{"gene":"RHBDD1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2008,"finding":"RHBDD1 is a serine protease (rhomboid family member) that cleaves BIK, a pro-apoptotic Bcl-2 family protein, at a site located in BIK's transmembrane region; glycine142 and serine144 of RHBDD1 are catalytically critical residues. Overexpression of RHBDD1 reduces BIK-mediated apoptosis, while knockdown enhances it, placing RHBDD1 upstream of BIK protein degradation.","method":"In vitro cleavage assay, active-site mutagenesis (G142, S144), overexpression and knockdown in HEK 293T cells with apoptosis readout","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro proteolytic activity established, active-site mutagenesis with functional validation, gain- and loss-of-function in cells with specific apoptosis readout","pmids":["18953687"],"is_preprint":false},{"year":2012,"finding":"RHBDD1 cleaves the multi-pass transmembrane protein TSAP6 in a dose- and activity-dependent manner; the major cleavage site is in the C-terminal portion of TSAP6's third transmembrane domain, identified by mass spectrometry and mutagenesis. Genetic inactivation of endogenous RHBDD1 in HCT116 and RKO colon cancer cells significantly elevated exosome secretion (detected via exosomal markers Tsg101, Tf-R, FasL, Trail); this elevation was reduced when TSAP6 was knocked down, establishing a TSAP6-dependent mechanism by which RHBDD1 restricts non-classical exosomal secretion.","method":"In vitro proteolysis assay, mass spectrometry, site-directed mutagenesis, somatic cell knock-in for endogenous RHBDD1 inactivation, TSAP6 knockdown rescue experiment, exosome quantification","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cleavage site identified by MS and mutagenesis, genetic inactivation with functional exosome phenotype, epistasis via TSAP6 knockdown rescue, multiple orthogonal methods in one study","pmids":["22624035"],"is_preprint":false},{"year":2017,"finding":"RHBDD1 upregulates EGFR expression via the AP-1 pathway in colorectal cancer: RHBDD1 knockdown or inactivation decreases c-Jun and EGFR protein levels; c-Jun overexpression in RHBDD1-inactivated cells rescues EGFR expression dose-dependently; conversely, c-Jun knockdown blocks RHBDD1-mediated EGFR restoration, placing c-Jun/AP-1 between RHBDD1 and EGFR transcriptional regulation.","method":"RHBDD1 knockdown/inactivation, c-Jun overexpression and knockdown rescue experiments, western blot, animal tumor models, tissue microarray","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via c-Jun rescue and c-Jun knockdown counter-rescue, replicated in cells and animal models, single lab","pmids":["28445956"],"is_preprint":false},{"year":2018,"finding":"RHBDD1 promotes CRC metastasis by activating the Wnt/β-catenin signaling pathway, specifically by regulating phosphorylation of β-catenin at Ser552 and Ser675; rescue of these phosphorylation events restores Wnt pathway activity, migration, and invasion in RHBDD1-knockdown cells. RHBDD1 also promotes EMT and a stem-like phenotype, and regulates the Wnt/β-catenin target ZEB1 at both mRNA and protein levels.","method":"RNA-seq, TOP/FOP flash reporter assay, western blot (phospho-β-catenin), Transwell assay, phosphorylation rescue experiments, Transwell in vitro and pleural metastasis in vivo","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Wnt pathway activity measured by TOP/FOP reporter, phospho-specific rescue demonstrates mechanistic link, multiple orthogonal methods, single lab","pmids":["29426364"],"is_preprint":false},{"year":2023,"finding":"RHBDD1 (also designated RHBDL4) directly cleaves SREBP-1c at the ER; the p97/VCP AAA-ATPase complex then extracts the remaining ER-embedded SREBP-1c fragment. The enzymatic activity of RHBDD1 is enhanced by saturated fatty acids (SFAs) and inhibited by polyunsaturated fatty acids (PUFAs). Genetic deletion of RHBDD1 in mice fed a Western diet prevents SREBP-1c-driven induction of lipogenic genes (especially for PUFA synthesis and incorporation) and lipoprotein secretion.","method":"In vitro cleavage assay, genetic deletion (knockout mice), Western diet feeding experiment, gene expression analysis of lipogenic targets, biochemical fractionation/p97 complex analysis","journal":"PNAS nexus","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct cleavage demonstrated in vitro, genetic KO in mice with defined metabolic phenotype, fatty acid regulation of enzymatic activity established, multiple orthogonal methods","pmids":["37954160"],"is_preprint":false},{"year":2021,"finding":"RHBDD1 promotes NSCLC cell growth and invasion via the ZEB1/PI3K/AKT signaling pathway: RHBDD1 silencing