{"gene":"LAPTM4B","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2003,"finding":"LAPTM4B encodes two protein isoforms (LAPTM4B-35 at 35 kDa and LAPTM4B-24 at 24 kDa) with four putative transmembrane regions; the protein localizes predominantly to intracellular membranes; co-immunoprecipitation demonstrated that LAPTM4B forms complexes with integrin α6 and EGFR when cells are seeded on laminin substrate.","method":"Western blot, 2D electrophoresis, immunohistochemistry, co-immunoprecipitation","journal":"Beijing da xue xue bao (Journal of Peking University Health Sciences)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, co-IP plus multiple orthogonal characterization methods; no functional rescue or reconstitution","pmids":["12947545"],"is_preprint":false},{"year":2003,"finding":"LAPTM4B overexpression in NIH3T3 cells promotes cell proliferation by accelerating S-phase entry with upregulation of Cyclin E, increases attachment/spreading on fibronectin/matrigel/laminin, decreases serum dependence, and causes tumorigenesis (fibrosarcoma formation at 50% rate) in mice.","method":"Eukaryotic expression, RT-PCR, Northern/Western blot, flow cytometry, cell growth curves, scanning electron microscopy, in vivo tumorigenesis assay","journal":"Beijing da xue xue bao (Journal of Peking University Health Sciences)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean overexpression with multiple orthogonal phenotypic readouts including in vivo tumorigenesis, single lab","pmids":["12947546"],"is_preprint":false},{"year":2009,"finding":"The PPRP motif in the N-terminal region of LAPTM4B-35 is critical for promoting cell proliferation, migration, and invasion, as well as upregulation of oncoproteins c-Myc, c-Jun, c-Fos, cyclin D1, and cyclin E; mutagenesis of the PPRP motif abolished these effects.","method":"Overexpression, site-directed mutagenesis, proliferation/migration/invasion assays, Western blot","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis establishing motif function, single lab, multiple phenotypic readouts","pmids":["19843073"],"is_preprint":false},{"year":2010,"finding":"LAPTM4B overexpression causes sequestration of the anthracycline doxorubicin in the cytosol, delaying its appearance in the nucleus, thereby contributing to anthracycline resistance; siRNA knockdown sensitizes tumor cells to anthracyclines.","method":"siRNA knockdown, overexpression, fluorescence imaging of doxorubicin localization, cell viability assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with direct drug localization imaging, replicated across multiple cohorts","pmids":["20098429"],"is_preprint":false},{"year":2010,"finding":"LAPTM4B-35 promotes multidrug resistance by (1) colocalizing and directly interacting with MDR1/P-glycoprotein to enhance drug efflux of doxorubicin, paclitaxel, and cisplatin, and (2) activating PI3K/AKT signaling through interaction of its N-terminal PPRP motif with the p85α regulatory subunit of PI3K.","method":"Co-IP, colocalization studies, PI3K inhibitor treatment, RNAi knockdown, drug efflux assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, colocalization, pharmacological inhibition, and loss-of-function all converging on same mechanism","pmids":["20711237"],"is_preprint":false},{"year":2011,"finding":"LAPTM4B is required for lysosome homeostasis and acidification; its depletion increases lysosomal membrane permeability, raises lysosomal pH, causes cathepsin release, and induces cellular apoptosis. LAPTM4B loss also blocks autophagosome maturation at late stages, rendering cells sensitive to nutrient deprivation or hypoxia. Conversely, overexpression promotes autophagic flux and cell survival during starvation and accelerates in vivo tumor growth.","method":"siRNA knockdown, overexpression, lysosomal permeability assays, pH measurement, cathepsin release assay, autophagy flux assays, in vivo xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with multiple orthogonal mechanistic readouts including in vivo validation","pmids":["22037872"],"is_preprint":false},{"year":2011,"finding":"Upregulation of LAPTM4B-35 in normal liver L02 cells activates the PI3K/AKT/Bcl-xL/Bad signaling pathway, inhibits caspase-3 activation, upregulates Bcl-2, and downregulates Bax, thereby promoting anchorage-independent proliferation, resistance to adriamycin-induced apoptosis, and 100% tumorigenesis in nude mice.","method":"Adenovirus-mediated overexpression, Western blot, apoptosis assays, in vivo xenograft","journal":"Anatomical record","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean overexpression with defined pathway readouts and in vivo validation, single lab","pmids":["21618708"],"is_preprint":false},{"year":2015,"finding":"LAPTM4B is a binding partner for the leucine transporter LAT1-4F2hc (SLC7A5-SLC3A2); LAPTM4B recruits LAT1-4F2hc to lysosomes, enabling leucine uptake into lysosomes, and is required for mTORC1 activation via V-ATPase following essential amino acid or leucine stimulation.","method":"Co-IP, colocalization, leucine uptake assay, mTORC1 activation assay (S6K phosphorylation), knockdown/overexpression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, functional amino acid uptake assay, and mTORC1 pathway readout with multiple orthogonal methods in single rigorous study","pmids":["25998567"],"is_preprint":false},{"year":2015,"finding":"LAPTM4B is a PtdIns(4,5)P2 effector on endosomes that inhibits EGF-induced EGFR intraluminal sorting and lysosomal degradation by promoting ubiquitination of Hrs (ESCRT-0 subunit), which inhibits Hrs association with ubiquitinated EGFR, thereby enhancing and prolonging EGFR signaling. The endosomal PIP kinase PIPKIγi5 directly binds LAPTM4B and counteracts its inhibitory function by generating PtdIns(4,5)P2 and recruiting SNX5, which protects Hrs from ubiquitination.","method":"Co-IP, siRNA knockdown, ubiquitination assay, EGFR degradation assay, EGFR signaling (phospho-EGFR), binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, ubiquitination assay, EGFR trafficking/signaling readouts) in single rigorous study establishing mechanistic pathway","pmids":["25588945"],"is_preprint":false},{"year":2015,"finding":"LAPTM4B interacts with ceramide in late endosomes and facilitates ceramide export from late endosomal organelles, reducing late endosomal ceramide levels in parallel with and independent of acid ceramidase-dependent catabolism. LAPTM4B silencing causes late endosomal sphingolipid accumulation and lysosomal membrane destabilization but confers resistance to ceramide-driven caspase-3 activation; conversely, LAPTM4B overexpression reduces LE ceramide, stabilizes lysosomes, but sensitizes cells to drug-induced caspase-3 activation.","method":"Novel ceramide probes, LAPTM4B silencing/overexpression, lysosomal membrane stability assay, caspase-3 activation assay, lipidomics","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with novel chemical probes and multiple orthogonal mechanistic readouts in a single rigorous study","pmids":["26280656"],"is_preprint":false},{"year":2015,"finding":"LAPTM4B directly binds to GARP in mammalian cells (identified by yeast two-hybrid with GARP as bait in a Treg cDNA library, confirmed in mammalian co-IP); LAPTM4B decreases cleavage of proTGF-β1, reduces secretion of soluble latent TGF-β1, and reduces surface presentation of GARP·TGF-β1 complexes in regulatory T cells, but does not contribute to TGF-β1 activation. Thus LAPTM4B is a negative regulator of TGF-β1 production in human Tregs.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, TGF-β1 cleavage/secretion/surface presentation assays, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid discovery confirmed by mammalian co-IP plus multiple functional TGF-β1 pathway readouts in one rigorous study","pmids":["26126825"],"is_preprint":false},{"year":2018,"finding":"Ceramide regulates LAPTM4B function through a sphingolipid interaction motif (SLim) and an adjacent aspartate residue in the third transmembrane helix (TM3): ceramide binding reduces TM3 bending via the neighboring membrane-embedded acidic residue, which facilitates LAPTM4B interaction with the amino acid transporter heavy chain 4F2hc to control mTORC signaling.","method":"Atomistic molecular dynamics simulation, mutagenesis of SLim motif and aspartate residue, co-IP of LAPTM4B with 4F2hc, mTORC signaling assay","journal":"ACS central science","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomistic simulation combined with mutagenesis and functional co-IP/signaling readouts providing mechanistic detail","pmids":["29806001"],"is_preprint":false},{"year":2018,"finding":"The transcription factor AP4 directly binds the polymorphism region of the LAPTM4B gene promoter (confirmed by luciferase reporter and EMSA), induces LAPTM4B transcription, and promotes HCC cell proliferation, metastasis, and chemotherapy resistance via LAPTM4B-mediated PI3K/AKT and caspase-dependent pathways. A positive feedback loop exists whereby LAPTM4B acting on c-Myc can in turn regulate AP4.","method":"Luciferase reporter assay, EMSA, ChIP, siRNA knockdown, overexpression, proliferation/invasion/apoptosis assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase + EMSA establishing direct binding, functional phenotypes, single lab","pmids":["29337428"],"is_preprint":false},{"year":2018,"finding":"The transcription factor AP4 directly binds to the polymorphism region of LAPTM4B promoter and modulates its transcription (confirmed by luciferase assay and EMSA); AP4 promotes breast cancer cell proliferation, migration, invasion, and cisplatin resistance in part through upregulation of LAPTM4B.","method":"Transcription factor profiling array, luciferase reporter assay, EMSA, overexpression, siRNA knockdown, proliferation/invasion assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA + luciferase confirming direct binding, functional phenotypes, single lab; replicates finding from PMID 29337428","pmids":["29378908"],"is_preprint":false},{"year":2020,"finding":"LAPTM4B downregulation during myocardial ischemia/reperfusion causes overactivation of mTORC1 (through a direct interaction between LAPTM4B's EC3 extracellular domain and mTOR), which represses TFEB, impairing autophagic flux and worsening cardiomyocyte death; restoration of LAPTM4B or inhibition of mTORC1 by rapamycin rescues autophagic flux and reduces infarct size.","method":"LAPTM4B knockout mice, adenovirus-mediated overexpression, co-IP (LAPTM4B-mTOR interaction via EC3 domain), autophagic