{"gene":"LAMTOR5","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2003,"finding":"HBXIP functions as a cofactor for survivin: survivin-HBXIP complexes (but neither protein alone) bind pro-caspase-9, preventing its recruitment to Apaf1 and thereby selectively suppressing apoptosis initiated via the mitochondria/cytochrome c pathway. Viral HBx protein also interacts with the survivin-HBXIP complex to suppress caspase activation in a survivin-dependent manner.","method":"Co-immunoprecipitation, biochemical complex reconstitution, caspase activity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal Co-IP with functional reconstitution showing complex-specific (not individual protein) activity, replicated across multiple assays in a single rigorous study","pmids":["12773388"],"is_preprint":false},{"year":2006,"finding":"HBXIP is required for bipolar spindle formation and centrosome duplication: HBXIP-deficient cells arrest in prometaphase with monopolar spindles, while HBXIP overexpression causes excessive centrosome replication and tripolar/multipolar spindles. HBXIP associates with microtubules of dividing cells and colocalizes with HBx on centrosomes. HBXIP-deficient cells also fail to complete cytokinesis and undergo apoptosis. In a mouse liver-regeneration model, antisense knockdown of HBXIP impairs hepatocyte growth and survival.","method":"RNAi knockdown, overexpression, immunolocalization, fluorescent protein tagging, antisense oligonucleotides in vivo","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, OE, imaging, in vivo model) establishing a defined centrosome/spindle regulatory role with specific cellular phenotypes","pmids":["16982752"],"is_preprint":false},{"year":2007,"finding":"The CRHK (residues 137-140) motif in HBx is necessary for binding HBXIP. Mutation of this motif abolishes HBx binding to HBXIP, prevents HBx localization to centrosomes, and abrogates HBx-induced dysregulation of centrosome assembly and modifications of pericentrin and centrin-2. Overexpression of HBXIP or HBXIP fragments that bind HBx neutralizes the effects of viral HBx on centrosome dynamics.","method":"Deletion mutagenesis, site-directed mutagenesis, Co-IP, subcellular fractionation, immunofluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis defining binding motif combined with functional rescue experiments and subcellular localization studies with multiple orthogonal methods","pmids":["18032378"],"is_preprint":false},{"year":2007,"finding":"HBXIP overexpression promotes cell proliferation in MCF-7, H7402, and L-O2 cells, upregulating c-Myc, Bcl-2, and PCNA while downregulating p27. RNAi-mediated knockdown of HBXIP produces opposite effects, demonstrating a role in cell proliferation regulation.","method":"Plasmid transfection, RNAi, MTT assay, BrdU incorporation, flow cytometry, Western blot","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with cell cycle readouts and molecular markers, single lab, multiple orthogonal methods","pmids":["17303008"],"is_preprint":false},{"year":2005,"finding":"HBXIP interacts with the mitochondrial RNA/DNA helicase hSuv3p. The HBXIP-binding domain identified within hSuv3p is important for mitochondrial import and stability of the Suv3 protein in vivo, suggesting involvement in a survivin-dependent antiapoptotic pathway.","method":"Co-immunoprecipitation, deletion analysis, in vivo stability assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with deletion mapping and in vivo functional consequence (protein stability), single lab","pmids":["16176273"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the shortest HBXIP isoform (91 aa) at 1.5 Å resolution reveals a profilin-like fold characteristic of the Roadblock/LC7 domain family. Small-angle X-ray scattering confirms the protein is dimeric in solution, with the dimer interface featuring an extended anti-parallel β-sheet and a small leucine zipper between α2 helices.","method":"X-ray crystallography, small-angle X-ray scattering (SAXS)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure validated by SAXS in solution, single rigorous study with two orthogonal structural methods","pmids":["21059355"],"is_preprint":false},{"year":2012,"finding":"HBXIP up-regulates S100A4 via two pathways: (1) HBXIP directly binds the +200~+239 region of the S100A4 promoter and activates it through interaction with transcription factor STAT4; (2) HBXIP activates PI3K/AKT signaling by inducing DNA methylation of PTEN, which boosts S100A4 expression. Both pathways promote growth and migration of breast cancer cells.","method":"ChIP assay, EMSA, co-immunoprecipitation, DNA methylation analysis, luciferase reporter assay, in vitro/in vivo functional assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, EMSA, Co-IP, methylation, luciferase, in vivo) establishing two distinct mechanistic pathways in one study","pmids":["22740693"],"is_preprint":false},{"year":2012,"finding":"HBXIP upregulates complement regulatory proteins CD46, CD55, and CD59 through activation of p-ERK1/2/NF-κB signaling, protecting breast cancer cells from complement-dependent cytotoxicity.","method":"Western blot, siRNA knockdown, luciferase reporter assay, in vivo animal experiments","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain/loss-of-function with pathway inhibition and in vivo validation, single lab","pmids":["22293503"],"is_preprint":false},{"year":2013,"finding":"HBXIP acts as a co-activator of TF IID by directly binding the TATA-binding protein (TBP): Co-IP and GST pull-down validate direct HBXIP-TBP binding; HBXIP occupies the Lin28B promoter region (-1199/-1073 nt) and transactivates Lin28B expression to promote breast cancer cell proliferation.","method":"Co-IP, GST pull-down, ChIP, EMSA, luciferase reporter assay, in vitro/in vivo proliferation assays","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein-protein interaction confirmed by two independent methods (Co-IP + GST pull-down) combined with ChIP and promoter functional assays","pmids":["23494474"],"is_preprint":false},{"year":2013,"finding":"HBXIP activates the LMO4 promoter by binding Sp1 at the -237/-206 region containing an Sp1 binding element; mutation of the Sp1 binding site blocks HBXIP-promoter interaction. HBXIP-elevated LMO4 upregulates cyclin D1 and cyclin E, promoting breast cancer cell proliferation.","method":"ChIP, EMSA, Co-IP, luciferase reporter assay, flow cytometry, MTT, EdU, xenograft assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, Co-IP, mutagenesis of binding site, functional assays), single lab","pmids":["23291272"],"is_preprint":false},{"year":2013,"finding":"HBXIP upregulates Skp2 by activating the Skp2 promoter (-640/-443 region) through binding E2F1 transcription factor, promoting breast cancer cell proliferation in vitro and in vivo.","method":"ChIP, luciferase reporter assay, siRNA knockdown, in vitro/in vivo functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP plus luciferase with functional validation in vitro and in vivo, single lab","pmids":["23352642"],"is_preprint":false},{"year":2014,"finding":"HBXIP promotes migration of breast cancer cells through the MEKK2/ERK1/2/Capn4 signaling cascade: HBXIP upregulates MEKK2, which activates ERK1/2, which upregulates Calpain small subunit 1 (Capn4), leading to increased filopodia formation and cell migration.","method":"Western blot, siRNA knockdown, luciferase reporter assay, immunofluorescence, migration assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — linear pathway established through sequential knockdown experiments with specific cellular phenotype readout, single lab","pmids":["25304384"],"is_preprint":false},{"year":2014,"finding":"HBXIP enhances angiogenesis in breast cancer through two pathways: (1) HBXIP directly binds CREB at the FGF8 promoter to upregulate FGF8; (2) HBXIP inhibits miR-503, which directly targets the 3'UTR of FGF8 and VEGF mRNA. HBXIP-induced FGF8 further upregulates VEGF via PI3K/Akt/HIF-1α signaling.","method":"ChIP, luciferase reporter assay, Co-IP, siRNA knockdown, Matrigel angiogenesis assay, in vivo hemoglobin content analysis","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple pathways characterized with ChIP, Co-IP, miRNA target validation, and in vivo readout, single lab","pmids":["24464787"],"is_preprint":false},{"year":2015,"finding":"HBXIP interacts directly with c-Myc through leucine zippers and recruits lncRNA Hotair along with histone demethylase LSD1 (for which Hotair serves as a scaffold) to activate transcription of c-Myc target genes (cyclin A, eIF4E, LDHA) in breast cancer cells.","method":"Co-IP, ChIP, luciferase reporter assay, RNAi knockdown, in vitro/in vivo tumor growth assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing direct leucine zipper interaction, combined with ChIP demonstrating promoter occupancy and functional in vivo validation","pmids":["26719542"],"is_preprint":false},{"year":2015,"finding":"HBXIP upregulates HDAC6 via NF-κB activation, causing HDAC6-mediated deacetylation of MST1 at lysine 35. Deacetylated MST1 interacts with HSC70, leading to lysosome-dependent (chaperone-mediated autophagy) degradation of MST1, reducing Hippo pathway tumor suppressor activity and promoting breast cancer growth.","method":"Co-IP, Western blot, trichostatin A treatment, siRNA knockdown, luciferase reporter assay, in vitro/in vivo functional assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — post-translational modification at specific residue identified, degradation mechanism characterized with inhibitor, Co-IP confirming protein-protein interactions, multiple orthogonal methods in single lab study","pmids":["26657153"],"is_preprint":false},{"year":2015,"finding":"HBXIP promotes glucose metabolism reprogramming in breast cancer by elevating miR-183/96/182 cluster expression through HIF-1α stabilization: HBXIP disassociates pVHL from HIF-1α to increase HIF-1α stability, and elevated miR-183 further increases HIF-1α by targeting VHL mRNA CDS (forming a feedback loop). miR-183/182 and miR-96 directly inhibit SCO2 and PDHA1 through their coding sequences, switching metabolism from oxidative phosphorylation to aerobic glycolysis.","method":"Western blot, Co-IP, luciferase reporter assay, miRNA target validation, metabolic assays (glucose/lactate/ROS), in vivo