDRG1 transfection, cell cycle analysis (flow cytometry), Western blot for p21/CDK4, in vivo xenograft tumor growth, mimosine-induced G0/G1 block\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable overexpression with cell cycle, molecular markers, and in vivo validation in two HCC lines\",\n      \"pmids\": [\"21775055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NDRG1 regulates endothelial cell migration under intermittent hypoxia: siRNA silencing of NDRG1 decreases endothelial cell migration under intermittent hypoxia (as identified by 2D-DIGE proteomics and confirmed by siRNA).\",\n      \"method\": \"2D-DIGE proteomics, mass spectrometry protein identification, siRNA knockdown, endothelial cell migration assay\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA knockdown with single migration assay readout, single lab\",\n      \"pmids\": [\"19760510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTK7 (a membrane-localized pseudokinase) interacts with and stabilizes NDRG1 adjacent to adherens junctions; downregulation of either PTK7 or NDRG1 eliminates AZD9291 resistance in NSCLC cells.\",\n      \"method\": \"BioID proximal labeling (BirA*-PTK7), Co-immunoprecipitation (PTK7-NDRG1), knockdown/overexpression, phospho- and proximal proteomics\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID proximity labeling plus Co-IP establishing PTK7-NDRG1 interaction, single lab\",\n      \"pmids\": [\"36205702\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDRG1 is a stress-responsive, iron-regulated metastasis suppressor that functions as a multi-pathway signaling disruptor: it is transcriptionally induced by p53, HIF-1α, and hypoxia (among other stimuli) and post-translationally regulated by SGK1/mTORC2-mediated phosphorylation (at C-terminal Ser/Thr residues), SUMO-2 modification (at Lys14), proteasomal degradation (downstream of CD28/IL-2 in T cells), and NSUN6-mediated m5C mRNA methylation; structurally, it possesses an α/β hydrolase fold domain with a disordered C-terminus containing three 10-amino acid metal-binding repeats that bind Ni(II)/Cu(II) via histidine imidazole coordination; mechanistically, NDRG1 directly binds PLCγ1 to support VEGF-A-induced angiogenesis, associates with PCNA and LANA to support viral DNA replication, interacts with γ-tubulin to maintain centrosome homeostasis, stabilizes HSP90-AR complexes to dampen androgen receptor signaling, binds apolipoproteins A-I/A-II to regulate lipid trafficking, attenuates NF-κB signaling by reducing IKKβ expression (requiring phosphorylation at both Ser330 and Thr346), stabilizes MGMT to confer alkylating drug resistance, inhibits EGFR/HER2/HER3 dimerization and degradation, disrupts RhoGDIα-CDC42 binding to control actin dynamics, and—upon mTORC2-mediated phosphorylation at Ser336—cooperates with CDC42 to orchestrate mitochondrial fission during fasting.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NDRG1 is a stress- and metal-responsive signaling scaffold that integrates transcriptional and post-translational inputs to suppress oncogenic signaling, regulate metabolism, and maintain cellular homeostasis [#2, #5, #28]. It is transcriptionally induced through multiple stress-sensing axes: p53 binds the proximal promoter to drive expression upon DNA damage and growth arrest [#2, #20], HIF-1 mediates hypoxic induction via a defined promoter element [#3, #21], and Ni(II) acts through a Ca2+/PI3K-Akt-HIF route [#0, #4], while VHL, ER\\u03b1, androgen, and KDM1A repress it [#7, #19, #41, #42]. Structurally, NDRG1 adopts an \\u03b1/\\u03b2 hydrolase fold with flexible N- and C-terminal regions that bind lipid vesicles, and a C-terminal 10-residue repeat domain coordinates Ni(II)/Cu(II) through histidine imidazole nitrogens [#5, #6, #26]. Its activity is gated by C-terminal Ser/Thr phosphorylation: SGK1 (and GSK3\\u03b2) phosphorylation at Ser330/Thr346 is required to attenuate NF-\\u03baB signaling by lowering IKK\\u03b2 and blocking p65/p50 nuclear translocation [#9, #10, #24], and mTORC2-dependent Ser336 phosphorylation directs NDRG1 to mitochondria where it cooperates with CDC42 to drive fission during fasting [#32]. As a metastasis suppressor it acts through an ATF3/NF-\\u03baB/KAI1 cascade and restrains cytoskeletal remodeling by preserving RhoGDI\\u03b1\\u2013CDC42 binding to limit CDC42/PAK1/Cofilin-driven invasion [#14, #27, #28]. NDRG1 also dampens receptor tyrosine kinase signaling by inhibiting EGFR/HER2/HER3 dimerization and promoting EGFR degradation [#23, #29], stabilizes the AR\\u2013HSP90 complex to suppress androgen receptor transactivation [#25], binds PLC\\u03b31 to support VEGF-A-induced angiogenesis [#30], and controls lipid handling through endosomal LDLR trafficking, lipid-droplet limitation, and apolipoprotein A-I/A-II association [#12, #13, #38]. Additional roles span DNA-repair-linked drug resistance via MGMT stabilization and NSUN6/ALYREF-controlled mRNA stability promoting homologous recombination [#8, #40], centrosome homeostasis through \\u03b3-tubulin association [#11, #15], immune regulation as an Egr2-induced T-cell anergy factor and a determinant of mast-cell degranulation [#17, #18], and ER-stress and autophagy modulation [#35, #37, #46]. Apolipoprotein binding links NDRG1 to Schwann-cell lipid trafficking, consistent with the HMSNL-associated R148X founder mutation [#13].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the upstream signal that drives NDRG1 induction, showing it is a metal- and Ca2+-responsive gene rather than constitutively expressed.\",\n      \"evidence\": \"mRNA differential display with Ca2+ ionophores and chelators across human/rodent cells\",\n      \"pmids\": [\"9605764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect Ca2+ signal to a specific transcription factor\", \"Functional consequence of induction not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placed NDRG1 transcription under defined stress transcription factors, linking it to the p53 DNA-damage program and the HIF-1/oxygen-sensing pathway.\",\n      \"evidence\": \"Promoter-reporter, RNAi, inducible expression, HIF-1 knockout cells, and dominant-negative PI3K/Akt in cancer cell lines\",\n      \"pmids\": [\"15377670\", \"15341671\", \"14729612\", \"12767066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How p53 vs HIF inputs are integrated at a single promoter is unresolved\", \"VHL\\u2192Sp1 repression mechanism not linked to protein function\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the structural basis of NDRG1 metal binding, showing histidine imidazole coordination of Ni(II)/Cu(II) in the C-terminal repeats.\",\n      \"evidence\": \"pH-metric and spectroscopic (UV-VIS, EPR, CD, NMR) analysis of synthetic repeat peptides\",\n      \"pmids\": [\"11330481\", \"15149799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of metal binding by full-length protein unclear\", \"Peptide studies do not capture intact-protein context\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the core anti-inflammatory/anti-metastatic mechanism: NDRG1 suppresses NF-\\u03baB by reducing IKK\\u03b2 and requires dual C-terminal phosphorylation by SGK1.\",\n      \"evidence\": \"Overexpression with IKK\\u03b2 rescue, site-directed Ser330/Thr346 mutagenesis, reporter/ChIP assays and xenografts\",\n      \"pmids\": [\"19491262\", \"20416281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism by which NDRG1 lowers IKK\\u03b2 expression not defined\", \"Whether phosphorylation creates a binding surface unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked NDRG1 to mitosis and genome stability through phosphorylation-dependent centrosome localization and \\u03b3-tubulin association.\",\n      \"evidence\": \"Cell-cycle synchronization with \\u03b3-tubulin co-localization and Co-IP in isogenic TP53 cells\",\n      \"pmids\": [\"21708134\", \"26324937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function of NDRG1 at the centrosome undefined\", \"Direct vs indirect \\u03b3-tubulin interaction not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the transcriptional output of NDRG1-mediated metastasis suppression via the ATF3/NF-\\u03baB/KAI1 axis.\",\n      \"evidence\": \"ChIP of ATF3 at KAI1 promoter, reporter assays, KAI1 knockdown epistasis, in vivo metastasis models\",\n      \"pmids\": [\"21454613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NDRG1 suppresses ATF3 mechanistically is unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined NDRG1 control of cytoskeletal dynamics, showing it preserves RhoGDI\\u03b1\\u2013CDC42 binding to restrain invasive actin remodeling.\",\n      \"evidence\": \"CDC42 pull-down, RhoGDI\\u03b1-CDC42 Co-IP, live-cell actin imaging and in vivo metastasis assays\",\n      \"pmids\": [\"33994856\", \"28371345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner of NDRG1 within the RhoGDI\\u03b1-CDC42 complex not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended NDRG1 to immune regulation as an Egr2-induced, proteasome-degraded T-cell anergy factor and a mast-cell degranulation determinant.