flux assays, lysosomal function assays, infarct size measurement, TFEB overexpression/knockdown rescue experiments","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO mouse + co-IP identifying molecular interaction domain + multiple orthogonal rescue experiments in one rigorous study","pmids":["32693673"],"is_preprint":false},{"year":2020,"finding":"LAPTM4B is sorted into intraluminal vesicles (ILVs) of multivesicular endosomes and released in small extracellular vesicles (sEVs); efficient ILV sorting depends on the sphingolipid interaction motif (SLim) in its third transmembrane domain. LAPTM4B controls the glycosphingolipid and ether lipid composition of sEVs: LAPTM4B knockout or SLim-deficient mutant expression causes strong enrichment of glycosphingolipids in sEVs and increased membrane nanodomain stability.","method":"LAPTM4B knockout cells, SLim mutant expression, unbiased lipidomics of sEVs, ILV sorting assays, membrane nanodomain stability assays","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells + structure-function mutagenesis (SLim) + unbiased lipidomics with multiple orthogonal readouts","pmids":["33181324"],"is_preprint":false},{"year":2022,"finding":"LAPTM4B-35 localizes specifically to filopodia through direct interaction with Cdc42, which promotes filopodia localization. LAPTM4B-35 stabilizes filopodia and regulates integrin β1 recycling via interaction and co-trafficking on endosomes, stimulating formation and dynamics of focal adhesions, thereby promoting cancer cell dissemination in a zebrafish xenograft model.","method":"Co-IP (LAPTM4B-35 with Cdc42 and integrin β1), confocal localization, filopodia quantification, focal adhesion dynamics assay, zebrafish xenograft model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing interaction partners, live imaging of trafficking, in vivo zebrafish model, single lab","pmids":["35381120"],"is_preprint":false},{"year":2023,"finding":"LAPTM4B promotes RhoA protein stability by suppressing ubiquitin-mediated proteasome degradation of RhoA, thereby activating the RhoA-LIMK-cofilin signaling pathway to regulate stress fiber organization and promote osteosarcoma cell migration and metastasis; miR-137 regulates LAPTM4B expression in osteosarcoma.","method":"siRNA knockdown, overexpression, RhoA ubiquitination assay, Western blot for RhoA/LIMK/cofilin pathway, migration assays, animal metastasis model, patient tissue analysis","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay + pathway readouts + in vivo model, single lab","pmids":["37147294"],"is_preprint":false},{"year":2023,"finding":"LAPTM4B interacts with RPS9 and positively regulates RPS9 protein stability, which in turn activates STAT3 to promote leukemia cell progression in AML.","method":"Co-IP (LAPTM4B-RPS9 interaction), protein stability assays, STAT3 activation assay, in vitro and in vivo leukemia progression assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus protein stability and signaling readouts, single lab","pmids":["36758682"],"is_preprint":false},{"year":2023,"finding":"LAPTM4B suppresses YAP phosphorylation and ubiquitination, preventing YAP degradation; stabilized YAP translocates to the nucleus and binds CREB1, which promotes LAPTM4B transcription, forming a positive feedback loop that maintains hepatocellular carcinoma stem cell stemness.","method":"Western blot (YAP phosphorylation/ubiquitination), nuclear/cytoplasmic fractionation, ChIP (YAP-CREB1 binding to LAPTM4B promoter), siRNA knockdown, overexpression, in vitro and in vivo stemness assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + ubiquitination assays + fractionation establishing feedback mechanism, single lab","pmids":["37213231"],"is_preprint":false},{"year":2024,"finding":"LAPTM4B suppresses ferroptosis in non-small cell lung cancer by inhibiting NEDD4L/ZRANB1-mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11, thereby maintaining SLC7A11 protein levels and preventing ferroptotic cell death.","method":"Metabolomic screens, LAPTM4B knockout cell models, ubiquitination assays, proteasome inhibition, SLC7A11 protein stability assays, in vitro and in vivo ferroptosis assays (erastin treatment), patient tissue samples","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased metabolomics + ubiquitination mechanism + in vivo validation + patient tissue correlation in a single comprehensive study","pmids":["38902268"],"is_preprint":false},{"year":2024,"finding":"HDAC2 binds specifically to the LAPTM4B promoter at four distinct binding sites, enhancing its transcriptional activation in HCC, thereby driving autophagy-related malignant progression.","method":"ChIP-seq/ChIP (HDAC2 binding to LAPTM4B promoter), HDAC2 inhibitor treatment, overexpression/knockdown, in vitro and in vivo autophagy and proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct promoter binding + functional phenotypes, single lab","pmids":["39147759"],"is_preprint":false},{"year":2024,"finding":"ETV1 transcription factor regulates LAPTM4B expression in liver cancer stem cells; LAPTM4B promotes liver cancer stem cell self-renewal and proliferation via the Wnt1/c-Myc/β-catenin pathway, and drives CXCL8 secretion to promote myeloid-derived suppressor cell migration, affecting the tumor immune microenvironment.","method":"siRNA knockdown, overexpression, pathway inhibitors, CXCL8 secretion assays, MDSC migration assay, in vitro and in vivo tumor growth assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional pathway studies with multiple phenotypic readouts but no direct binding confirmation of ETV1-LAPTM4B, single lab","pmids":["38388484"],"is_preprint":false},{"year":2024,"finding":"LAPTM4B promotes stemness of CD133+ liver cancer stem-like cells by activating WNT/β-catenin signaling: LAPTM4B inhibits β-catenin phosphorylation and interacts with deubiquitinating enzymes USP1 and USP14, reducing β-catenin ubiquitination and degradation, thereby enabling β-catenin nuclear translocation.","method":"Co-IP (LAPTM4B with USP1/USP14), nucleocytoplasmic separation, β-catenin ubiquitination/phosphorylation assays, Western blot, immunofluorescence, in vitro/in vivo stemness assays","journal":"JHEP reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying deubiquitinase partners + ubiquitination assays + functional rescue, single lab","pmids":["40171299"],"is_preprint":false},{"year":2024,"finding":"In the EVI1-driven myeloid malignancy context, EVI1 directly upregulates KDM6B, which demethylates H3K27me3 to activate LAPTM4B transcription; hyperactivation of the LAPTM4B-driven mTOR pathway is crucial for the growth of EVI1-high leukemia cells, and Laptm4b knockdown partially rescues EVI1-induced abnormal hematopoiesis in vivo.","method":"Evi1-transgenic mouse model, global gene expression profiling, EVI1 binding site profiling (ChIP), H3K27me3 ChIP, KDM6B inhibition, Laptm4b knockdown in vivo, mTOR pathway assays, leukemia cell line validation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model + ChIP for multiple pathway steps + in vivo Laptm4b rescue establishing epistatic pathway","pmids":["39680456"],"is_preprint":false},{"year":2017,"finding":"Beclin1 interacts with both the N- and C-termini of LAPTM4B (independent of the Vps34 complex) and competes with EGFR for LAPTM4B binding, thereby repressing LAPTM4B-mediated EGFR activation and gastric cancer cell growth.","method":"Co-IP (Beclin1-LAPTM4B interaction), domain mapping (N- and C-termini), competition binding assay, EGFR activation assay, cell growth assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with domain mapping + competition assay + functional readout, single lab","pmids":["28479384"],"is_preprint":false},{"year":2019,"finding":"LAPTM4B interacts with EGFR and stabilizes it in endosomes; LAPTM4B also interacts with Beclin1, promoting autophagy initiation. LAPTM4B knockdown decreases radioresistance in nasopharyngeal cancer cells by inhibiting autophagy.","method":"Co-immunoprecipitation, confocal immunofluorescence colocalization, Western blot, flow cytometry (apoptosis), siRNA knockdown, colony formation assay","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus colocalization establishing interactions, functional knockdown phenotype, single lab","pmids":["31410015"],"is_preprint":false},{"year":2019,"finding":"LAPTM4B activates ATG3 transcription to modulate HCC cell apoptosis and autophagy; upon starvation, LAPTM4B facilitates cell survival, inhibits apoptosis, and induces autophagic flux.","method":"LAPTM4B silencing, microarray expression profiling, real-time PCR, immunofluorescence, Western blot, in vivo xenograft","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptional activation inferred from expression profiling + functional phenotypes, limited mechanistic detail on how LAPTM4B activates ATG3, single lab","pmids":["31118766"],"is_preprint":false},{"year":2024,"finding":"LAPTM4B confers resistance to EGFR-TKIs in NSCLC by interacting with ATP1A1 and facilitating its endocytosis while preventing its proteasomal degradation by suppressing TRIM8-mediated K63-linked ubiquitination of ATP1A1, thereby stabilizing ATP1A1 and enhancing lysosomal acidification and EGFR phosphorylation/downstream signaling. EGFR-TKIs impair WWP2-mediated proteasomal degradation of LAPTM4B, increasing LAPTM4B levels.","method":"Co-IP (LAPTM4B-ATP1A1 interaction), K63-ubiquitination assay, endocytosis assay, lysosomal acidification measurement, EGFR phosphorylation assay, in vitro and in vivo drug resistance assays, high-content drug screen, patient tissue analysis","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP + ubiquitination mechanism + endocytosis/lysosomal readouts + in vivo validation + drug screen in comprehensive single study","pmids":["41362742"],"is_preprint":false},{"year":2024,"finding":"LAPTM4B recruits the E3 ubiquitin ligase NEDD4L to endosomes, leading to increased ubiquitin-mediated proteasomal degradation of TGFβR2 and active SMAD2/3, thereby blocking the TGF-β/SMAD signaling pathway and alleviating pulmonary fibrosis.","method":"In vivo bleomycin-induced fibrosis model (LAPTM4B deficiency and restoration), co-IP (LAPTM4B-NEDD4L), ubiquitination/degradation assays for TGFβR2 and SMAD2/3, TGF-β signaling readouts","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model + co-IP + ubiquitination mechanism, preprint not yet peer reviewed","pmids":[],"is_preprint":true},{"year":2015,"finding":"LAPTM4B protein is ubiquitinated in bovine granulosa cells: affinity-purified