xenograft","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mechanistic pathway established with multiple methods, single lab, pathway complexity adds uncertainty","pmids":["26309161"],"is_preprint":false},{"year":2015,"finding":"HBXIP promotes migration of breast cancer cells via GCN5-mediated microtubule acetylation: HBXIP increases α-tubulin acetylation, requires acetyltransferase GCN5 for this effect, and GCN5 is required for HBXIP-enhanced directional cell migration.","method":"Immunofluorescence, Western blot, wound-healing assay, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional epistasis between HBXIP and GCN5 in microtubule acetylation and migration, single lab, limited mechanistic depth on HBXIP-GCN5 interaction","pmids":["25686500"],"is_preprint":false},{"year":2016,"finding":"HBXIP contributes to abnormal lipid metabolism in breast cancer by coactivating nuclear receptors LXRs independent of ligand (via a corepressor/nuclear receptor motif with special flanking sequence), upregulating SREBP-1c (SREBF1), which activates FAS transcription. SREBP-1c in turn activates HBXIP transcription, forming a positive feedback loop (HBXIP→LXR→SREBP-1c→FAS and SREBP-1c→HBXIP).","method":"Co-IP, luciferase reporter assay, ChIP, siRNA knockdown, lipogenesis assay, in vitro/in vivo tumor growth assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein-protein interaction (Co-IP), promoter occupancy (ChIP), and functional validation in vivo, multiple orthogonal methods","pmids":["26980761"],"is_preprint":false},{"year":2016,"finding":"HBXIP suppresses gluconeogenesis in hepatoma cells by inhibiting PCK1 through two mechanisms: (1) upregulation of miR-135a targeting FOXO1 mRNA 3'UTR; (2) activation of PI3K/Akt pathway, increasing FOXO1 phosphorylation and nuclear export, thereby reducing PCK1 transcription. PCK1 overexpression abolishes HBXIP-promoted hepatoma growth.","method":"Western blot, luciferase reporter assay, siRNA knockdown, PI3K/Akt pathway inhibition, in vitro/in vivo functional assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — two mechanistic pathways characterized with functional rescue experiment, single lab","pmids":["27609066"],"is_preprint":false},{"year":2016,"finding":"HBXIP upregulates YAP in hepatoma cells by co-activating transcription factor c-Myb at the YAP promoter. Silencing YAP abolishes HBXIP-mediated hepatoma cell proliferation in vitro and in vivo.","method":"ChIP, luciferase reporter assay, Co-IP, siRNA knockdown, in vitro/in vivo proliferation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ChIP establishing co-activation mechanism with functional validation, single lab","pmids":["27765671"],"is_preprint":false},{"year":2017,"finding":"HBXIP upregulates METTL3 by suppressing miRNA let-7g (which targets METTL3 3'UTR). METTL3 in turn increases HBXIP expression through m6A modification, forming a positive feedback loop (HBXIP→suppression of let-7g→METTL3→m6A modification→HBXIP). This loop promotes breast cancer cell proliferation.","method":"Western blot, luciferase reporter assay, m6A modification assay, siRNA knockdown, cell proliferation/apoptosis assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — feedback loop established with multiple methods, but m6A mechanism details are limited in the abstract, single lab","pmids":["29174803"],"is_preprint":false},{"year":2017,"finding":"TNF-α upregulates HBXIP expression in breast cancer cells via TNFR1: NF-κB and/or p38 signaling activates STAT3, which increases HBXIP promoter activity. HBXIP reciprocally upregulates TNFR1, forming a positive feedback loop (TNFR1→NF-κB/p38→p-STAT3→HBXIP→TNFR1) that promotes breast cancer growth.","method":"Western blot, luciferase reporter assay, siRNA knockdown, in vitro/in vivo tumor growth assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — signaling pathway established with receptor knockdown and multiple pathway inhibition experiments, in vivo validation, single lab","pmids":["28938560"],"is_preprint":false},{"year":2017,"finding":"HBXIP upregulates ACSL1 in breast cancer cells by acting as a coactivator of transcription factor Sp1, binding to the ACSL1 promoter as demonstrated by ChIP assay.","method":"Western blot, qRT-PCR, ChIP, luciferase reporter assay, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP confirming promoter binding with luciferase reporter validation, single lab","pmids":["28132807"],"is_preprint":false},{"year":2018,"finding":"HBXIP prevents chaperone-mediated autophagy (CMA)-dependent degradation of HOXB13 by enhancing HOXB13 acetylation at lysine 277, causing HOXB13 protein accumulation. HBXIP also acts as a co-activator of HOXB13 to stimulate IL-6 transcription, promoting tamoxifen resistance in breast cancer.","method":"Co-IP, Western blot, luciferase reporter assay, ChIP, site-directed mutagenesis of K277, siRNA knockdown, xenograft assay","journal":"Journal of hematology & oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific acetylation site identified with mutagenesis, CMA mechanism characterized, co-activation demonstrated by ChIP and Co-IP, in vivo validation, multiple orthogonal methods","pmids":["29471853"],"is_preprint":false},{"year":2018,"finding":"HBXIP modulates the MDM2/p53 feedback loop: HBXIP suppresses miR-18b by inducing DNA methylation of the miR-18b gene, elevating MDM2. HBXIP also promotes MDM2 phosphorylation via activating AKT and directly binds phospho-MDM2, enhancing MDM2-p53 interaction and p53 degradation in breast cancer cells.","method":"Western blot, Co-IP, luciferase reporter assay, DNA methylation analysis, siRNA knockdown, in vivo xenograft","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — two mechanistic pathways with Co-IP confirming HBXIP-pMDM2 interaction, in vivo validation, single lab","pmids":["30181579"],"is_preprint":false},{"year":2018,"finding":"HBXIP upregulates PKM2 in ER+ breast cancer cells by co-activating E2F1 at the PKM promoter (-779/-579 region), accelerating cell proliferation.","method":"ChIP, luciferase reporter assay, Western blot, Co-IP, tissue microarray, xenograft assay","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP confirming promoter occupancy with Co-IP and functional validation, single lab","pmids":["29925919"],"is_preprint":false},{"year":2019,"finding":"LAMTOR5 (HBXIP) regulates TLR4 signaling and inflammation: Lamtor5 associates with TLR4 via their LZ/TIR domains and facilitates colocalization at autolysosomes, preventing lysosomal tethering and mTORC1 activation upon LPS stimulation, thereby de-repressing TFEB to promote autophagic degradation of TLR4. Loss of Lamtor5 leads to sustained inflammation and increased mortality in endotoxic shock mice. Leucine deprivation blunts inflammatory signaling through this Lamtor5-dependent mechanism.","method":"Co-IP (LZ/TIR domain interaction), colocalization imaging, TFEB reporter assay, Lamtor5 haploinsufficient mouse model, in vivo endotoxic shock model","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein-protein interaction defined by domain mapping, in vivo mouse model with specific mortality phenotype, mechanistic pathway (mTORC1-TFEB-autophagy) characterized with multiple methods","pmids":["31467416"],"is_preprint":false},{"year":2019,"finding":"LAMTOR5 stimulates transcription of O-glycosylation enzyme GALNT1 by coactivating c-Jun at the GALNT1 promoter, and triggers dislocation of GALNT1 from the ER via LAMTOR5-dependent activation of c-Src, leading to accumulation of Tn-modified glycoproteins (MUC1, OPN) and promoting breast cancer metastasis.","method":"ChIP, luciferase reporter assay, Co-IP, immunofluorescence, Western blot, secondary metastasis mouse model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirming co-activation of c-Jun, Co-IP for c-Src interaction, subcellular localization change demonstrated, in vivo metastasis model, multiple orthogonal methods","pmids":["31836847"],"is_preprint":false},{"year":2019,"finding":"HBXIP competitively binds KEAP1 via its conserved GLNLG motif, displacing NRF2 from KEAP1 complexes, promoting NRF2 accumulation and nuclear entry, activating ARE-dependent signaling and reducing intracellular ROS. Mutation of the GLNLG motif abolishes HBXIP-KEAP1 interaction and potently inhibits breast cancer malignancy in vivo and in vitro.","method":"Co-IP, competitive binding assay, GLNLG motif mutagenesis, NRF2 nuclear localization assay, ROS measurement, in vitro/in vivo functional assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific binding motif identified with mutagenesis abolishing interaction, competitive displacement mechanism demonstrated, in vivo functional validation","pmids":["30692632"],"is_preprint":false},{"year":2020,"finding":"HBXIP induces HMGA2 acetylation at lysine 26 (K26) by activating acetyltransferase PCAF through the Akt pathway (HBXIP→Akt→p-PCAF→PCAF-HMGA2 interaction→K26 acetylation). K26 acetylation enhances HMGA2 DNA binding capacity, blocks ubiquitination, and inhibits proteasomal degradation, stabilizing HMGA2 to promote ESCC growth.","method":"Co-IP, site-directed mutagenesis (K26), Western blot, Akt pathway inhibition, ubiquitination assay, in vitro/in vivo functional assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific acetylation site identified by mutagenesis, kinase pathway established, writer (PCAF) identified via Co-IP, ubiquitination crosstalk demonstrated, in vivo validation","pmids":["32313942"],"is_preprint":false},{"year":2020,"finding":"HBXIP drives metabolic reprogramming in HCC cells via upregulation of METTL3, which mediates m6A modification of HIF-1α mRNA. METTL3 was shown to physically bind HIF-1α and mediate its m6A modification; HBXIP-mediated METTL3 upregulation restores metabolic reprogramming when HBXIP is partially lost.","method":"m6A RNA immunoprecipitation, dot-blot assay, Co-IP (METTL3-HIF-1α binding), Western blot, siRNA knockdown, rescue experiments","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — m6A modification and binding relationship demonstrated, functional rescue performed, single lab","pmids":["33305825"],"is_preprint":false},{"year":2021,"finding":"HBXIP stimulates PD-L1 transcription by co-activating transcription factor ETS2, and induces PD-L1 acetylation at K270 by interacting with acetyltransferase p300, leading to PD-L1 protein stability and promotion of breast cancer