reduces ZEB1 mRNA and protein levels, decreases PI3K and AKT phosphorylation, and inhibits proliferation/invasion; overexpression of ZEB1 or activated AKT reverses these effects, placing RHBDD1 upstream of ZEB1 and PI3K/AKT in NSCLC.","method":"RNAi knockdown, ZEB1/AKT overexpression rescue, western blot (phospho-PI3K, phospho-AKT), cell proliferation and invasion assays","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via ZEB1/AKT rescue, knockdown with defined phospho-signaling readouts, single lab","pmids":["33515112"],"is_preprint":false},{"year":2021,"finding":"RHBDD1 promotes proliferation, migration, invasion, and EMT in renal cell carcinoma via activation of the EGFR/AKT signaling pathway; EGFR inhibitor gefitinib partially reverses the pro-tumorigenic effects of RHBDD1 overexpression.","method":"RHBDD1 knockdown and overexpression in RCC cell lines, CCK-8, wound healing and Transwell assays, western blot for EGFR/AKT phosphorylation, gefitinib pharmacological rescue","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological rescue with EGFR inhibitor links RHBDD1 to EGFR/AKT, single lab, no structural or in vitro enzymatic data","pmids":["34581421"],"is_preprint":false},{"year":2025,"finding":"In TP53-mutant NSCLC cells, RHBDD1 promotes endoplasmic reticulum-associated degradation (ERAD) of mutant p53 and DNA-PKcs (encoded by PRKDC); co-localization of p53 with RHBDD1 and DNA-PKcs is observed specifically in TP53-mutant cells. RHBDD1-mediated ERAD of these substrates causes S-phase cell cycle arrest, while simultaneously inhibiting DNA-PKcs-regulated apoptosis, thereby enhancing cell survival.","method":"shRNA knockdown and overexpression of RHBDD1 in TP53-mutant vs. wild-type NSCLC cells, immunofluorescence co-localization, western blot for p53/DNA-PKcs/ER stress markers, flow cytometry cell cycle analysis, pharmacological rescue with p53 activators (Nutlin-3a, HBX41108) and DNA-PKcs inhibitor (STL127705)","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-localization and pharmacological rescue support ERAD mechanism, multiple readouts, but single lab and no direct in vitro reconstitution of RHBDD1-mediated ERAD of p53/DNA-PKcs","pmids":["41013641"],"is_preprint":false},{"year":2026,"finding":"RHBDD1 physically associates with EGFR (confirmed by co-immunoprecipitation) and activates EGFR/PI3K/AKT signaling to promote proliferation, EMT (including Snail upregulation), migration, and invasion in cervical cancer cells; gefitinib and LY294002 mitigate RHBDD1-induced oncogenicity, while AKT activator SC79 partially reverses RHBDD1-knockdown suppression.","method":"Co-immunoprecipitation (RHBDD1–EGFR), RHBDD1 knockdown and overexpression, pharmacological pathway inhibitors (gefitinib, LY294002) and activator (SC79), western blot for AKT phosphorylation and EMT markers, xenograft mouse model","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP establishes physical RHBDD1–EGFR interaction, pharmacological epistasis with multiple inhibitors/activators, single lab","pmids":["41759697"],"is_preprint":false},{"year":2013,"finding":"Lentiviral shRNA-mediated silencing of RHBDD1 in glioblastoma cell lines (U251 and U87MG) inhibited cell proliferation by >50% and completely abolished colony formation, with cell cycle arrest identified as the mechanism; this establishes RHBDD1 as required for cell cycle progression in glioblastoma cells.","method":"Lentiviral shRNA knockdown, proliferation assay, colony formation assay, cell cycle analysis","journal":"Technology in cancer research & treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown with proliferation and cell cycle phenotype, single lab, no pathway placement or molecular mechanism identified","pmids":["23883433"],"is_preprint":false}],"current_model":"RHBDD1 is an ER-resident serine protease (rhomboid family) whose catalytic residues G142 and S144 cleave transmembrane substrates including the pro-apoptotic protein BIK (dampening BIK-driven apoptosis), the exosome regulator TSAP6 (suppressing non-classical exosome secretion in a TSAP6-dependent manner), and the lipogenic transcription factor SREBP-1c (a cleavage enhanced by saturated fatty acids and inhibited by PUFAs, with residual ER-embedded fragment extracted by the p97/VCP complex); beyond direct proteolysis, RHBDD1 activates the EGFR signaling axis (physically associating with EGFR and promoting AP-1/c-Jun-dependent EGFR transcription) and the Wnt/β-catenin pathway (via β-catenin Ser552/Ser675 phosphorylation and ZEB1 induction), and in TP53-mutant cells promotes ERAD-dependent degradation of mutant p53 and DNA-PKcs to induce S-phase arrest while suppressing apoptosis."