His-tagged LAPTM4B overexpressed in HEK cells showed that the 31.5 kDa isoform represents the ubiquitinated form of the 26.3 kDa native protein, and the ubiquitinated form is differentially expressed during follicular development.","method":"Immunoblotting with anti-LAPTM4B antibody, His-tag affinity purification, identification of ubiquitinated vs. non-ubiquitinated isoforms","journal":"Journal of ovarian research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method identifying ubiquitination but no writer/eraser/reader identified and limited functional follow-up","pmids":["25881887"],"is_preprint":false},{"year":2025,"finding":"CDX1 transcription factor promotes LAPTM4B transcription, and CDX1-mediated LAPTM4B upregulation inhibits mTORC1 pathway activation, thereby alleviating autophagic flux impairment and protecting against nicotine-induced cardiac fibroblast activation and cardiomyocyte hypertrophy.","method":"CDX1 overexpression/knockdown, LAPTM4B knockdown, mTOR pathway assays, autophagic flux assays, cardiac fibroblast activation and hypertrophy readouts","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional pathway data showing CDX1-LAPTM4B-mTORC1 axis but no direct binding assay for CDX1-LAPTM4B promoter, single lab","pmids":["40121311"],"is_preprint":false}],"current_model":"LAPTM4B is a four-transmembrane lysosomal/late endosomal protein that acts as a multifunctional regulator of lysosomal homeostasis, mTORC1 signaling, and cell survival: it recruits the leucine transporter LAT1-4F2hc to lysosomes to enable leucine uptake and V-ATPase-dependent mTORC1 activation, directly interacts with mTOR via its EC3 domain to suppress mTORC1 overactivation, facilitates ceramide export from late endosomes to compartmentalize sphingolipid-mediated cell death signals, inhibits EGFR intraluminal sorting by promoting Hrs ubiquitination (counteracted by PIPKIγi5/PtdIns(4,5)P2/SNX5), promotes drug efflux through interaction with P-glycoprotein, activates PI3K/AKT signaling via its PPRP motif binding to p85α, promotes autophagic flux and lysosomal acidification to confer resistance to metabolic and genotoxic stress, suppresses ferroptosis by preventing NEDD4L/ZRANB1-mediated ubiquitination of SLC7A11, stabilizes ATP1A1 by blocking TRIM8-mediated ubiquitination to enhance lysosomal acidification and EGFR-TKI resistance, promotes RhoA stability to drive cytoskeletal remodeling and migration, and is transcriptionally regulated by AP4, HDAC2, EVI1/KDM6B/H3K27me3, and CDX1."},"narrative":{"mechanistic_narrative":"LAPTM4B is a four-transmembrane lysosomal/late-endosomal protein that governs lysosomal homeostasis, amino-acid-dependent mTORC1 signaling, and endosomal sorting to promote cell survival and tumor progression [PMID:12947545, PMID:22037872, PMID:25998567]. It is required for lysosomal acidification and autophagosome maturation: its depletion raises lysosomal pH, increases membrane permeability, releases cathepsins, and triggers apoptosis, whereas its overexpression sustains autophagic flux and survival under metabolic stress [PMID:22037872]. On lysosomes LAPTM4B binds the leucine transporter LAT1-4F2hc (SLC7A5-SLC3A2) and recruits it to enable luminal leucine uptake and V-ATPase-dependent mTORC1 activation [PMID:25998567]; a sphingolipid-interaction motif and adjacent TM3 aspartate sense ceramide to modulate this 4F2hc engagement [PMID:29806001], and at late endosomes LAPTM4B binds ceramide to drive its export and control lysosomal membrane stability and ceramide-driven caspase-3 death signaling [PMID:26280656]. On endosomes it acts as a PtdIns(4,5)P2 effector that suppresses EGFR intraluminal sorting and degradation by promoting Hrs ubiquitination—an activity opposed by PIPKIγi5/SNX5—thereby prolonging EGFR signaling [PMID:25588945], and it directly stabilizes EGFR while engaging Beclin1 to support autophagy [PMID:28479384, PMID:31410015]. LAPTM4B broadly stabilizes oncogenic effectors by blocking their ubiquitin-mediated degradation: it preserves SLC7A11 against NEDD4L/ZRANB1 to suppress ferroptosis [PMID:38902268], RhoA to drive LIMK-cofilin cytoskeletal remodeling and migration [PMID:37147294], ATP1A1 against TRIM8 to confer EGFR-TKI resistance [PMID:41362742], and β-catenin via USP1/USP14 to sustain liver cancer stem-cell stemness [PMID:40171299]. It also confers multidrug resistance through cytosolic doxorubicin sequestration, P-glycoprotein interaction, and PI3K/AKT activation via its N-terminal PPRP motif binding p85α [PMID:20098429, PMID:20711237, PMID:19843073]. Conversely, in regulatory T cells and fibrotic tissue LAPTM4B negatively regulates TGF-β by suppressing proTGF-β1 production and by recruiting NEDD4L to degrade TGFβR2/SMAD2/3 [PMID:26126825], and its loss drives mTORC1 overactivation through a direct EC3-domain–mTOR interaction that worsens ischemia/reperfusion cardiac injury [PMID:32693673]. LAPTM4B transcription is controlled by AP4, HDAC2, and an EVI1/KDM6B/H3K27me3 axis that couples it to mTOR-dependent leukemia growth [PMID:29337428, PMID:39147759, PMID:39680456].","teleology":[{"year":2003,"claim":"Established LAPTM4B as a two-isoform, four-transmembrane intracellular-membrane protein that physically associates with integrin α6 and EGFR, providing the first link between this protein and cell-adhesion/growth-factor receptors.","evidence":"Western blot, 2D electrophoresis, immunohistochemistry, and co-IP in laminin-seeded cells","pmids":["12947545"],"confidence":"Medium","gaps":["No functional consequence of the integrin/EGFR association tested","Interaction directness and stoichiometry not established"]},{"year":2003,"claim":"Showed LAPTM4B is oncogenic, answering whether its overexpression alone drives transformation by demonstrating accelerated S-phase entry and tumorigenesis in vivo.","evidence":"Overexpression in NIH3T3 with flow cytometry, growth curves, and mouse tumorigenesis assay","pmids":["12947546"],"confidence":"Medium","gaps":["Molecular mechanism of Cyclin E upregulation not defined","Single cell-line/single-lab system"]},{"year":2009,"claim":"Mapped the oncogenic activity to the N-terminal PPRP motif, defining a discrete structural determinant required for proliferation, invasion, and oncoprotein induction.","evidence":"Site-directed mutagenesis with proliferation/migration/invasion assays and Western blot","pmids":["19843073"],"confidence":"Medium","gaps":["Direct binding partner of PPRP not yet identified at this stage","Single-lab phenotypic readouts"]},{"year":2010,"claim":"Defined a multidrug-resistance mechanism, resolving how LAPTM4B confers chemoresistance via cytosolic drug sequestration, P-glycoprotein interaction, and PPRP-p85α-driven PI3K/AKT signaling.","evidence":"Reciprocal siRNA/overexpression, drug-localization imaging, co-IP, colocalization, and PI3K inhibition","pmids":["20098429","20711237"],"confidence":"High","gaps":["Structural basis of PPRP-p85α binding not resolved","Relative contribution of sequestration vs. efflux vs. signaling not quantified"]},{"year":2011,"claim":"Established LAPTM4B as essential for lysosomal acidification, membrane integrity, and late-stage autophagosome maturation, explaining its pro-survival role under nutrient/hypoxic stress.","evidence":"Reciprocal knockdown/overexpression with lysosomal pH/permeability, cathepsin release, autophagy flux assays, and xenografts","pmids":["22037872","21618708"],"confidence":"High","gaps":["Direct molecular driver of acidification not identified here","How autophagosome maturation is blocked mechanistically left open"]},{"year":2015,"claim":"Identified the lysosomal leucine-sensing function, answering how LAPTM4B activates mTORC1 by recruiting LAT1-4F2hc to enable luminal leucine uptake and V-ATPase-dependent signaling.","evidence":"Co-IP, colocalization, leucine uptake assay, and S6K-phosphorylation readout with knockdown/overexpression","pmids":["25998567"],"confidence":"High","gaps":["Stoichiometry of the LAPTM4B-LAT1-4F2hc-V-ATPase assembly not defined","Whether leucine uptake is direct or indirect not fully resolved"]},{"year":2015,"claim":"Defined LAPTM4B as a PtdIns(4,5)P2 effector controlling EGFR fate, showing it blocks EGFR intraluminal sorting by promoting Hrs ubiquitination, counteracted by PIPKIγi5/SNX5.","evidence":"Co-IP, ubiquitination assay, EGFR degradation/signaling readouts, and binding assays","pmids":["25588945"],"confidence":"High","gaps":["E3 ligase ubiquitinating Hrs not identified","Quantitative link between PIP2 levels and LAPTM4B activity not established"]},{"year":2015,"claim":"Revealed LAPTM4B as a ceramide-handling protein that exports ceramide from late endosomes, decoupling lysosomal stability from sensitivity to ceramide-driven apoptosis.","evidence":"Novel ceramide probes, reciprocal silencing/overexpression, lysosomal stability and caspase-3 assays, lipidomics","pmids":["26280656"],"confidence":"High","gaps":["Mechanism of ceramide export (transporter vs. carrier) not defined","Acceptor compartment for exported ceramide unclear"]},{"year":2015,"claim":"Extended LAPTM4B to immune regulation, establishing it as a GARP-binding negative regulator of TGF-β1 production in human Tregs.","evidence":"Yeast two-hybrid, mammalian co-IP, and TGF-β1 cleavage/secretion/surface-presentation assays","pmids":["26126825"],"confidence":"High","gaps":["Structural basis of GARP-LAPTM4B binding not resolved","In vivo Treg consequence not tested"]},{"year":2018,"claim":"Provided atomistic mechanism for ceramide sensing, showing a TM3 SLim motif and adjacent aspartate translate ceramide binding into altered 4F2hc engagement and mTORC signaling.","evidence":"Molecular dynamics simulation, SLim/aspartate mutagenesis, co-IP with 4F2hc, mTORC signaling assay","pmids":["29806001"],"confidence":"High","gaps":["Simulation-predicted TM3 bending not directly observed structurally","In vivo relevance of ceramide-tuned mTORC not tested"]},{"year":2018,"claim":"Identified AP4 as a direct transcriptional activator of LAPTM4B in HCC and breast cancer, linking promoter polymorphism to LAPTM4B-driven PI3K/AKT chemoresistance and a c-Myc feedback loop.","evidence":"Luciferase reporter, EMSA, ChIP, and knockdown/overexpression phenotypes across two cancer types","pmids":["29337428","29378908"],"confidence":"Medium","gaps":["Single-lab origin of both reports","Functional impact of the promoter polymorphism on AP4 binding not quantified"]},{"year":2020,"claim":"Defined a tumor-suppressive mTORC1-restraint function via direct EC3-domain–mTOR