growth.","method":"Co-IP, ChIP, luciferase reporter assay, RNA-seq, acetylation assay, siRNA knockdown, in vitro/in vivo functional assays","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — two mechanisms (transcriptional co-activation and acetylation writer identification) established with Co-IP and ChIP, single lab","pmids":["33824459"],"is_preprint":false},{"year":2022,"finding":"HBXIP (LAMTOR5) interacts with the Ragulator complex subunits and is required for mTORC1 activation by amino acids; homozygous knockout of Hbxip in mice causes embryonic lethality with retarded growth at ~E7.5. Hbxip-null ESCs show defects in self-renewal, reduced pluripotency gene expression, and impaired ectodermal/mesodermal differentiation, mirroring phenotypes of Lamtor3 and Lamtor4 knockout ESCs.","method":"Co-IP (Ragulator complex interaction), homozygous knockout mouse model, ESC culture/differentiation assays, gene expression analysis, epistasis with other Ragulator subunit knockouts","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct Ragulator complex membership confirmed by Co-IP, in vivo lethality phenotype replicated across multiple Ragulator subunit knockouts demonstrating pathway epistasis, in vitro ESC differentiation assays","pmids":["35608036"],"is_preprint":false},{"year":2022,"finding":"HBXIP directly interacts with the assembly-competent domain (ACD) of non-muscle myosin heavy chain IIA (NMHC-IIA) as shown by mass spectrometry, Co-IP, and GST pull-down. HBXIP recruits PKCβII (whose transcription HBXIP induces via Sp1 coactivation), which phosphorylates NMHC-IIA at S1916, enhancing HBXIP-NMHC-IIA interaction and promoting myosin-IIA disassembly, thereby facilitating breast cancer cell migration.","method":"Mass spectrometry, Co-IP, GST pull-down, Western blot, phosphorylation assay, RNA-seq, in vivo metastasis model","journal":"Acta pharmaceutica Sinica. B","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction confirmed by three independent methods (MS, Co-IP, GST pull-down), phosphorylation site identified, kinase writer identified, in vivo validation","pmids":["36970214"],"is_preprint":false},{"year":2022,"finding":"HBXIP acts as a chaperone of IRE1α (UPR transducer inositol-requiring enzyme 1a) to diminish tamoxifen-induced ER stress in tamoxifen-resistant breast cancer. HBXIP deficiency hyperactivates IRE1α and its downstream pro-apoptotic pathways, and simultaneously induces ROS accumulation that activates PERK and ATF6α branches of the UPR.","method":"Co-IP, Western blot, luciferase UPR-element reporter assay, ROS measurement, siRNA knockdown, in vitro/in vivo functional assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP establishing IRE1α chaperone interaction with functional consequences characterized, single lab","pmids":["35093383"],"is_preprint":false},{"year":2022,"finding":"HBXIP prevents sorafenib-induced ferroptosis in HCC by transcriptionally inducing stearoyl-CoA desaturase (SCD) via coactivation of transcription factor ZNF263, resulting in accumulation of free fatty acids and suppression of lipid peroxidation/ferroptosis.","method":"ChIP, luciferase reporter assay, Co-IP, malondialdehyde (MDA) measurement, glutathione (GSH) assay, ferroptosis inhibitor rescue, in vitro/in vivo functional assays","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-activation of ZNF263 at SCD promoter established by ChIP and Co-IP, ferroptosis mechanism confirmed with pharmacological rescue, single lab","pmids":["36109580"],"is_preprint":false},{"year":2024,"finding":"Lamtor5 is physically associated with ATP6V1A (essential subunit of vacuolar H+-ATPase/v-ATPase) and promotes V0/V1 holoenzyme assembly to facilitate lysosome acidification. Lamtor5 binding to v-ATPase also affects lysosomal tethering of Rag GTPase and weakens Rag GTPase interaction with mTORC1. Loss of Lamtor5 impairs lysosomal function and causes aberrant mTORC1 activation, blunted autolysosomal pathway, and SLE-like manifestations in myeloid-specific knockout mice.","method":"Co-IP (Lamtor5-ATP6V1A interaction), v-ATPase assembly assay, lysosome acidification assay, myeloid-specific knockout mouse model, Rag GTPase-mTORC1 interaction assays, analysis of PBMCs from SLE patients","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein-protein interaction (Co-IP), enzymatic complex assembly demonstrated, in vivo mouse model with SLE-like phenotype, mechanistic pathway (v-ATPase→lysosome acidification→Rag-mTORC1) characterized with multiple methods","pmids":["38639386"],"is_preprint":false},{"year":2024,"finding":"LAMTOR5 silences CHOP expression via two mechanisms: (1) LAMTOR5 recruits DNMT1 to the CpG3 region (-559/-429) of the CHOP promoter to promote DNA hypermethylation, blocking TFII-I binding; (2) LAMTOR5-enhanced miR-182/miR-769 reduce CHOP expression by targeting its 3'UTR. CHOP suppression reduces ER stress-related apoptosis and promotes liver cancer growth.","method":"Co-IP (DNMT1 recruitment), ChIP (promoter methylation), DNA methylation assay, luciferase reporter assay, miRNA target validation, siRNA knockdown, in vitro/in vivo functional assays","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — two distinct silencing mechanisms characterized with ChIP, Co-IP, methylation assay, and miRNA validation, single lab","pmids":["38942954"],"is_preprint":false},{"year":2015,"finding":"HBXIP modulates the MDM2/p53 feedback loop by directly binding p53 at the P2 promoter of MDM2 and recruiting acetyltransferase p300 to p53 at the MDM2 promoter, increasing MDM2 transcription. Elevated MDM2 enhances p53 degradation, forming an accelerated feedback loop promoting breast cancer growth.","method":"Co-IP (HBXIP-p53 and HBXIP-p300 interactions), ChIP, luciferase reporter assay, siRNA knockdown, in vitro/in vivo functional assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP confirming direct protein-protein interactions, ChIP demonstrating promoter occupancy, functional validation in vivo, single lab","pmids":["26229107"],"is_preprint":false},{"year":2021,"finding":"HBXIP promotes NSCLC tumorigenesis by binding MEK1 protein, preventing proteasome-mediated degradation of MEK1 and thereby promoting MAPK/ERK signaling pathway activation. In vivo xenografts confirm HBXIP deficiency decreases MEK1 protein levels and tumor growth.","method":"Co-IP, Western blot, immunofluorescence, proteasome inhibition assays, siRNA knockdown, in vivo xenograft","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP establishing HBXIP-MEK1 interaction with proteasomal degradation mechanism, in vivo validation, single lab","pmids":["33628588"],"is_preprint":false},{"year":2008,"finding":"HBXIP significantly stimulates hTERT promoter activity and telomerase activity in human mesenchymal stem cells, upregulating hTERT, c-Myc, and Bcl-2 expression, providing a mechanism for HBXIP-promoted cell proliferation.","method":"Luciferase reporter assay, TRAP (telomeric repeat amplification protocol), Western blot, RNAi knockdown, plasmid transfection","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain- and loss-of-function with specific telomerase activity assay and promoter reporter, single lab","pmids":["18158869"],"is_preprint":false}],"current_model":"LAMTOR5/HBXIP is a multifunctional oncogenic scaffold protein that serves as: (1) a core subunit of the Ragulator complex on late endosomes/lysosomes, required for mTORC1 activation by amino acids, v-ATPase assembly and lysosomal acidification, and regulation of TLR4 autophagic degradation; (2) an anti-apoptotic cofactor that, in complex with survivin, binds pro-caspase-9 to suppress mitochondria-initiated apoptosis; (3) a transcriptional co-activator that directly binds transcription factors (Sp1, c-Myc, E2F1, STAT4, LXRs, c-Jun, ETS2, c-Myb, NF-κB/p65) and recruits chromatin-modifying complexes (LSD1/Hotair, p300, PCAF) to activate diverse cancer-promoting gene programs; and (4) a regulator of post-translational modifications (promoting acetylation of MST1, HOXB13, HMGA2, PD-L1; interacting with KEAP1 to activate NRF2; recruiting PKCβII to phosphorylate NMHC-IIA) that collectively reprogram cell metabolism, cytoskeletal dynamics, centrosome duplication, and immune evasion to drive cancer progression."},"narrative":{"mechanistic_narrative":"LAMTOR5 (HBXIP) is a small Roadblock/LC7-domain protein that adopts a profilin-like fold and dimerizes in solution [PMID:21059355], functioning as both a core lysosomal signaling subunit and a multifunctional oncogenic scaffold/transcriptional co-activator. As a Ragulator subunit, it associates with the complex and is required for amino-acid-dependent mTORC1 activation, with homozygous knockout causing embryonic lethality and ESC self-renewal/differentiation defects that phenocopy other Ragulator subunit losses [PMID:35608036]; it physically binds the v-ATPase subunit ATP6V1A to promote V0/V1 holoenzyme assembly and lysosomal acidification, thereby tuning Rag GTPase–mTORC1 coupling, with myeloid-specific loss producing SLE-like disease in mice [PMID:38639386]. Through interaction of its leucine-zipper/TIR-like surface with TLR4, LAMTOR5 routes TLR4 to autolysosomal degradation by restraining mTORC1 and de-repressing TFEB, limiting inflammation [PMID:31467416]. In its earliest-described role it acts with survivin to bind pro-caspase-9 and block mitochondrial apoptosis [PMID:12773388], and it controls centrosome duplication and bipolar spindle formation, associating with mitotic microtubules [PMID:16982752]. A dominant theme across cancer studies is its function as a transcriptional co-activator that directly binds TBP and diverse transcription factors—Sp1, c-Myc, E2F1, STAT4, c-Jun, c-Myb, ETS2, CREB, LXRs, ZNF263—to drive proliferative, metabolic, angiogenic and immune-evasion gene programs [PMID:23494474, PMID:26719542, PMID:26980761, PMID:22740693], recruiting chromatin and modifying machinery such as the Hotair/LSD1 scaffold to c-Myc target genes [PMID:26719542]. LAMTOR5 additionally governs protein stability and post-translational modification: it displaces NRF2 from KEAP1 via a GLNLG motif to activate antioxidant ARE signaling [PMID:30692632], directs site-specific acetylation of HMGA2 (K26 via PCAF) and HOXB13 (K277) to block their degradation [PMID:32313942, PMID:29471853], and recruits PKCβII to phosphorylate NMHC-IIA to promote myosin