\",\n      \"evidence\": \"Ndrg1 knockout mice, proteasome inhibition, anergy and Fc\\u03b5RI degranulation assays\",\n      \"pmids\": [\"26507712\", \"17513753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets of NDRG1 enforcing anergy unknown\", \"Degranulation defect mechanism not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected NDRG1 to therapy resistance and lipid trafficking, stabilizing MGMT and regulating endosomal LDLR sorting.\",\n      \"evidence\": \"Reciprocal Co-IP (NDRG1-MGMT), IDOL co-depletion epistasis, LDLR ubiquitylation and uptake assays\",\n      \"pmids\": [\"24367102\", \"23813961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NDRG1 mechanistically promotes MVB formation unclear\", \"Whether MGMT stabilization is direct not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established NDRG1 as an angiogenic signaling adaptor by direct PLC\\u03b31 binding required for VEGF-A responses.\",\n      \"evidence\": \"NDRG1-PLC\\u03b31 Co-IP, Ndrg1 knockout mice, corneal/aortic angiogenesis assays\",\n      \"pmids\": [\"32144393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite-dependence of the PLC\\u03b31 interaction not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined NDRG1 suppression of androgen receptor signaling via AR\\u2013HSP90 stabilization and CAP-domain dependence.\",\n      \"evidence\": \"AR-HSP90 Co-IP, CAP-domain deletion mutants, AR reporter and PSA assays\",\n      \"pmids\": [\"34785213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CAP domain action on AR unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural model of NDRG1, defining the \\u03b1/\\u03b2 hydrolase fold and lipid-binding flexible termini.\",\n      \"evidence\": \"X-ray crystallography (PDB 6ZMM), SAXS, CD and lipid vesicle binding\",\n      \"pmids\": [\"33305529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic activity of the hydrolase fold, if any, not demonstrated\", \"Aggregation with metals leaves physiological metal role unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a metabolic membrane-remodeling function: mTORC2 phosphorylates NDRG1 at Ser336 to drive CDC42-dependent mitochondrial fission during fasting.\",\n      \"evidence\": \"Live imaging, S336A mutant, DRP1/Rictor/Cdc42 KO epistasis, proteomics and CDC42 Co-IP\",\n      \"pmids\": [\"37386153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phospho-NDRG1 physically engages the fission machinery is not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked NDRG1 mRNA stability to DNA repair and immune evasion through NSUN6/ALYREF m5C methylation and ATG9A-dependent MHC-I control.\",\n      \"evidence\": \"m5C-seq with RIP and HR repair assays; autophagy inhibitor epistasis with MHC-I/T-cell readouts in vivo\",\n      \"pmids\": [\"38970106\", \"38228036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct HR repair role of NDRG1 protein vs transcriptional consequence not separated\", \"Mechanism of ATG9A pathway inhibition incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of the conserved \\u03b1/\\u03b2 hydrolase fold and the unifying mechanism by which a single scaffold coordinates NF-\\u03baB, RTK, cytoskeletal, metabolic and trafficking outputs remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No catalytic substrate identified for the hydrolase fold\", \"No structure of full-length phosphorylated NDRG1 with a partner\", \"Whether the many reported interactions share a common binding determinant is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [30, 25, 36, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 23, 27, 25]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [26, 38, 13]},\n      {\"term_id\": \"GO:0046914\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [32, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [11, 15]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [36, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 30, 23, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 8, 40]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [38, 32, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 18, 46]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 35, 43]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [12, 37]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MGMT\", \"PLCG1\", \"AR\", \"HSP90\", \"PCNA\", \"TUBG1\", \"CDC42\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}