interaction, showing LAPTM4B loss overactivates mTORC1, represses TFEB, and worsens cardiac I/R injury.","evidence":"LAPTM4B-knockout mice, adenoviral rescue, EC3-mTOR co-IP, autophagic flux and infarct measurements, TFEB rescue","pmids":["32693673"],"confidence":"High","gaps":["Reconciliation of mTORC1-activating (lysosomal LAT1) vs. mTORC1-suppressing (EC3-mTOR) roles not mechanistically unified","Direct EC3-mTOR binding interface not structurally mapped"]},{"year":2020,"claim":"Showed LAPTM4B controls the lipid composition of secreted extracellular vesicles, with SLim-dependent ILV sorting shaping sEV glycosphingolipid and ether-lipid content.","evidence":"Knockout cells, SLim-mutant expression, unbiased sEV lipidomics, ILV sorting and nanodomain stability assays","pmids":["33181324"],"confidence":"High","gaps":["Functional consequence of altered sEV lipids on recipient cells not tested","Machinery sorting LAPTM4B into ILVs not identified"]},{"year":2022,"claim":"Connected LAPTM4B to actin-based motility, showing Cdc42-dependent filopodial localization and integrin-β1 co-trafficking that stabilizes focal adhesions and drives cancer dissemination.","evidence":"Co-IP with Cdc42 and integrin β1, confocal localization, focal-adhesion dynamics, zebrafish xenograft","pmids":["35381120"],"confidence":"Medium","gaps":["Directness of Cdc42 binding vs. complex-mediated not fully resolved","Single-lab in vivo model"]},{"year":2023,"claim":"Established a recurring theme of LAPTM4B stabilizing oncogenic effectors against ubiquitination, here preserving RhoA to activate RhoA-LIMK-cofilin signaling and osteosarcoma metastasis.","evidence":"RhoA ubiquitination assay, pathway Western blots, migration and in vivo metastasis models, miR-137 regulation","pmids":["37147294"],"confidence":"Medium","gaps":["E3 ligase targeting RhoA not identified","Mechanism by which LAPTM4B blocks RhoA ubiquitination unknown"]},{"year":2023,"claim":"Extended the stabilization theme to translation and stemness signaling, showing LAPTM4B stabilizes RPS9 to activate STAT3 in AML and stabilizes YAP to feed a CREB1-driven HCC stemness loop.","evidence":"Co-IP, protein-stability and ubiquitination/phosphorylation assays, fractionation, ChIP, and in vivo progression models","pmids":["36758682","37213231"],"confidence":"Medium","gaps":["Mechanism of RPS9/YAP stabilization (direct vs. via deubiquitinase) not fully defined","Single-lab studies"]},{"year":2024,"claim":"Unified the ubiquitination-control theme across ferroptosis, drug resistance, and stemness, showing LAPTM4B protects SLC7A11 (anti-ferroptosis), ATP1A1 (EGFR-TKI resistance), and β-catenin (stemness via USP1/USP14) from degradation.","evidence":"Metabolomic/drug screens, knockout models, ubiquitination assays, co-IP of NEDD4L/TRIM8/USP partners, in vivo and patient-tissue validation","pmids":["38902268","41362742","40171299"],"confidence":"High","gaps":["Whether a single shared biochemical activity underlies all stabilization events not determined","β-catenin/USP findings remain single-lab"]},{"year":2024,"claim":"Defined transcriptional and immune-microenvironment axes, showing HDAC2 and EVI1/KDM6B/H3K27me3 activate LAPTM4B transcription to drive autophagy- and mTOR-dependent malignancy, while LAPTM4B drives CXCL8-mediated MDSC recruitment.","evidence":"ChIP/ChIP-seq, H3K27me3 profiling, inhibitor and in vivo knockdown studies, CXCL8/MDSC migration assays","pmids":["39147759","39680456","38388484"],"confidence":"High","gaps":["Direct ETV1-LAPTM4B promoter binding not confirmed","Interplay among the multiple transcriptional regulators not integrated"]},{"year":2024,"claim":"Showed LAPTM4B can suppress TGF-β signaling in fibrosis by recruiting NEDD4L to degrade TGFβR2 and active SMAD2/3, paralleling its Treg TGF-β1 role.","evidence":"Bleomycin fibrosis model with LAPTM4B deficiency/restoration, co-IP, and TGFβR2/SMAD ubiquitination assays (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer reviewed","Reconciliation with LAPTM4B's NEDD4L-blocking role on SLC7A11 not addressed"]},{"year":2025,"claim":"Linked CDX1-driven LAPTM4B upregulation to mTORC1 suppression and autophagy restoration, protecting against nicotine-induced cardiac remodeling.","evidence":"CDX1 and LAPTM4B perturbation with mTOR/autophagy and cardiac fibroblast/hypertrophy readouts","pmids":["40121311"],"confidence":"Low","gaps":["No direct CDX1-LAPTM4B promoter binding assay","Single-lab functional inference of the transcriptional axis"]},{"year":null,"claim":"How LAPTM4B mechanistically reconciles opposing roles in mTORC1 signaling (lysosomal LAT1-driven activation vs. EC3-domain-mediated suppression) and in ubiquitination (protecting some substrates while recruiting NEDD4L to degrade others) remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of LAPTM4B explaining context-dependent substrate selection","No unifying biochemical activity proposed for its bidirectional control of degradation","How tissue context switches LAPTM4B between mTORC1-activating and -suppressing states is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,14,20,28]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,23,29]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[16,17]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,7,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8,16,29]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,14,23]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5,14,21,27]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,20]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8,15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17,20,23,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,28]}],"complexes":[],"partners":["SLC7A5","SLC3A2","EGFR","MTOR","BECLIN1","CDC42","GARP","NEDD4L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86VI4","full_name":"Lysosomal-associated transmembrane protein 4B","aliases":["Lysosome-associated transmembrane protein 4-beta"],"length_aa":317,"mass_kda":35.1,"function":"Required for optimal lysosomal function (PubMed:21224396). Blocks EGF-stimulated EGFR intraluminal sorting and degradation. Conversely by binding with the phosphatidylinositol 4,5-bisphosphate, regulates its PIP5K1C interaction, inhibits HGS ubiquitination and relieves LAPTM4B inhibition of EGFR degradation (PubMed:25588945). Recruits SLC3A2 and SLC7A5 (the Leu transporter) to the lysosome, promoting entry of leucine and other essential amino acid (EAA) into the lysosome, stimulating activation of proton-transporting vacuolar (V)-ATPase protein pump (V-ATPase) and hence mTORC1 activation (PubMed:25998567). Plays a role as negative regulator of TGFB1 production in regulatory T cells (PubMed:26126825). Binds ceramide and facilitates its exit from late endosome in order to control cell death pathways (PubMed:26280656)","subcellular_location":"Endomembrane system; Late endosome membrane; Cell membrane; Cell projection; Lysosome membrane; Endosome membrane; Endosome, multivesicular body membrane; Endosome, multivesicular body lumen","url":"https://www.uniprot.org/uniprotkb/Q86VI4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LAPTM4B","classification":"Not Classified","n_dependent_lines":39,"n_total_lines":1208,"dependency_fraction":0.03228476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LAPTM4B","total_profiled":1310},"omim":[{"mim_id":"613296","title":"LYSOSOME-ASSOCIATED PROTEIN, TRANSMEMBRANE 4, BETA; LAPTM4B","url":"https://www.omim.org/entry/613296"},{"mim_id":"601288","title":"TYROSINE 3-MONOOXYGENASE/TRYPTOPHAN 5-MONOOXYGENASE ACTIVATION PROTEIN, ZETA ISOFORM; YWHAZ","url":"https://www.omim.org/entry/601288"},{"mim_id":"114480","title":"BREAST CANCER","url":"https://www.omim.org/entry/114480"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"retina","ntpm":352.2}],"url":"https://www.proteinatlas.org/search/LAPTM4B"},"hgnc":{"alias_symbol":["LC27"],"prev_symbol":[]},"alphafold":{"accession":"Q86VI4","domains":[{"cath_id":"1.10.287","chopping":"111-187","consensus_level":"medium","plddt":70.5182,"start":111,"end":187},{"cath_id":"1.10.287","chopping":"190-290","consensus_level":"medium","plddt":79.3051,"start":190,"end":290}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VI4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VI4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VI4-F1-predicted_aligned_error_v6.png","plddt_mean":63.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LAPTM4B","jax_strain_url":"https://www.jax.org/strain/search?query=LAPTM4B"},"sequence":{"accession":"Q86VI4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86VI4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86VI4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VI4"}},"corpus_meta":[{"pmid":"20098429","id":"PMC_20098429","title":"Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.","date":"2010","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20098429","citation_count":291,"is_preprint":false},{"pmid":"25998567","id":"PMC_25998567","title":"LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25998567","citation_count":170,"is_preprint":false},{"pmid":"12902989","id":"PMC_12902989","title":"Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12902989","citation_count":148,"is_preprint":false},{"pmid":"32693673","id":"PMC_32693673","title":"Downregulation of LAPTM4B Contributes to the Impairment of the Autophagic Flux via Unopposed Activation of mTORC1 Signaling During Myocardial Ischemia/Reperfusion Injury.","date":"2020","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/32693673","citation_count":113,"is_preprint":false},{"pmid":"20711237","id":"PMC_20711237","title":"LAPTM4B: a novel cancer-associated gene motivates multidrug resistance through efflux and activating PI3K/AKT signaling.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20711237","citation_count":104,"is_preprint":false},{"pmid":"15911104","id":"PMC_15911104","title":"The human LAPTM4b transcript is upregulated in various types of solid tumours and seems to play a dual functional role during tumour progression.","date":"2004","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/15911104","citation_count":88,"is_preprint":false},{"pmid":"25714029","id":"PMC_25714029","title":"miR-188-5p inhibits tumour growth and metastasis in prostate cancer by repressing LAPTM4B expression.