disassembly and migration [PMID:36970214].","teleology":[{"year":2003,"claim":"Established the first molecular function of HBXIP—how a small protein could suppress apoptosis—by showing it acts only in complex with survivin rather than alone.","evidence":"Co-IP, complex reconstitution and caspase assays showing survivin-HBXIP (not either alone) binds pro-caspase-9","pmids":["12773388"],"confidence":"High","gaps":["Structural basis of the survivin-HBXIP-procaspase-9 interaction not resolved","Did not address whether this role is separable from later scaffold/Ragulator functions"]},{"year":2006,"claim":"Defined a cell-cycle function by linking HBXIP to centrosome duplication and bipolar spindle assembly, explaining its requirement for mitotic fidelity and growth.","evidence":"RNAi, overexpression, immunolocalization to mitotic microtubules, and in vivo liver regeneration model","pmids":["16982752"],"confidence":"High","gaps":["Direct molecular partners at the centrosome not identified","Mechanism linking centrosome role to its other activities unclear"]},{"year":2010,"claim":"Provided the structural foundation, revealing a Roadblock/LC7 profilin-like fold and a dimeric architecture that rationalizes scaffolding and complex membership.","evidence":"1.5 Å X-ray crystal structure of the 91-aa isoform plus SAXS confirming solution dimer","pmids":["21059355"],"confidence":"High","gaps":["Structures of HBXIP within Ragulator or with transcription-factor partners not determined","Functional consequence of dimerization for signaling untested"]},{"year":2013,"claim":"Recast HBXIP as a transcriptional co-activator by demonstrating direct TBP binding and promoter occupancy, generalizing a mechanism that would explain its broad gene-activation activity.","evidence":"Co-IP, GST pull-down, ChIP and reporter assays at the Lin28B promoter","pmids":["23494474"],"confidence":"High","gaps":["How HBXIP is recruited to specific promoters genome-wide not defined","Stoichiometry within transcription preinitiation complexes unknown"]},{"year":2015,"claim":"Showed how HBXIP couples to chromatin-modifying machinery, binding c-Myc via leucine zippers and recruiting the Hotair/LSD1 scaffold to activate c-Myc target genes.","evidence":"Reciprocal Co-IP, ChIP, reporter and in vivo tumor growth assays","pmids":["26719542"],"confidence":"High","gaps":["Direct vs. bridged contact with LSD1 not dissected","Generality of Hotair recruitment to other TF partners untested"]},{"year":2016,"claim":"Demonstrated a metabolic gene-regulatory role through ligand-independent LXR co-activation feeding a SREBP-1c/FAS lipogenic loop, defining HBXIP as a driver of tumor lipid metabolism.","evidence":"Co-IP, ChIP, reporter, lipogenesis and in vivo tumor assays","pmids":["26980761"],"confidence":"High","gaps":["Structural basis of ligand-independent nuclear-receptor coactivation not resolved"]},{"year":2019,"claim":"Identified motif-specific control of protein stability—HBXIP displaces NRF2 from KEAP1 via a GLNLG motif—establishing an antioxidant/ROS-lowering function distinct from its transcriptional role.","evidence":"Co-IP, competitive binding, GLNLG mutagenesis abolishing interaction, ROS and in vivo assays","pmids":["30692632"],"confidence":"High","gaps":["Whether KEAP1 competition is regulated dynamically in cells unknown"]},{"year":2019,"claim":"Connected LAMTOR5 to innate immunity by showing it routes TLR4 to autolysosomal degradation through mTORC1 restraint and TFEB de-repression, defining an anti-inflammatory checkpoint.","evidence":"Domain-mapped Co-IP (LZ/TIR), colocalization, TFEB reporter, and haploinsufficient endotoxic-shock mouse model","pmids":["31467416"],"confidence":"High","gaps":["How leucine availability gates this pathway mechanistically not fully resolved"]},{"year":2020,"claim":"Resolved a mechanism by which HBXIP stabilizes oncoproteins, directing PCAF-mediated K26 acetylation of HMGA2 to block its ubiquitination and degradation.","evidence":"Co-IP, K26 mutagenesis, Akt-pathway inhibition, ubiquitination and in vivo ESCC assays","pmids":["32313942"],"confidence":"High","gaps":["Whether HBXIP directly contacts PCAF or acts via Akt signaling not fully separated"]},{"year":2022,"claim":"Defined LAMTOR5 as a bona fide Ragulator subunit essential for amino-acid-driven mTORC1 activation and embryonic development, anchoring its lysosomal-signaling identity.","evidence":"Co-IP, homozygous knockout (embryonic lethal), and ESC self-renewal/differentiation assays with epistasis to other Ragulator subunits","pmids":["35608036"],"confidence":"High","gaps":["Structural position within Ragulator not defined","Relationship between Ragulator role and transcriptional functions unresolved"]},{"year":2022,"claim":"Linked LAMTOR5 to cytoskeletal dynamics by direct binding of the NMHC-IIA assembly-competent domain and recruitment of PKCβII to phosphorylate myosin-IIA, explaining a migration-promoting mechanism.","evidence":"MS, Co-IP, GST pull-down, phospho-site mapping (S1916) and in vivo metastasis model","pmids":["36970214"],"confidence":"High","gaps":["How HBXIP couples its scaffolding to kinase recruitment spatially unknown"]},{"year":2024,"claim":"Mechanistically tied LAMTOR5 to lysosomal acidification through ATP6V1A binding and v-ATPase holoenzyme assembly, linking its loss to defective mTORC1 control and SLE-like autoimmunity.","evidence":"Co-IP, v-ATPase assembly and acidification assays, myeloid-specific knockout mice, and SLE patient PBMC analysis","pmids":["38639386"],"confidence":"High","gaps":["Structural interface with ATP6V1A not determined","How acidification feeds back to its transcriptional functions unknown"]},{"year":null,"claim":"How a single small Roadblock-domain protein integrates a lysosomal Ragulator/v-ATPase signaling identity with a nuclear transcriptional co-activator identity—what governs its partitioning between these compartments and partners—remains unresolved.","evidence":"No single study reconciles the lysosomal and nuclear roles within one mechanistic framework","pmids":[],"confidence":"Low","gaps":["No structural model of HBXIP bound to its diverse TF partners","Determinants of subcellular partitioning between lysosome and nucleus unknown","Whether dimerization switches between functional pools untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,13,17,6,9,10,19,22,25,31,35]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,32,36,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[28,26,39]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[26,36]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,13,17]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[32,36,26]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,13,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[26,36]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,36]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[17,15,18]}],"complexes":["Ragulator","survivin-HBXIP complex","v-ATPase (via ATP6V1A)"],"partners":["SURVIVIN","TBP","C-MYC","KEAP1","ATP6V1A","TLR4","NMHC-IIA","P300"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43504","full_name":"Ragulator complex protein LAMTOR5","aliases":["Hepatitis B virus X-interacting protein","HBV X-interacting protein","HBX-interacting protein","Late endosomal/lysosomal adaptor and MAPK and MTOR activator 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Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it (1) acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and (2) mediates recruitment of Rag GTPases to the lysosome membrane (PubMed:22980980, PubMed:28935770, PubMed:29107538, PubMed:29158492, PubMed:30181260). Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:22980980, PubMed:29158492, PubMed:30181260). When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway (PubMed:12773388)","subcellular_location":"Lysosome; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O43504/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LAMTOR5","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"LAMTOR2","stoichiometry":10.0},{"gene":"PIP4P1","stoichiometry":10.0},{"gene":"SLC31A1","stoichiometry":10.0},{"gene":"LAMP1","stoichiometry":0.2},{"gene":"PMVK","stoichiometry":0.2},{"gene":"SLC18B1","stoichiometry":0.2},{"gene":"STX12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LAMTOR5","total_profiled":1310},"omim":[{"mim_id":"618834","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 4; LAMTOR4","url":"https://www.omim.org/entry/618834"},{"mim_id":"615112","title":"UROFACIAL SYNDROME 2; UFS2","url":"https://www.omim.org/entry/615112"},{"mim_id":"608869","title":"LEUCINE-RICH REPEATS- AND IMMUNOGLOBULIN-LIKE DOMAINS-CONTAINING PROTEIN 2; LRIG2","url":"https://www.omim.org/entry/608869"},{"mim_id":"608521","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 5; LAMTOR5","url":"https://www.omim.org/entry/608521"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LAMTOR5"},"hgnc":{"alias_symbol":["XIP","MGC71071"],"prev_symbol":["HBXIP"]},"alphafold":{"accession":"O43504","domains":[{"cath_id":"3.30.450.30","chopping":"1-9_16-91","consensus_level":"medium","plddt":96.4327,"start":1,"end":91}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43504","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43504-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43504-F1-predicted_aligned_error_v6.png","plddt_mean":96.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LAMTOR5","jax_strain_url":"https://www.jax.org/strain/search?query=LAMTOR5"},"sequence":{"accession":"O43504","fasta_url":"https://rest.uniprot.org/uniprotkb/O43504.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43504/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43504"}},"corpus_meta":[{"pmid":"29174803","id":"PMC_29174803","title":"HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/29174803","citation_count":390,"is_preprint":false},{"pmid":"12773388","id":"PMC_12773388","title":"HBXIP functions as a cofactor of survivin in apoptosis suppression.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12773388","citation_count":367,"is_preprint":false},{"pmid":"19930558","id":"PMC_19930558","title":"Genome-wide analysis of major intrinsic proteins in the tree plant Populus trichocarpa: characterization of XIP subfamily of aquaporins from evolutionary perspective.","date":"2009","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/19930558","citation_count":163,"is_preprint":false},{"pmid":"26719542","id":"PMC_26719542","title":"HBXIP and LSD1 Scaffolded by lncRNA Hotair Mediate Transcriptional Activation by c-Myc.","date":"2015","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26719542","citation_count":115,"is_preprint":false},{"pmid":"33305825","id":"PMC_33305825","title":"HBXIP drives metabolic reprogramming in hepatocellular carcinoma cells via METTL3-mediated m6A modification of HIF-1α.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33305825","citation_count":100,"is_preprint":false},{"pmid":"15181003","id":"PMC_15181003","title":"The dual nature of the wheat xylanase protein inhibitor XIP-I: structural basis for the inhibition of family 10 and family 11 xylanases.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15181003","citation_count":95,"is_preprint":false},{"pmid":"26980761","id":"PMC_26980761","title":"Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26980761","citation_count":83,"is_preprint":false},{"pmid":"28938560","id":"PMC_28938560","title":"Inflammatory factor TNF-α promotes the growth of breast cancer via the positive feedback loop of TNFR1/NF-κB (and/or p38)/p-STAT3/HBXIP/TNFR1.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28938560","citation_count":82,"is_preprint":false},{"pmid":"10751315","id":"PMC_10751315","title":"Interaction of PIP(2) with the XIP region of the cardiac Na/Ca exchanger.","date":"2000","source":"American journal of physiology. 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17715986","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52095,"output_tokens":10733,"usd":0.15864,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21378,"output_tokens":4413,"usd":0.108607,"stage2_stop_reason":"end_turn"},"total_usd":0.267247,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"HBXIP functions as a cofactor for survivin: survivin-HBXIP complexes (but neither protein alone) bind pro-caspase-9, preventing its recruitment to Apaf1 and thereby selectively suppressing apoptosis initiated via the mitochondria/cytochrome c pathway. Viral HBx protein also interacts with the survivin-HBXIP complex to suppress caspase activation in a survivin-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, biochemical complex reconstitution, caspase activity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal Co-IP with functional reconstitution showing complex-specific (not individual protein) activity, replicated across multiple assays in a single rigorous study\",\n      \"pmids\": [\"12773388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HBXIP is required for bipolar spindle formation and centrosome duplication: HBXIP-deficient cells arrest in prometaphase with monopolar spindles, while HBXIP overexpression causes excessive centrosome replication and tripolar/multipolar spindles. HBXIP associates with microtubules of dividing cells and colocalizes with HBx on centrosomes. HBXIP-deficient cells also fail to complete cytokinesis and undergo apoptosis. In a mouse liver-regeneration model, antisense knockdown of HBXIP impairs hepatocyte growth and survival.\",\n      \"method\": \"RNAi knockdown, overexpression, immunolocalization, fluorescent protein tagging, antisense oligonucleotides in vivo\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, OE, imaging, in vivo model) establishing a defined centrosome/spindle regulatory role with specific cellular phenotypes\",\n      \"pmids\": [\"16982752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The CRHK (residues 137-140) motif in HBx is necessary for binding HBXIP. Mutation of this motif abolishes HBx binding to HBXIP, prevents HBx localization to centrosomes, and abrogates HBx-induced dysregulation of centrosome assembly and modifications of pericentrin and centrin-2. Overexpression of HBXIP or HBXIP fragments that bind HBx neutralizes the effects of viral HBx on centrosome dynamics.\",\n      \"method\": \"Deletion mutagenesis, site-directed mutagenesis, Co-IP, subcellular fractionation, immunofluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis defining binding motif combined with functional rescue experiments and subcellular localization studies with multiple orthogonal methods\",\n      \"pmids\": [\"18032378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HBXIP overexpression promotes cell proliferation in MCF-7, H7402, and L-O2 cells, upregulating c-Myc, Bcl-2, and PCNA while downregulating p27. RNAi-mediated knockdown of HBXIP produces opposite effects, demonstrating a role in cell proliferation regulation.\",\n      \"method\": \"Plasmid transfection, RNAi, MTT assay, BrdU incorporation, flow cytometry, Western blot\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with cell cycle readouts and molecular markers, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17303008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HBXIP interacts with the mitochondrial RNA/DNA helicase hSuv3p. The HBXIP-binding domain identified within hSuv3p is important for mitochondrial import and stability of the Suv3 protein in vivo, suggesting involvement in a survivin-dependent antiapoptotic pathway.\",\n      \"method\": \"Co-immunoprecipitation, deletion analysis, in vivo stability assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with deletion mapping and in vivo functional consequence (protein stability), single lab\",\n      \"pmids\": [\"16176273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the shortest HBXIP isoform (91 aa) at 1.5 Å resolution reveals a profilin-like fold characteristic of the Roadblock/LC7 domain family. Small-angle X-ray scattering confirms the protein is dimeric in solution, with the dimer interface featuring an extended anti-parallel β-sheet and a small leucine zipper between α2 helices.\",\n      \"method\": \"X-ray crystallography, small-angle X-ray scattering (SAXS)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure validated by SAXS in solution, single rigorous study with two orthogonal structural methods\",\n      \"pmids\": [\"21059355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HBXIP up-regulates S100A4 via two pathways: (1) HBXIP directly binds the +200~+239 region of the S100A4 promoter and activates it through interaction with transcription factor STAT4; (2) HBXIP activates PI3K/AKT signaling by inducing DNA methylation of PTEN, which boosts S100A4 expression. Both pathways promote growth and migration of breast cancer cells.\",\n      \"method\": \"ChIP assay, EMSA, co-immunoprecipitation, DNA methylation analysis, luciferase reporter assay, in vitro/in vivo functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, EMSA, Co-IP, methylation, luciferase, in vivo) establishing two distinct mechanistic pathways in one study\",\n      \"pmids\": [\"22740693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HBXIP upregulates complement regulatory proteins CD46, CD55, and CD59 through activation of p-ERK1/2/NF-κB signaling, protecting breast cancer cells from complement-dependent cytotoxicity.\",\n      \"method\": \"Western blot, siRNA knockdown, luciferase reporter assay, in vivo animal experiments\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain/loss-of-function with pathway inhibition and in vivo validation, single lab\",\n      \"pmids\": [\"22293503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HBXIP acts as a co-activator of TF IID by directly binding the TATA-binding protein (TBP): Co-IP and GST pull-down validate direct HBXIP-TBP binding; HBXIP occupies the Lin28B promoter region (-1199/-1073 nt) and transactivates Lin28B expression to promote breast cancer cell proliferation.\",\n      \"method\": \"Co-IP, GST pull-down, ChIP, EMSA, luciferase reporter assay, in vitro/in vivo proliferation assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein-protein interaction confirmed by two independent methods (Co-IP + GST pull-down) combined with ChIP and promoter functional assays\",\n      \"pmids\": [\"23494474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HBXIP activates the LMO4 promoter by binding Sp1 at the -237/-206 region containing an Sp1 binding element; mutation of the Sp1 binding site blocks HBXIP-promoter interaction. HBXIP-elevated LMO4 upregulates cyclin D1 and cyclin E, promoting breast cancer cell proliferation.\",\n      \"method\": \"ChIP, EMSA, Co-IP, luciferase reporter assay, flow cytometry, MTT, EdU, xenograft assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, EMSA, Co-IP, mutagenesis of binding site, functional assays), single lab\",\n      \"pmids\": [\"23291272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HBXIP upregulates Skp2 by activating the Skp2 promoter (-640/-443 region) through binding E2F1 transcription factor, promoting breast cancer cell proliferation in vitro and in vivo.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, in vitro/in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP plus luciferase with functional validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"23352642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HBXIP promotes migration of breast cancer cells through the MEKK2/ERK1/2/Capn4 signaling cascade: HBXIP upregulates MEKK2, which activates ERK1/2, which upregulates Calpain small subunit 1 (Capn4), leading to increased filopodia formation and cell migration.\",\n      \"method\": \"Western blot, siRNA knockdown, luciferase reporter assay, immunofluorescence, migration assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — linear pathway established through sequential knockdown experiments with specific cellular phenotype readout, single lab\",\n      \"pmids\": [\"25304384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HBXIP enhances angiogenesis in breast cancer through two pathways: (1) HBXIP directly binds CREB at the FGF8 promoter to upregulate FGF8; (2) HBXIP inhibits miR-503, which directly targets the 3'UTR of FGF8 and VEGF mRNA. HBXIP-induced FGF8 further upregulates VEGF via PI3K/Akt/HIF-1α signaling.