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25714029","citation_count":86,"is_preprint":false},{"pmid":"25588945","id":"PMC_25588945","title":"LAPTM4B is a PtdIns(4,5)P2 effector that regulates EGFR signaling, lysosomal sorting, and degradation.","date":"2015","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/25588945","citation_count":80,"is_preprint":false},{"pmid":"22037872","id":"PMC_22037872","title":"Lysosomal transmembrane protein LAPTM4B promotes autophagy and tolerance to metabolic stress in cancer cells.","date":"2011","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/22037872","citation_count":76,"is_preprint":false},{"pmid":"29246322","id":"PMC_29246322","title":"Long Noncoding RNA HCAL Facilitates the Growth and Metastasis of Hepatocellular Carcinoma by Acting as a ceRNA of LAPTM4B.","date":"2017","source":"Molecular therapy. 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Yi xue ban = Journal of Peking University. 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Between LAPTM4B Gene Polymorphism and Susceptibility of Malignant Melanoma in Chinese Patients.","date":"2014","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25389459","citation_count":10,"is_preprint":false},{"pmid":"26526574","id":"PMC_26526574","title":"Predictive significance of combined LAPTM4B and VEGF expression in patients with cervical cancer.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26526574","citation_count":10,"is_preprint":false},{"pmid":"21144292","id":"PMC_21144292","title":"[Relationship between LAPTM4B gene polymorphism and susceptibility of lung cancer].","date":"2006","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21144292","citation_count":9,"is_preprint":false},{"pmid":"25881887","id":"PMC_25881887","title":"Differential expression of lysosome-associated 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hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40171299","citation_count":5,"is_preprint":false},{"pmid":"28090574","id":"PMC_28090574","title":"Association between LAPTM4B gene polymorphism and prostate cancer susceptibility in an Iranian population.","date":"2016","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28090574","citation_count":5,"is_preprint":false},{"pmid":"39680456","id":"PMC_39680456","title":"Evi1 governs Kdm6b-mediated histone demethylation to regulate the Laptm4b-driven mTOR pathway in hematopoietic progenitor cells.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39680456","citation_count":4,"is_preprint":false},{"pmid":"32651973","id":"PMC_32651973","title":"LAPTM4B promotes the progression of nasopharyngeal cancer.","date":"2021","source":"Bosnian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32651973","citation_count":4,"is_preprint":false},{"pmid":"34589144","id":"PMC_34589144","title":"LAPTM4B promotes the progression of bladder cancer by stimulating cell proliferation and invasion.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34589144","citation_count":4,"is_preprint":false},{"pmid":"24746178","id":"PMC_24746178","title":"LAPTM4B polymorphism increases susceptibility to multiple cancers in Chinese populations: a meta-analysis.","date":"2014","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24746178","citation_count":4,"is_preprint":false},{"pmid":"34393233","id":"PMC_34393233","title":"[Serum LAPTM4B-35 protein as a novel diagnostic marker for hepatocellular carcinoma].","date":"2021","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. 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the protein localizes predominantly to intracellular membranes; co-immunoprecipitation demonstrated that LAPTM4B forms complexes with integrin α6 and EGFR when cells are seeded on laminin substrate.\",\n      \"method\": \"Western blot, 2D electrophoresis, immunohistochemistry, co-immunoprecipitation\",\n      \"journal\": \"Beijing da xue xue bao (Journal of Peking University Health Sciences)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, co-IP plus multiple orthogonal characterization methods; no functional rescue or reconstitution\",\n      \"pmids\": [\"12947545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LAPTM4B overexpression in NIH3T3 cells promotes cell proliferation by accelerating S-phase entry with upregulation of Cyclin E, increases attachment/spreading on fibronectin/matrigel/laminin, decreases serum dependence, and causes tumorigenesis (fibrosarcoma formation at 50% rate) in mice.\",\n      \"method\": \"Eukaryotic expression, RT-PCR, Northern/Western blot, flow cytometry, cell growth curves, scanning electron microscopy, in vivo tumorigenesis assay\",\n      \"journal\": \"Beijing da xue xue bao (Journal of Peking University Health Sciences)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean overexpression with multiple orthogonal phenotypic readouts including in vivo tumorigenesis, single lab\",\n      \"pmids\": [\"12947546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The PPRP motif in the N-terminal region of LAPTM4B-35 is critical for promoting cell proliferation, migration, and invasion, as well as upregulation of oncoproteins c-Myc, c-Jun, c-Fos, cyclin D1, and cyclin E; mutagenesis of the PPRP motif abolished these effects.\",\n      \"method\": \"Overexpression, site-directed mutagenesis, proliferation/migration/invasion assays, Western blot\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis establishing motif function, single lab, multiple phenotypic readouts\",\n      \"pmids\": [\"19843073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LAPTM4B overexpression causes sequestration of the anthracycline doxorubicin in the cytosol, delaying its appearance in the nucleus, thereby contributing to anthracycline resistance; siRNA knockdown sensitizes tumor cells to anthracyclines.\",\n      \"method\": \"siRNA knockdown, overexpression, fluorescence imaging of doxorubicin localization, cell viability assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with direct drug localization imaging, replicated across multiple cohorts\",\n      \"pmids\": [\"20098429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LAPTM4B-35 promotes multidrug resistance by (1) colocalizing and directly interacting with MDR1/P-glycoprotein to enhance drug efflux of doxorubicin, paclitaxel, and cisplatin, and (2) activating PI3K/AKT signaling through interaction of its N-terminal PPRP motif with the p85α regulatory subunit of PI3K.\",\n      \"method\": \"Co-IP, colocalization studies, PI3K inhibitor treatment, RNAi knockdown, drug efflux assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, colocalization, pharmacological inhibition, and loss-of-function all converging on same mechanism\",\n      \"pmids\": [\"20711237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LAPTM4B is required for lysosome homeostasis and acidification; its depletion increases lysosomal membrane permeability, raises lysosomal pH, causes cathepsin release, and induces cellular apoptosis. LAPTM4B loss also blocks autophagosome maturation at late stages, rendering cells sensitive to nutrient deprivation or hypoxia. Conversely, overexpression promotes autophagic flux and cell survival during starvation and accelerates in vivo tumor growth.\",\n      \"method\": \"siRNA knockdown, overexpression, lysosomal permeability assays, pH measurement, cathepsin release assay, autophagy flux assays, in vivo xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with multiple orthogonal mechanistic readouts including in vivo validation\",\n      \"pmids\": [\"22037872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Upregulation of LAPTM4B-35 in normal liver L02 cells activates the PI3K/AKT/Bcl-xL/Bad signaling pathway, inhibits caspase-3 activation, upregulates Bcl-2, and downregulates Bax, thereby promoting anchorage-independent proliferation, resistance to adriamycin-induced apoptosis, and 100% tumorigenesis in nude mice.\",\n      \"method\": \"Adenovirus-mediated overexpression, Western blot, apoptosis assays, in vivo xenograft\",\n      \"journal\": \"Anatomical record\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean overexpression with defined pathway readouts and in vivo validation, single lab\",\n      \"pmids\": [\"21618708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LAPTM4B is a binding partner for the leucine transporter LAT1-4F2hc (SLC7A5-SLC3A2); LAPTM4B recruits LAT1-4F2hc to lysosomes, enabling leucine uptake into lysosomes, and is required for mTORC1 activation via V-ATPase following essential amino acid or leucine stimulation.\",\n      \"method\": \"Co-IP, colocalization, leucine uptake assay, mTORC1 activation assay (S6K phosphorylation), knockdown/overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, functional amino acid uptake assay, and mTORC1 pathway readout with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"25998567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LAPTM4B is a PtdIns(4,5)P2 effector on endosomes that inhibits EGF-induced EGFR intraluminal sorting and lysosomal degradation by promoting ubiquitination of Hrs (ESCRT-0 subunit), which inhibits Hrs association with ubiquitinated EGFR, thereby enhancing and prolonging EGFR signaling. The endosomal PIP kinase PIPKIγi5 directly binds LAPTM4B and counteracts its inhibitory function by generating PtdIns(4,5)P2 and recruiting SNX5, which protects Hrs from ubiquitination.\",\n      \"method\": \"Co-IP, siRNA knockdown, ubiquitination assay, EGFR degradation assay, EGFR signaling (phospho-EGFR), binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, ubiquitination assay, EGFR trafficking/signaling readouts) in single rigorous study establishing mechanistic pathway\",\n      \"pmids\": [\"25588945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LAPTM4B interacts with ceramide in late endosomes and facilitates ceramide export from late endosomal organelles, reducing late endosomal ceramide levels in parallel with and independent of acid ceramidase-dependent catabolism. LAPTM4B silencing causes late endosomal sphingolipid accumulation and lysosomal membrane destabilization but confers resistance to ceramide-driven caspase-3 activation; conversely, LAPTM4B overexpression reduces LE ceramide, stabilizes lysosomes, but sensitizes cells to drug-induced caspase-3 activation.