\",\n      \"method\": \"ChIP, luciferase reporter assay, Co-IP, siRNA knockdown, Matrigel angiogenesis assay, in vivo hemoglobin content analysis\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple pathways characterized with ChIP, Co-IP, miRNA target validation, and in vivo readout, single lab\",\n      \"pmids\": [\"24464787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HBXIP interacts directly with c-Myc through leucine zippers and recruits lncRNA Hotair along with histone demethylase LSD1 (for which Hotair serves as a scaffold) to activate transcription of c-Myc target genes (cyclin A, eIF4E, LDHA) in breast cancer cells.\",\n      \"method\": \"Co-IP, ChIP, luciferase reporter assay, RNAi knockdown, in vitro/in vivo tumor growth assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing direct leucine zipper interaction, combined with ChIP demonstrating promoter occupancy and functional in vivo validation\",\n      \"pmids\": [\"26719542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HBXIP upregulates HDAC6 via NF-κB activation, causing HDAC6-mediated deacetylation of MST1 at lysine 35. Deacetylated MST1 interacts with HSC70, leading to lysosome-dependent (chaperone-mediated autophagy) degradation of MST1, reducing Hippo pathway tumor suppressor activity and promoting breast cancer growth.\",\n      \"method\": \"Co-IP, Western blot, trichostatin A treatment, siRNA knockdown, luciferase reporter assay, in vitro/in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — post-translational modification at specific residue identified, degradation mechanism characterized with inhibitor, Co-IP confirming protein-protein interactions, multiple orthogonal methods in single lab study\",\n      \"pmids\": [\"26657153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HBXIP promotes glucose metabolism reprogramming in breast cancer by elevating miR-183/96/182 cluster expression through HIF-1α stabilization: HBXIP disassociates pVHL from HIF-1α to increase HIF-1α stability, and elevated miR-183 further increases HIF-1α by targeting VHL mRNA CDS (forming a feedback loop). miR-183/182 and miR-96 directly inhibit SCO2 and PDHA1 through their coding sequences, switching metabolism from oxidative phosphorylation to aerobic glycolysis.\",\n      \"method\": \"Western blot, Co-IP, luciferase reporter assay, miRNA target validation, metabolic assays (glucose/lactate/ROS), in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mechanistic pathway established with multiple methods, single lab, pathway complexity adds uncertainty\",\n      \"pmids\": [\"26309161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HBXIP promotes migration of breast cancer cells via GCN5-mediated microtubule acetylation: HBXIP increases α-tubulin acetylation, requires acetyltransferase GCN5 for this effect, and GCN5 is required for HBXIP-enhanced directional cell migration.\",\n      \"method\": \"Immunofluorescence, Western blot, wound-healing assay, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional epistasis between HBXIP and GCN5 in microtubule acetylation and migration, single lab, limited mechanistic depth on HBXIP-GCN5 interaction\",\n      \"pmids\": [\"25686500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HBXIP contributes to abnormal lipid metabolism in breast cancer by coactivating nuclear receptors LXRs independent of ligand (via a corepressor/nuclear receptor motif with special flanking sequence), upregulating SREBP-1c (SREBF1), which activates FAS transcription. SREBP-1c in turn activates HBXIP transcription, forming a positive feedback loop (HBXIP→LXR→SREBP-1c→FAS and SREBP-1c→HBXIP).\",\n      \"method\": \"Co-IP, luciferase reporter assay, ChIP, siRNA knockdown, lipogenesis assay, in vitro/in vivo tumor growth assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein-protein interaction (Co-IP), promoter occupancy (ChIP), and functional validation in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"26980761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HBXIP suppresses gluconeogenesis in hepatoma cells by inhibiting PCK1 through two mechanisms: (1) upregulation of miR-135a targeting FOXO1 mRNA 3'UTR; (2) activation of PI3K/Akt pathway, increasing FOXO1 phosphorylation and nuclear export, thereby reducing PCK1 transcription. PCK1 overexpression abolishes HBXIP-promoted hepatoma growth.\",\n      \"method\": \"Western blot, luciferase reporter assay, siRNA knockdown, PI3K/Akt pathway inhibition, in vitro/in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — two mechanistic pathways characterized with functional rescue experiment, single lab\",\n      \"pmids\": [\"27609066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HBXIP upregulates YAP in hepatoma cells by co-activating transcription factor c-Myb at the YAP promoter. Silencing YAP abolishes HBXIP-mediated hepatoma cell proliferation in vitro and in vivo.\",\n      \"method\": \"ChIP, luciferase reporter assay, Co-IP, siRNA knockdown, in vitro/in vivo proliferation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ChIP establishing co-activation mechanism with functional validation, single lab\",\n      \"pmids\": [\"27765671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HBXIP upregulates METTL3 by suppressing miRNA let-7g (which targets METTL3 3'UTR). METTL3 in turn increases HBXIP expression through m6A modification, forming a positive feedback loop (HBXIP→suppression of let-7g→METTL3→m6A modification→HBXIP). This loop promotes breast cancer cell proliferation.\",\n      \"method\": \"Western blot, luciferase reporter assay, m6A modification assay, siRNA knockdown, cell proliferation/apoptosis assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — feedback loop established with multiple methods, but m6A mechanism details are limited in the abstract, single lab\",\n      \"pmids\": [\"29174803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TNF-α upregulates HBXIP expression in breast cancer cells via TNFR1: NF-κB and/or p38 signaling activates STAT3, which increases HBXIP promoter activity. HBXIP reciprocally upregulates TNFR1, forming a positive feedback loop (TNFR1→NF-κB/p38→p-STAT3→HBXIP→TNFR1) that promotes breast cancer growth.\",\n      \"method\": \"Western blot, luciferase reporter assay, siRNA knockdown, in vitro/in vivo tumor growth assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — signaling pathway established with receptor knockdown and multiple pathway inhibition experiments, in vivo validation, single lab\",\n      \"pmids\": [\"28938560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HBXIP upregulates ACSL1 in breast cancer cells by acting as a coactivator of transcription factor Sp1, binding to the ACSL1 promoter as demonstrated by ChIP assay.\",\n      \"method\": \"Western blot, qRT-PCR, ChIP, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP confirming promoter binding with luciferase reporter validation, single lab\",\n      \"pmids\": [\"28132807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HBXIP prevents chaperone-mediated autophagy (CMA)-dependent degradation of HOXB13 by enhancing HOXB13 acetylation at lysine 277, causing HOXB13 protein accumulation. HBXIP also acts as a co-activator of HOXB13 to stimulate IL-6 transcription, promoting tamoxifen resistance in breast cancer.\",\n      \"method\": \"Co-IP, Western blot, luciferase reporter assay, ChIP, site-directed mutagenesis of K277, siRNA knockdown, xenograft assay\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific acetylation site identified with mutagenesis, CMA mechanism characterized, co-activation demonstrated by ChIP and Co-IP, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"29471853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HBXIP modulates the MDM2/p53 feedback loop: HBXIP suppresses miR-18b by inducing DNA methylation of the miR-18b gene, elevating MDM2. HBXIP also promotes MDM2 phosphorylation via activating AKT and directly binds phospho-MDM2, enhancing MDM2-p53 interaction and p53 degradation in breast cancer cells.\",\n      \"method\": \"Western blot, Co-IP, luciferase reporter assay, DNA methylation analysis, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — two mechanistic pathways with Co-IP confirming HBXIP-pMDM2 interaction, in vivo validation, single lab\",\n      \"pmids\": [\"30181579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HBXIP upregulates PKM2 in ER+ breast cancer cells by co-activating E2F1 at the PKM promoter (-779/-579 region), accelerating cell proliferation.\",\n      \"method\": \"ChIP, luciferase reporter assay, Western blot, Co-IP, tissue microarray, xenograft assay\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP confirming promoter occupancy with Co-IP and functional validation, single lab\",\n      \"pmids\": [\"29925919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LAMTOR5 (HBXIP) regulates TLR4 signaling and inflammation: Lamtor5 associates with TLR4 via their LZ/TIR domains and facilitates colocalization at autolysosomes, preventing lysosomal tethering and mTORC1 activation upon LPS stimulation, thereby de-repressing TFEB to promote autophagic degradation of TLR4. Loss of Lamtor5 leads to sustained inflammation and increased mortality in endotoxic shock mice. Leucine deprivation blunts inflammatory signaling through this Lamtor5-dependent mechanism.\",\n      \"method\": \"Co-IP (LZ/TIR domain interaction), colocalization imaging, TFEB reporter assay, Lamtor5 haploinsufficient mouse model, in vivo endotoxic shock model\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein-protein interaction defined by domain mapping, in vivo mouse model with specific mortality phenotype, mechanistic pathway (mTORC1-TFEB-autophagy) characterized with multiple methods\",\n      \"pmids\": [\"31467416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LAMTOR5 stimulates transcription of O-glycosylation enzyme GALNT1 by coactivating c-Jun at the GALNT1 promoter, and triggers dislocation of GALNT1 from the ER via LAMTOR5-dependent activation of c-Src, leading to accumulation of Tn-modified glycoproteins (MUC1, OPN) and promoting breast cancer metastasis.\",\n      \"method\": \"ChIP, luciferase reporter assay, Co-IP, immunofluorescence, Western blot, secondary metastasis mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirming co-activation of c-Jun, Co-IP for c-Src interaction, subcellular localization change demonstrated, in vivo metastasis model, multiple orthogonal methods\",\n      \"pmids\": [\"31836847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBXIP competitively binds KEAP1 via its conserved GLNLG motif, displacing NRF2 from KEAP1 complexes, promoting NRF2 accumulation and nuclear entry, activating ARE-dependent signaling and reducing intracellular ROS. Mutation of the GLNLG motif abolishes HBXIP-KEAP1 interaction and potently inhibits breast cancer malignancy in vivo and in vitro.