\",\n      \"method\": \"Novel ceramide probes, LAPTM4B silencing/overexpression, lysosomal membrane stability assay, caspase-3 activation assay, lipidomics\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with novel chemical probes and multiple orthogonal mechanistic readouts in a single rigorous study\",\n      \"pmids\": [\"26280656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LAPTM4B directly binds to GARP in mammalian cells (identified by yeast two-hybrid with GARP as bait in a Treg cDNA library, confirmed in mammalian co-IP); LAPTM4B decreases cleavage of proTGF-β1, reduces secretion of soluble latent TGF-β1, and reduces surface presentation of GARP·TGF-β1 complexes in regulatory T cells, but does not contribute to TGF-β1 activation. Thus LAPTM4B is a negative regulator of TGF-β1 production in human Tregs.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, TGF-β1 cleavage/secretion/surface presentation assays, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid discovery confirmed by mammalian co-IP plus multiple functional TGF-β1 pathway readouts in one rigorous study\",\n      \"pmids\": [\"26126825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ceramide regulates LAPTM4B function through a sphingolipid interaction motif (SLim) and an adjacent aspartate residue in the third transmembrane helix (TM3): ceramide binding reduces TM3 bending via the neighboring membrane-embedded acidic residue, which facilitates LAPTM4B interaction with the amino acid transporter heavy chain 4F2hc to control mTORC signaling.\",\n      \"method\": \"Atomistic molecular dynamics simulation, mutagenesis of SLim motif and aspartate residue, co-IP of LAPTM4B with 4F2hc, mTORC signaling assay\",\n      \"journal\": \"ACS central science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomistic simulation combined with mutagenesis and functional co-IP/signaling readouts providing mechanistic detail\",\n      \"pmids\": [\"29806001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The transcription factor AP4 directly binds the polymorphism region of the LAPTM4B gene promoter (confirmed by luciferase reporter and EMSA), induces LAPTM4B transcription, and promotes HCC cell proliferation, metastasis, and chemotherapy resistance via LAPTM4B-mediated PI3K/AKT and caspase-dependent pathways. A positive feedback loop exists whereby LAPTM4B acting on c-Myc can in turn regulate AP4.\",\n      \"method\": \"Luciferase reporter assay, EMSA, ChIP, siRNA knockdown, overexpression, proliferation/invasion/apoptosis assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase + EMSA establishing direct binding, functional phenotypes, single lab\",\n      \"pmids\": [\"29337428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The transcription factor AP4 directly binds to the polymorphism region of LAPTM4B promoter and modulates its transcription (confirmed by luciferase assay and EMSA); AP4 promotes breast cancer cell proliferation, migration, invasion, and cisplatin resistance in part through upregulation of LAPTM4B.\",\n      \"method\": \"Transcription factor profiling array, luciferase reporter assay, EMSA, overexpression, siRNA knockdown, proliferation/invasion assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA + luciferase confirming direct binding, functional phenotypes, single lab; replicates finding from PMID 29337428\",\n      \"pmids\": [\"29378908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LAPTM4B downregulation during myocardial ischemia/reperfusion causes overactivation of mTORC1 (through a direct interaction between LAPTM4B's EC3 extracellular domain and mTOR), which represses TFEB, impairing autophagic flux and worsening cardiomyocyte death; restoration of LAPTM4B or inhibition of mTORC1 by rapamycin rescues autophagic flux and reduces infarct size.\",\n      \"method\": \"LAPTM4B knockout mice, adenovirus-mediated overexpression, co-IP (LAPTM4B-mTOR interaction via EC3 domain), autophagic flux assays, lysosomal function assays, infarct size measurement, TFEB overexpression/knockdown rescue experiments\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO mouse + co-IP identifying molecular interaction domain + multiple orthogonal rescue experiments in one rigorous study\",\n      \"pmids\": [\"32693673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LAPTM4B is sorted into intraluminal vesicles (ILVs) of multivesicular endosomes and released in small extracellular vesicles (sEVs); efficient ILV sorting depends on the sphingolipid interaction motif (SLim) in its third transmembrane domain. LAPTM4B controls the glycosphingolipid and ether lipid composition of sEVs: LAPTM4B knockout or SLim-deficient mutant expression causes strong enrichment of glycosphingolipids in sEVs and increased membrane nanodomain stability.\",\n      \"method\": \"LAPTM4B knockout cells, SLim mutant expression, unbiased lipidomics of sEVs, ILV sorting assays, membrane nanodomain stability assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells + structure-function mutagenesis (SLim) + unbiased lipidomics with multiple orthogonal readouts\",\n      \"pmids\": [\"33181324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LAPTM4B-35 localizes specifically to filopodia through direct interaction with Cdc42, which promotes filopodia localization. LAPTM4B-35 stabilizes filopodia and regulates integrin β1 recycling via interaction and co-trafficking on endosomes, stimulating formation and dynamics of focal adhesions, thereby promoting cancer cell dissemination in a zebrafish xenograft model.\",\n      \"method\": \"Co-IP (LAPTM4B-35 with Cdc42 and integrin β1), confocal localization, filopodia quantification, focal adhesion dynamics assay, zebrafish xenograft model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing interaction partners, live imaging of trafficking, in vivo zebrafish model, single lab\",\n      \"pmids\": [\"35381120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LAPTM4B promotes RhoA protein stability by suppressing ubiquitin-mediated proteasome degradation of RhoA, thereby activating the RhoA-LIMK-cofilin signaling pathway to regulate stress fiber organization and promote osteosarcoma cell migration and metastasis; miR-137 regulates LAPTM4B expression in osteosarcoma.\",\n      \"method\": \"siRNA knockdown, overexpression, RhoA ubiquitination assay, Western blot for RhoA/LIMK/cofilin pathway, migration assays, animal metastasis model, patient tissue analysis\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay + pathway readouts + in vivo model, single lab\",\n      \"pmids\": [\"37147294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LAPTM4B interacts with RPS9 and positively regulates RPS9 protein stability, which in turn activates STAT3 to promote leukemia cell progression in AML.\",\n      \"method\": \"Co-IP (LAPTM4B-RPS9 interaction), protein stability assays, STAT3 activation assay, in vitro and in vivo leukemia progression assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus protein stability and signaling readouts, single lab\",\n      \"pmids\": [\"36758682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LAPTM4B suppresses YAP phosphorylation and ubiquitination, preventing YAP degradation; stabilized YAP translocates to the nucleus and binds CREB1, which promotes LAPTM4B transcription, forming a positive feedback loop that maintains hepatocellular carcinoma stem cell stemness.\",\n      \"method\": \"Western blot (YAP phosphorylation/ubiquitination), nuclear/cytoplasmic fractionation, ChIP (YAP-CREB1 binding to LAPTM4B promoter), siRNA knockdown, overexpression, in vitro and in vivo stemness assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + ubiquitination assays + fractionation establishing feedback mechanism, single lab\",\n      \"pmids\": [\"37213231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LAPTM4B suppresses ferroptosis in non-small cell lung cancer by inhibiting NEDD4L/ZRANB1-mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11, thereby maintaining SLC7A11 protein levels and preventing ferroptotic cell death.\",\n      \"method\": \"Metabolomic screens, LAPTM4B knockout cell models, ubiquitination assays, proteasome inhibition, SLC7A11 protein stability assays, in vitro and in vivo ferroptosis assays (erastin treatment), patient tissue samples\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased metabolomics + ubiquitination mechanism + in vivo validation + patient tissue correlation in a single comprehensive study\",\n      \"pmids\": [\"38902268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC2 binds specifically to the LAPTM4B promoter at four distinct binding sites, enhancing its transcriptional activation in HCC, thereby driving autophagy-related malignant progression.\",\n      \"method\": \"ChIP-seq/ChIP (HDAC2 binding to LAPTM4B promoter), HDAC2 inhibitor treatment, overexpression/knockdown, in vitro and in vivo autophagy and proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct promoter binding + functional phenotypes, single lab\",\n      \"pmids\": [\"39147759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ETV1 transcription factor regulates LAPTM4B expression in liver cancer stem cells; LAPTM4B promotes liver cancer stem cell self-renewal and proliferation via the Wnt1/c-Myc/β-catenin pathway, and drives CXCL8 secretion to promote myeloid-derived suppressor cell migration, affecting the tumor immune microenvironment.\",\n      \"method\": \"siRNA knockdown, overexpression, pathway inhibitors, CXCL8 secretion assays, MDSC migration assay, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional pathway studies with multiple phenotypic readouts but no direct binding confirmation of ETV1-LAPTM4B, single lab\",\n      \"pmids\": [\"38388484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LAPTM4B promotes stemness of CD133+ liver cancer stem-like cells by activating WNT/β-catenin signaling: LAPTM4B inhibits β-catenin phosphorylation and interacts with deubiquitinating enzymes USP1 and USP14, reducing β-catenin ubiquitination and degradation, thereby enabling β-catenin nuclear translocation.\",\n      \"method\": \"Co-IP (LAPTM4B with USP1/USP14), nucleocytoplasmic separation, β-catenin ubiquitination/phosphorylation assays, Western blot, immunofluorescence, in vitro/in vivo stemness assays\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying deubiquitinase partners + ubiquitination assays + functional rescue, single lab\",\n      \"pmids\": [\"40171299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the EVI1-driven myeloid malignancy context, EVI1 directly upregulates KDM6B, which demethylates H3K27me3 to activate LAPTM4B transcription; hyperactivation of the LAPTM4B-driven mTOR pathway is crucial for the growth of EVI1-high leukemia cells, and Laptm4b knockdown partially rescues EVI1-induced abnormal hematopoiesis in vivo.