\",\n      \"method\": \"Co-IP, competitive binding assay, GLNLG motif mutagenesis, NRF2 nuclear localization assay, ROS measurement, in vitro/in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific binding motif identified with mutagenesis abolishing interaction, competitive displacement mechanism demonstrated, in vivo functional validation\",\n      \"pmids\": [\"30692632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HBXIP induces HMGA2 acetylation at lysine 26 (K26) by activating acetyltransferase PCAF through the Akt pathway (HBXIP→Akt→p-PCAF→PCAF-HMGA2 interaction→K26 acetylation). K26 acetylation enhances HMGA2 DNA binding capacity, blocks ubiquitination, and inhibits proteasomal degradation, stabilizing HMGA2 to promote ESCC growth.\",\n      \"method\": \"Co-IP, site-directed mutagenesis (K26), Western blot, Akt pathway inhibition, ubiquitination assay, in vitro/in vivo functional assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific acetylation site identified by mutagenesis, kinase pathway established, writer (PCAF) identified via Co-IP, ubiquitination crosstalk demonstrated, in vivo validation\",\n      \"pmids\": [\"32313942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HBXIP drives metabolic reprogramming in HCC cells via upregulation of METTL3, which mediates m6A modification of HIF-1α mRNA. METTL3 was shown to physically bind HIF-1α and mediate its m6A modification; HBXIP-mediated METTL3 upregulation restores metabolic reprogramming when HBXIP is partially lost.\",\n      \"method\": \"m6A RNA immunoprecipitation, dot-blot assay, Co-IP (METTL3-HIF-1α binding), Western blot, siRNA knockdown, rescue experiments\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — m6A modification and binding relationship demonstrated, functional rescue performed, single lab\",\n      \"pmids\": [\"33305825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HBXIP stimulates PD-L1 transcription by co-activating transcription factor ETS2, and induces PD-L1 acetylation at K270 by interacting with acetyltransferase p300, leading to PD-L1 protein stability and promotion of breast cancer growth.\",\n      \"method\": \"Co-IP, ChIP, luciferase reporter assay, RNA-seq, acetylation assay, siRNA knockdown, in vitro/in vivo functional assays\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — two mechanisms (transcriptional co-activation and acetylation writer identification) established with Co-IP and ChIP, single lab\",\n      \"pmids\": [\"33824459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HBXIP (LAMTOR5) interacts with the Ragulator complex subunits and is required for mTORC1 activation by amino acids; homozygous knockout of Hbxip in mice causes embryonic lethality with retarded growth at ~E7.5. Hbxip-null ESCs show defects in self-renewal, reduced pluripotency gene expression, and impaired ectodermal/mesodermal differentiation, mirroring phenotypes of Lamtor3 and Lamtor4 knockout ESCs.\",\n      \"method\": \"Co-IP (Ragulator complex interaction), homozygous knockout mouse model, ESC culture/differentiation assays, gene expression analysis, epistasis with other Ragulator subunit knockouts\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct Ragulator complex membership confirmed by Co-IP, in vivo lethality phenotype replicated across multiple Ragulator subunit knockouts demonstrating pathway epistasis, in vitro ESC differentiation assays\",\n      \"pmids\": [\"35608036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HBXIP directly interacts with the assembly-competent domain (ACD) of non-muscle myosin heavy chain IIA (NMHC-IIA) as shown by mass spectrometry, Co-IP, and GST pull-down. HBXIP recruits PKCβII (whose transcription HBXIP induces via Sp1 coactivation), which phosphorylates NMHC-IIA at S1916, enhancing HBXIP-NMHC-IIA interaction and promoting myosin-IIA disassembly, thereby facilitating breast cancer cell migration.\",\n      \"method\": \"Mass spectrometry, Co-IP, GST pull-down, Western blot, phosphorylation assay, RNA-seq, in vivo metastasis model\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction confirmed by three independent methods (MS, Co-IP, GST pull-down), phosphorylation site identified, kinase writer identified, in vivo validation\",\n      \"pmids\": [\"36970214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HBXIP acts as a chaperone of IRE1α (UPR transducer inositol-requiring enzyme 1a) to diminish tamoxifen-induced ER stress in tamoxifen-resistant breast cancer. HBXIP deficiency hyperactivates IRE1α and its downstream pro-apoptotic pathways, and simultaneously induces ROS accumulation that activates PERK and ATF6α branches of the UPR.\",\n      \"method\": \"Co-IP, Western blot, luciferase UPR-element reporter assay, ROS measurement, siRNA knockdown, in vitro/in vivo functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP establishing IRE1α chaperone interaction with functional consequences characterized, single lab\",\n      \"pmids\": [\"35093383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HBXIP prevents sorafenib-induced ferroptosis in HCC by transcriptionally inducing stearoyl-CoA desaturase (SCD) via coactivation of transcription factor ZNF263, resulting in accumulation of free fatty acids and suppression of lipid peroxidation/ferroptosis.\",\n      \"method\": \"ChIP, luciferase reporter assay, Co-IP, malondialdehyde (MDA) measurement, glutathione (GSH) assay, ferroptosis inhibitor rescue, in vitro/in vivo functional assays\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-activation of ZNF263 at SCD promoter established by ChIP and Co-IP, ferroptosis mechanism confirmed with pharmacological rescue, single lab\",\n      \"pmids\": [\"36109580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lamtor5 is physically associated with ATP6V1A (essential subunit of vacuolar H+-ATPase/v-ATPase) and promotes V0/V1 holoenzyme assembly to facilitate lysosome acidification. Lamtor5 binding to v-ATPase also affects lysosomal tethering of Rag GTPase and weakens Rag GTPase interaction with mTORC1. Loss of Lamtor5 impairs lysosomal function and causes aberrant mTORC1 activation, blunted autolysosomal pathway, and SLE-like manifestations in myeloid-specific knockout mice.\",\n      \"method\": \"Co-IP (Lamtor5-ATP6V1A interaction), v-ATPase assembly assay, lysosome acidification assay, myeloid-specific knockout mouse model, Rag GTPase-mTORC1 interaction assays, analysis of PBMCs from SLE patients\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein-protein interaction (Co-IP), enzymatic complex assembly demonstrated, in vivo mouse model with SLE-like phenotype, mechanistic pathway (v-ATPase→lysosome acidification→Rag-mTORC1) characterized with multiple methods\",\n      \"pmids\": [\"38639386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LAMTOR5 silences CHOP expression via two mechanisms: (1) LAMTOR5 recruits DNMT1 to the CpG3 region (-559/-429) of the CHOP promoter to promote DNA hypermethylation, blocking TFII-I binding; (2) LAMTOR5-enhanced miR-182/miR-769 reduce CHOP expression by targeting its 3'UTR. CHOP suppression reduces ER stress-related apoptosis and promotes liver cancer growth.\",\n      \"method\": \"Co-IP (DNMT1 recruitment), ChIP (promoter methylation), DNA methylation assay, luciferase reporter assay, miRNA target validation, siRNA knockdown, in vitro/in vivo functional assays\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — two distinct silencing mechanisms characterized with ChIP, Co-IP, methylation assay, and miRNA validation, single lab\",\n      \"pmids\": [\"38942954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HBXIP modulates the MDM2/p53 feedback loop by directly binding p53 at the P2 promoter of MDM2 and recruiting acetyltransferase p300 to p53 at the MDM2 promoter, increasing MDM2 transcription. Elevated MDM2 enhances p53 degradation, forming an accelerated feedback loop promoting breast cancer growth.\",\n      \"method\": \"Co-IP (HBXIP-p53 and HBXIP-p300 interactions), ChIP, luciferase reporter assay, siRNA knockdown, in vitro/in vivo functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP confirming direct protein-protein interactions, ChIP demonstrating promoter occupancy, functional validation in vivo, single lab\",\n      \"pmids\": [\"26229107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HBXIP promotes NSCLC tumorigenesis by binding MEK1 protein, preventing proteasome-mediated degradation of MEK1 and thereby promoting MAPK/ERK signaling pathway activation. In vivo xenografts confirm HBXIP deficiency decreases MEK1 protein levels and tumor growth.\",\n      \"method\": \"Co-IP, Western blot, immunofluorescence, proteasome inhibition assays, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP establishing HBXIP-MEK1 interaction with proteasomal degradation mechanism, in vivo validation, single lab\",\n      \"pmids\": [\"33628588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HBXIP significantly stimulates hTERT promoter activity and telomerase activity in human mesenchymal stem cells, upregulating hTERT, c-Myc, and Bcl-2 expression, providing a mechanism for HBXIP-promoted cell proliferation.