\",\n      \"method\": \"Evi1-transgenic mouse model, global gene expression profiling, EVI1 binding site profiling (ChIP), H3K27me3 ChIP, KDM6B inhibition, Laptm4b knockdown in vivo, mTOR pathway assays, leukemia cell line validation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model + ChIP for multiple pathway steps + in vivo Laptm4b rescue establishing epistatic pathway\",\n      \"pmids\": [\"39680456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Beclin1 interacts with both the N- and C-termini of LAPTM4B (independent of the Vps34 complex) and competes with EGFR for LAPTM4B binding, thereby repressing LAPTM4B-mediated EGFR activation and gastric cancer cell growth.\",\n      \"method\": \"Co-IP (Beclin1-LAPTM4B interaction), domain mapping (N- and C-termini), competition binding assay, EGFR activation assay, cell growth assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with domain mapping + competition assay + functional readout, single lab\",\n      \"pmids\": [\"28479384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LAPTM4B interacts with EGFR and stabilizes it in endosomes; LAPTM4B also interacts with Beclin1, promoting autophagy initiation. LAPTM4B knockdown decreases radioresistance in nasopharyngeal cancer cells by inhibiting autophagy.\",\n      \"method\": \"Co-immunoprecipitation, confocal immunofluorescence colocalization, Western blot, flow cytometry (apoptosis), siRNA knockdown, colony formation assay\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus colocalization establishing interactions, functional knockdown phenotype, single lab\",\n      \"pmids\": [\"31410015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LAPTM4B activates ATG3 transcription to modulate HCC cell apoptosis and autophagy; upon starvation, LAPTM4B facilitates cell survival, inhibits apoptosis, and induces autophagic flux.\",\n      \"method\": \"LAPTM4B silencing, microarray expression profiling, real-time PCR, immunofluorescence, Western blot, in vivo xenograft\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptional activation inferred from expression profiling + functional phenotypes, limited mechanistic detail on how LAPTM4B activates ATG3, single lab\",\n      \"pmids\": [\"31118766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LAPTM4B confers resistance to EGFR-TKIs in NSCLC by interacting with ATP1A1 and facilitating its endocytosis while preventing its proteasomal degradation by suppressing TRIM8-mediated K63-linked ubiquitination of ATP1A1, thereby stabilizing ATP1A1 and enhancing lysosomal acidification and EGFR phosphorylation/downstream signaling. EGFR-TKIs impair WWP2-mediated proteasomal degradation of LAPTM4B, increasing LAPTM4B levels.\",\n      \"method\": \"Co-IP (LAPTM4B-ATP1A1 interaction), K63-ubiquitination assay, endocytosis assay, lysosomal acidification measurement, EGFR phosphorylation assay, in vitro and in vivo drug resistance assays, high-content drug screen, patient tissue analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP + ubiquitination mechanism + endocytosis/lysosomal readouts + in vivo validation + drug screen in comprehensive single study\",\n      \"pmids\": [\"41362742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LAPTM4B recruits the E3 ubiquitin ligase NEDD4L to endosomes, leading to increased ubiquitin-mediated proteasomal degradation of TGFβR2 and active SMAD2/3, thereby blocking the TGF-β/SMAD signaling pathway and alleviating pulmonary fibrosis.\",\n      \"method\": \"In vivo bleomycin-induced fibrosis model (LAPTM4B deficiency and restoration), co-IP (LAPTM4B-NEDD4L), ubiquitination/degradation assays for TGFβR2 and SMAD2/3, TGF-β signaling readouts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model + co-IP + ubiquitination mechanism, preprint not yet peer reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LAPTM4B protein is ubiquitinated in bovine granulosa cells: affinity-purified His-tagged LAPTM4B overexpressed in HEK cells showed that the 31.5 kDa isoform represents the ubiquitinated form of the 26.3 kDa native protein, and the ubiquitinated form is differentially expressed during follicular development.\",\n      \"method\": \"Immunoblotting with anti-LAPTM4B antibody, His-tag affinity purification, identification of ubiquitinated vs. non-ubiquitinated isoforms\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method identifying ubiquitination but no writer/eraser/reader identified and limited functional follow-up\",\n      \"pmids\": [\"25881887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CDX1 transcription factor promotes LAPTM4B transcription, and CDX1-mediated LAPTM4B upregulation inhibits mTORC1 pathway activation, thereby alleviating autophagic flux impairment and protecting against nicotine-induced cardiac fibroblast activation and cardiomyocyte hypertrophy.\",\n      \"method\": \"CDX1 overexpression/knockdown, LAPTM4B knockdown, mTOR pathway assays, autophagic flux assays, cardiac fibroblast activation and hypertrophy readouts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional pathway data showing CDX1-LAPTM4B-mTORC1 axis but no direct binding assay for CDX1-LAPTM4B promoter, single lab\",\n      \"pmids\": [\"40121311\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LAPTM4B is a four-transmembrane lysosomal/late endosomal protein that acts as a multifunctional regulator of lysosomal homeostasis, mTORC1 signaling, and cell survival: it recruits the leucine transporter LAT1-4F2hc to lysosomes to enable leucine uptake and V-ATPase-dependent mTORC1 activation, directly interacts with mTOR via its EC3 domain to suppress mTORC1 overactivation, facilitates ceramide export from late endosomes to compartmentalize sphingolipid-mediated cell death signals, inhibits EGFR intraluminal sorting by promoting Hrs ubiquitination (counteracted by PIPKIγi5/PtdIns(4,5)P2/SNX5), promotes drug efflux through interaction with P-glycoprotein, activates PI3K/AKT signaling via its PPRP motif binding to p85α, promotes autophagic flux and lysosomal acidification to confer resistance to metabolic and genotoxic stress, suppresses ferroptosis by preventing NEDD4L/ZRANB1-mediated ubiquitination of SLC7A11, stabilizes ATP1A1 by blocking TRIM8-mediated ubiquitination to enhance lysosomal acidification and EGFR-TKI resistance, promotes RhoA stability to drive cytoskeletal remodeling and migration, and is transcriptionally regulated by AP4, HDAC2, EVI1/KDM6B/H3K27me3, and CDX1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LAPTM4B is a four-transmembrane lysosomal/late-endosomal protein that governs lysosomal homeostasis, amino-acid-dependent mTORC1 signaling, and endosomal sorting to promote cell survival and tumor progression [#0, #5, #7]. It is required for lysosomal acidification and autophagosome maturation: its depletion raises lysosomal pH, increases membrane permeability, releases cathepsins, and triggers apoptosis, whereas its overexpression sustains autophagic flux and survival under metabolic stress [#5]. On lysosomes LAPTM4B binds the leucine transporter LAT1-4F2hc (SLC7A5-SLC3A2) and recruits it to enable luminal leucine uptake and V-ATPase-dependent mTORC1 activation [#7]; a sphingolipid-interaction motif and adjacent TM3 aspartate sense ceramide to modulate this 4F2hc engagement [#11], and at late endosomes LAPTM4B binds ceramide to drive its export and control lysosomal membrane stability and ceramide-driven caspase-3 death signaling [#9]. On endosomes it acts as a PtdIns(4,5)P2 effector that suppresses EGFR intraluminal sorting and degradation by promoting Hrs ubiquitination—an activity opposed by PIPKIγi5/SNX5—thereby prolonging EGFR signaling [#8], and it directly stabilizes EGFR while engaging Beclin1 to support autophagy [#25, #26]. LAPTM4B broadly stabilizes oncogenic effectors by blocking their ubiquitin-mediated degradation: it preserves SLC7A11 against NEDD4L/ZRANB1 to suppress ferroptosis [#20], RhoA to drive LIMK-cofilin cytoskeletal remodeling and migration [#17], ATP1A1 against TRIM8 to confer EGFR-TKI resistance [#28], and β-catenin via USP1/USP14 to sustain liver cancer stem-cell stemness [#23]. It also confers multidrug resistance through cytosolic doxorubicin sequestration, P-glycoprotein interaction, and PI3K/AKT activation via its N-terminal PPRP motif binding p85α [#3, #4, #2]. Conversely, in regulatory T cells and fibrotic tissue LAPTM4B negatively regulates TGF-β by suppressing proTGF-β1 production and by recruiting NEDD4L to degrade TGFβR2/SMAD2/3 [#10], and its loss drives mTORC1 overactivation through a direct EC3-domain–mTOR interaction that worsens ischemia/reperfusion cardiac injury [#14]. LAPTM4B transcription is controlled by AP4, HDAC2, and an EVI1/KDM6B/H3K27me3 axis that couples it to mTOR-dependent leukemia growth [#12, #21, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established LAPTM4B as a two-isoform, four-transmembrane intracellular-membrane protein that physically associates with integrin α6 and EGFR, providing the first link between this protein and cell-adhesion/growth-factor receptors.\",\n      \"evidence\": \"Western blot, 2D electrophoresis, immunohistochemistry, and co-IP in laminin-seeded cells\",\n      \"pmids\": [\"12947545\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the integrin/EGFR association tested\", \"Interaction directness and stoichiometry not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed LAPTM4B is oncogenic, answering whether its overexpression alone drives transformation by demonstrating accelerated S-phase entry and tumorigenesis in vivo.\",\n      \"evidence\": \"Overexpression in NIH3T3 with flow cytometry, growth curves, and mouse tumorigenesis assay\",\n      \"pmids\": [\"12947546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of Cyclin E upregulation not defined\", \"Single cell-line/single-lab system\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped the oncogenic activity to the N-terminal PPRP motif, defining a discrete structural determinant required for proliferation, invasion, and oncoprotein induction.\",\n      \"evidence\": \"Site-directed mutagenesis with proliferation/migration/invasion assays and Western blot\",\n      \"pmids\": [\"19843073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partner of PPRP not yet identified at this stage\", \"Single-lab phenotypic readouts\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a multidrug-resistance mechanism, resolving how LAPTM4B confers chemoresistance via cytosolic drug sequestration, P-glycoprotein interaction, and PPRP-p85α-driven PI3K/AKT signaling.