\",\n      \"method\": \"Luciferase reporter assay, TRAP (telomeric repeat amplification protocol), Western blot, RNAi knockdown, plasmid transfection\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain- and loss-of-function with specific telomerase activity assay and promoter reporter, single lab\",\n      \"pmids\": [\"18158869\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LAMTOR5/HBXIP is a multifunctional oncogenic scaffold protein that serves as: (1) a core subunit of the Ragulator complex on late endosomes/lysosomes, required for mTORC1 activation by amino acids, v-ATPase assembly and lysosomal acidification, and regulation of TLR4 autophagic degradation; (2) an anti-apoptotic cofactor that, in complex with survivin, binds pro-caspase-9 to suppress mitochondria-initiated apoptosis; (3) a transcriptional co-activator that directly binds transcription factors (Sp1, c-Myc, E2F1, STAT4, LXRs, c-Jun, ETS2, c-Myb, NF-κB/p65) and recruits chromatin-modifying complexes (LSD1/Hotair, p300, PCAF) to activate diverse cancer-promoting gene programs; and (4) a regulator of post-translational modifications (promoting acetylation of MST1, HOXB13, HMGA2, PD-L1; interacting with KEAP1 to activate NRF2; recruiting PKCβII to phosphorylate NMHC-IIA) that collectively reprogram cell metabolism, cytoskeletal dynamics, centrosome duplication, and immune evasion to drive cancer progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LAMTOR5 (HBXIP) is a small Roadblock/LC7-domain protein that adopts a profilin-like fold and dimerizes in solution [#5], functioning as both a core lysosomal signaling subunit and a multifunctional oncogenic scaffold/transcriptional co-activator. As a Ragulator subunit, it associates with the complex and is required for amino-acid-dependent mTORC1 activation, with homozygous knockout causing embryonic lethality and ESC self-renewal/differentiation defects that phenocopy other Ragulator subunit losses [#32]; it physically binds the v-ATPase subunit ATP6V1A to promote V0/V1 holoenzyme assembly and lysosomal acidification, thereby tuning Rag GTPase–mTORC1 coupling, with myeloid-specific loss producing SLE-like disease in mice [#36]. Through interaction of its leucine-zipper/TIR-like surface with TLR4, LAMTOR5 routes TLR4 to autolysosomal degradation by restraining mTORC1 and de-repressing TFEB, limiting inflammation [#26]. In its earliest-described role it acts with survivin to bind pro-caspase-9 and block mitochondrial apoptosis [#0], and it controls centrosome duplication and bipolar spindle formation, associating with mitotic microtubules [#1]. A dominant theme across cancer studies is its function as a transcriptional co-activator that directly binds TBP and diverse transcription factors—Sp1, c-Myc, E2F1, STAT4, c-Jun, c-Myb, ETS2, CREB, LXRs, ZNF263—to drive proliferative, metabolic, angiogenic and immune-evasion gene programs [#8, #13, #17, #6], recruiting chromatin and modifying machinery such as the Hotair/LSD1 scaffold to c-Myc target genes [#13]. LAMTOR5 additionally governs protein stability and post-translational modification: it displaces NRF2 from KEAP1 via a GLNLG motif to activate antioxidant ARE signaling [#28], directs site-specific acetylation of HMGA2 (K26 via PCAF) and HOXB13 (K277) to block their degradation [#29, #23], and recruits PKCβII to phosphorylate NMHC-IIA to promote myosin disassembly and migration [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the first molecular function of HBXIP—how a small protein could suppress apoptosis—by showing it acts only in complex with survivin rather than alone.\",\n      \"evidence\": \"Co-IP, complex reconstitution and caspase assays showing survivin-HBXIP (not either alone) binds pro-caspase-9\",\n      \"pmids\": [\"12773388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the survivin-HBXIP-procaspase-9 interaction not resolved\", \"Did not address whether this role is separable from later scaffold/Ragulator functions\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a cell-cycle function by linking HBXIP to centrosome duplication and bipolar spindle assembly, explaining its requirement for mitotic fidelity and growth.\",\n      \"evidence\": \"RNAi, overexpression, immunolocalization to mitotic microtubules, and in vivo liver regeneration model\",\n      \"pmids\": [\"16982752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular partners at the centrosome not identified\", \"Mechanism linking centrosome role to its other activities unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural foundation, revealing a Roadblock/LC7 profilin-like fold and a dimeric architecture that rationalizes scaffolding and complex membership.\",\n      \"evidence\": \"1.5 Å X-ray crystal structure of the 91-aa isoform plus SAXS confirming solution dimer\",\n      \"pmids\": [\"21059355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of HBXIP within Ragulator or with transcription-factor partners not determined\", \"Functional consequence of dimerization for signaling untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Recast HBXIP as a transcriptional co-activator by demonstrating direct TBP binding and promoter occupancy, generalizing a mechanism that would explain its broad gene-activation activity.\",\n      \"evidence\": \"Co-IP, GST pull-down, ChIP and reporter assays at the Lin28B promoter\",\n      \"pmids\": [\"23494474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HBXIP is recruited to specific promoters genome-wide not defined\", \"Stoichiometry within transcription preinitiation complexes unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed how HBXIP couples to chromatin-modifying machinery, binding c-Myc via leucine zippers and recruiting the Hotair/LSD1 scaffold to activate c-Myc target genes.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, reporter and in vivo tumor growth assays\",\n      \"pmids\": [\"26719542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. bridged contact with LSD1 not dissected\", \"Generality of Hotair recruitment to other TF partners untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a metabolic gene-regulatory role through ligand-independent LXR co-activation feeding a SREBP-1c/FAS lipogenic loop, defining HBXIP as a driver of tumor lipid metabolism.\",\n      \"evidence\": \"Co-IP, ChIP, reporter, lipogenesis and in vivo tumor assays\",\n      \"pmids\": [\"26980761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ligand-independent nuclear-receptor coactivation not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified motif-specific control of protein stability—HBXIP displaces NRF2 from KEAP1 via a GLNLG motif—establishing an antioxidant/ROS-lowering function distinct from its transcriptional role.\",\n      \"evidence\": \"Co-IP, competitive binding, GLNLG mutagenesis abolishing interaction, ROS and in vivo assays\",\n      \"pmids\": [\"30692632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KEAP1 competition is regulated dynamically in cells unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected LAMTOR5 to innate immunity by showing it routes TLR4 to autolysosomal degradation through mTORC1 restraint and TFEB de-repression, defining an anti-inflammatory checkpoint.\",\n      \"evidence\": \"Domain-mapped Co-IP (LZ/TIR), colocalization, TFEB reporter, and haploinsufficient endotoxic-shock mouse model\",\n      \"pmids\": [\"31467416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How leucine availability gates this pathway mechanistically not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved a mechanism by which HBXIP stabilizes oncoproteins, directing PCAF-mediated K26 acetylation of HMGA2 to block its ubiquitination and degradation.\",\n      \"evidence\": \"Co-IP, K26 mutagenesis, Akt-pathway inhibition, ubiquitination and in vivo ESCC assays\",\n      \"pmids\": [\"32313942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HBXIP directly contacts PCAF or acts via Akt signaling not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined LAMTOR5 as a bona fide Ragulator subunit essential for amino-acid-driven mTORC1 activation and embryonic development, anchoring its lysosomal-signaling identity.\",\n      \"evidence\": \"Co-IP, homozygous knockout (embryonic lethal), and ESC self-renewal/differentiation assays with epistasis to other Ragulator subunits\",\n      \"pmids\": [\"35608036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural position within Ragulator not defined\", \"Relationship between Ragulator role and transcriptional functions unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked LAMTOR5 to cytoskeletal dynamics by direct binding of the NMHC-IIA assembly-competent domain and recruitment of PKCβII to phosphorylate myosin-IIA, explaining a migration-promoting mechanism.\",\n      \"evidence\": \"MS, Co-IP, GST pull-down, phospho-site mapping (S1916) and in vivo metastasis model\",\n      \"pmids\": [\"36970214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HBXIP couples its scaffolding to kinase recruitment spatially unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mechanistically tied LAMTOR5 to lysosomal acidification through ATP6V1A binding and v-ATPase holoenzyme assembly, linking its loss to defective mTORC1 control and SLE-like autoimmunity.\",\n      \"evidence\": \"Co-IP, v-ATPase assembly and acidification assays, myeloid-specific knockout mice, and SLE patient PBMC analysis\",\n      \"pmids\": [\"38639386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural interface with ATP6V1A not determined\", \"How acidification feeds back to its transcriptional functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single small Roadblock-domain protein integrates a lysosomal Ragulator/v-ATPase signaling identity with a nuclear transcriptional co-activator identity—what governs its partitioning between these compartments and partners—remains unresolved.\",\n      \"evidence\": \"No single study reconciles the lysosomal and nuclear roles within one mechanistic framework\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of HBXIP bound to its diverse TF partners\", \"Determinants of subcellular partitioning between lysosome and nucleus unknown\", \"Whether dimerization switches between functional pools untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 13, 17, 6, 9, 10, 19, 22, 25, 31, 35]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 32, 36, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [28, 26, 39]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [26, 36]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 13, 17]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [32, 36, 26]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 13, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [26, 36]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 36]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [17, 15, 18]}\n    ],\n    \"complexes\": [\"Ragulator\", \"survivin-HBXIP complex\", \"v-ATPase (via ATP6V1A)\"],\n    \"partners\": [\"survivin\", \"TBP\", \"c-Myc\", \"KEAP1\", \"ATP6V1A\", \"TLR4\", \"NMHC-IIA\", \"p300\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}