\",\n      \"evidence\": \"Reciprocal siRNA/overexpression, drug-localization imaging, co-IP, colocalization, and PI3K inhibition\",\n      \"pmids\": [\"20098429\", \"20711237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PPRP-p85α binding not resolved\", \"Relative contribution of sequestration vs. efflux vs. signaling not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established LAPTM4B as essential for lysosomal acidification, membrane integrity, and late-stage autophagosome maturation, explaining its pro-survival role under nutrient/hypoxic stress.\",\n      \"evidence\": \"Reciprocal knockdown/overexpression with lysosomal pH/permeability, cathepsin release, autophagy flux assays, and xenografts\",\n      \"pmids\": [\"22037872\", \"21618708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular driver of acidification not identified here\", \"How autophagosome maturation is blocked mechanistically left open\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the lysosomal leucine-sensing function, answering how LAPTM4B activates mTORC1 by recruiting LAT1-4F2hc to enable luminal leucine uptake and V-ATPase-dependent signaling.\",\n      \"evidence\": \"Co-IP, colocalization, leucine uptake assay, and S6K-phosphorylation readout with knockdown/overexpression\",\n      \"pmids\": [\"25998567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the LAPTM4B-LAT1-4F2hc-V-ATPase assembly not defined\", \"Whether leucine uptake is direct or indirect not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined LAPTM4B as a PtdIns(4,5)P2 effector controlling EGFR fate, showing it blocks EGFR intraluminal sorting by promoting Hrs ubiquitination, counteracted by PIPKIγi5/SNX5.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, EGFR degradation/signaling readouts, and binding assays\",\n      \"pmids\": [\"25588945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase ubiquitinating Hrs not identified\", \"Quantitative link between PIP2 levels and LAPTM4B activity not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed LAPTM4B as a ceramide-handling protein that exports ceramide from late endosomes, decoupling lysosomal stability from sensitivity to ceramide-driven apoptosis.\",\n      \"evidence\": \"Novel ceramide probes, reciprocal silencing/overexpression, lysosomal stability and caspase-3 assays, lipidomics\",\n      \"pmids\": [\"26280656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ceramide export (transporter vs. carrier) not defined\", \"Acceptor compartment for exported ceramide unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended LAPTM4B to immune regulation, establishing it as a GARP-binding negative regulator of TGF-β1 production in human Tregs.\",\n      \"evidence\": \"Yeast two-hybrid, mammalian co-IP, and TGF-β1 cleavage/secretion/surface-presentation assays\",\n      \"pmids\": [\"26126825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GARP-LAPTM4B binding not resolved\", \"In vivo Treg consequence not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided atomistic mechanism for ceramide sensing, showing a TM3 SLim motif and adjacent aspartate translate ceramide binding into altered 4F2hc engagement and mTORC signaling.\",\n      \"evidence\": \"Molecular dynamics simulation, SLim/aspartate mutagenesis, co-IP with 4F2hc, mTORC signaling assay\",\n      \"pmids\": [\"29806001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Simulation-predicted TM3 bending not directly observed structurally\", \"In vivo relevance of ceramide-tuned mTORC not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified AP4 as a direct transcriptional activator of LAPTM4B in HCC and breast cancer, linking promoter polymorphism to LAPTM4B-driven PI3K/AKT chemoresistance and a c-Myc feedback loop.\",\n      \"evidence\": \"Luciferase reporter, EMSA, ChIP, and knockdown/overexpression phenotypes across two cancer types\",\n      \"pmids\": [\"29337428\", \"29378908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab origin of both reports\", \"Functional impact of the promoter polymorphism on AP4 binding not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a tumor-suppressive mTORC1-restraint function via direct EC3-domain–mTOR interaction, showing LAPTM4B loss overactivates mTORC1, represses TFEB, and worsens cardiac I/R injury.\",\n      \"evidence\": \"LAPTM4B-knockout mice, adenoviral rescue, EC3-mTOR co-IP, autophagic flux and infarct measurements, TFEB rescue\",\n      \"pmids\": [\"32693673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of mTORC1-activating (lysosomal LAT1) vs. mTORC1-suppressing (EC3-mTOR) roles not mechanistically unified\", \"Direct EC3-mTOR binding interface not structurally mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed LAPTM4B controls the lipid composition of secreted extracellular vesicles, with SLim-dependent ILV sorting shaping sEV glycosphingolipid and ether-lipid content.\",\n      \"evidence\": \"Knockout cells, SLim-mutant expression, unbiased sEV lipidomics, ILV sorting and nanodomain stability assays\",\n      \"pmids\": [\"33181324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of altered sEV lipids on recipient cells not tested\", \"Machinery sorting LAPTM4B into ILVs not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected LAPTM4B to actin-based motility, showing Cdc42-dependent filopodial localization and integrin-β1 co-trafficking that stabilizes focal adhesions and drives cancer dissemination.\",\n      \"evidence\": \"Co-IP with Cdc42 and integrin β1, confocal localization, focal-adhesion dynamics, zebrafish xenograft\",\n      \"pmids\": [\"35381120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of Cdc42 binding vs. complex-mediated not fully resolved\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a recurring theme of LAPTM4B stabilizing oncogenic effectors against ubiquitination, here preserving RhoA to activate RhoA-LIMK-cofilin signaling and osteosarcoma metastasis.\",\n      \"evidence\": \"RhoA ubiquitination assay, pathway Western blots, migration and in vivo metastasis models, miR-137 regulation\",\n      \"pmids\": [\"37147294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase targeting RhoA not identified\", \"Mechanism by which LAPTM4B blocks RhoA ubiquitination unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the stabilization theme to translation and stemness signaling, showing LAPTM4B stabilizes RPS9 to activate STAT3 in AML and stabilizes YAP to feed a CREB1-driven HCC stemness loop.\",\n      \"evidence\": \"Co-IP, protein-stability and ubiquitination/phosphorylation assays, fractionation, ChIP, and in vivo progression models\",\n      \"pmids\": [\"36758682\", \"37213231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of RPS9/YAP stabilization (direct vs. via deubiquitinase) not fully defined\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Unified the ubiquitination-control theme across ferroptosis, drug resistance, and stemness, showing LAPTM4B protects SLC7A11 (anti-ferroptosis), ATP1A1 (EGFR-TKI resistance), and β-catenin (stemness via USP1/USP14) from degradation.\",\n      \"evidence\": \"Metabolomic/drug screens, knockout models, ubiquitination assays, co-IP of NEDD4L/TRIM8/USP partners, in vivo and patient-tissue validation\",\n      \"pmids\": [\"38902268\", \"41362742\", \"40171299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether a single shared biochemical activity underlies all stabilization events not determined\", \"β-catenin/USP findings remain single-lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined transcriptional and immune-microenvironment axes, showing HDAC2 and EVI1/KDM6B/H3K27me3 activate LAPTM4B transcription to drive autophagy- and mTOR-dependent malignancy, while LAPTM4B drives CXCL8-mediated MDSC recruitment.\",\n      \"evidence\": \"ChIP/ChIP-seq, H3K27me3 profiling, inhibitor and in vivo knockdown studies, CXCL8/MDSC migration assays\",\n      \"pmids\": [\"39147759\", \"39680456\", \"38388484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ETV1-LAPTM4B promoter binding not confirmed\", \"Interplay among the multiple transcriptional regulators not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed LAPTM4B can suppress TGF-β signaling in fibrosis by recruiting NEDD4L to degrade TGFβR2 and active SMAD2/3, paralleling its Treg TGF-β1 role.\",\n      \"evidence\": \"Bleomycin fibrosis model with LAPTM4B deficiency/restoration, co-IP, and TGFβR2/SMAD ubiquitination assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer reviewed\", \"Reconciliation with LAPTM4B's NEDD4L-blocking role on SLC7A11 not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked CDX1-driven LAPTM4B upregulation to mTORC1 suppression and autophagy restoration, protecting against nicotine-induced cardiac remodeling.\",\n      \"evidence\": \"CDX1 and LAPTM4B perturbation with mTOR/autophagy and cardiac fibroblast/hypertrophy readouts\",\n      \"pmids\": [\"40121311\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct CDX1-LAPTM4B promoter binding assay\", \"Single-lab functional inference of the transcriptional axis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LAPTM4B mechanistically reconciles opposing roles in mTORC1 signaling (lysosomal LAT1-driven activation vs. EC3-domain-mediated suppression) and in ubiquitination (protecting some substrates while recruiting NEDD4L to degrade others) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of LAPTM4B explaining context-dependent substrate selection\", \"No unifying biochemical activity proposed for its bidirectional control of degradation\", \"How tissue context switches LAPTM4B between mTORC1-activating and -suppressing states is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 14, 20, 28]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 23, 29]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 7, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8, 16, 29]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 14, 23]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 14, 21, 27]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 20]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17, 20, 23, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLC7A5\", \"SLC3A2\", \"EGFR\", \"MTOR\", \"Beclin1\", \"Cdc42\", \"GARP\", \"NEDD4L\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}