},"narrative":{"mechanistic_narrative":"RHBDD1 is an ER-resident rhomboid-family serine protease that controls cell fate by cleaving transmembrane substrates and, in cancer, by potentiating growth-signaling pathways [PMID:18953687, PMID:37954160]. Its proteolytic activity depends on the catalytic residues Gly142 and Ser144, which it uses to cleave the pro-apoptotic Bcl-2 protein BIK within its transmembrane region, thereby restraining BIK-driven apoptosis [PMID:18953687]. The same activity cleaves the multi-pass membrane protein TSAP6 in its third transmembrane domain, and loss of RHBDD1 elevates non-classical exosome secretion in a TSAP6-dependent manner [PMID:22624035]. RHBDD1 (also designated RHBDL4) further cleaves the lipogenic transcription factor SREBP-1c at the ER, with the residual membrane-embedded fragment extracted by the p97/VCP complex; this cleavage is enhanced by saturated fatty acids and inhibited by polyunsaturated fatty acids, and its genetic deletion in mice blunts SREBP-1c-driven lipogenic gene induction [PMID:37954160]. Beyond direct proteolysis, RHBDD1 acts as a pro-tumorigenic regulator across multiple carcinomas: it physically associates with EGFR and drives c-Jun/AP-1-dependent EGFR transcription and EGFR/PI3K/AKT signaling [PMID:28445956, PMID:41759697], and it activates Wnt/β-catenin signaling through β-catenin Ser552/Ser675 phosphorylation while inducing ZEB1 to promote EMT and invasion [PMID:29426364, PMID:33515112]. In TP53-mutant cells RHBDD1 promotes ERAD-dependent degradation of mutant p53 and DNA-PKcs, producing S-phase arrest while suppressing apoptosis to favor survival [PMID:41013641].","teleology":[{"year":2008,"claim":"Established RHBDD1 as a catalytically active rhomboid protease and identified its first substrate, linking it to apoptotic control.","evidence":"In vitro cleavage assay with active-site mutagenesis (G142, S144) and gain/loss-of-function apoptosis readout in HEK293T cells","pmids":["18953687"],"confidence":"High","gaps":["Physiological context of BIK cleavage in tissues not defined","No structural model of the protease-substrate interaction"]},{"year":2012,"claim":"Showed RHBDD1 cleaves a second transmembrane substrate (TSAP6) and thereby restrains non-classical exosome secretion, broadening its substrate repertoire and physiological output.","evidence":"In vitro proteolysis, MS-mapped cleavage site, endogenous genetic inactivation, and TSAP6-knockdown epistasis with exosome quantification in colon cancer cells","pmids":["22624035"],"confidence":"High","gaps":["Functional consequence of altered exosome flux in vivo unresolved","Whether TSAP6 cleavage is regulated remains unknown"]},{"year":2013,"claim":"Implicated RHBDD1 as required for cell cycle progression in glioblastoma, the first link to a proliferative phenotype.","evidence":"Lentiviral shRNA knockdown with proliferation, colony formation, and cell cycle assays in U251/U87MG cells","pmids":["23883433"],"confidence":"Low","gaps":["No molecular mechanism or pathway placement identified","Single lab, descriptive phenotype only"]},{"year":2017,"claim":"Defined a non-proteolytic transcriptional axis whereby RHBDD1 drives EGFR expression through c-Jun/AP-1 in colorectal cancer.","evidence":"Knockdown/inactivation with c-Jun overexpression and knockdown rescue, western blot, tumor models, tissue microarray","pmids":["28445956"],"confidence":"Medium","gaps":["Whether protease activity is needed for AP-1/EGFR regulation not tested","Direct molecular link between RHBDD1 and c-Jun unclear"]},{"year":2018,"claim":"Connected RHBDD1 to Wnt/β-catenin signaling and EMT via β-catenin phosphorylation and ZEB1 induction, explaining its pro-metastatic role.","evidence":"RNA-seq, TOP/FOP reporter, phospho-β-catenin western blot, phosphorylation rescue, Transwell and in vivo pleural metastasis","pmids":["29426364"],"confidence":"Medium","gaps":["Kinase mediating β-catenin Ser552/Ser675 phosphorylation not identified","Mechanism linking protease to Wnt activation unresolved"]},{"year":2021,"claim":"Extended the RHBDD1–ZEB1 and EGFR/AKT oncogenic axes to NSCLC and renal cell carcinoma, indicating these signaling roles generalize across tumor types.","evidence":"RNAi knockdown with ZEB1/AKT and gefitinib pharmacological rescue, phospho-signaling western blots, proliferation/invasion assays in NSCLC and RCC cells","pmids":["33515112","34581421"],"confidence":"Medium","gaps":["Direct versus indirect engagement of EGFR/AKT not distinguished","No in vitro enzymatic or structural data in these contexts"]},{"year":2023,"claim":"Identified SREBP-1c as a metabolically regulated substrate cleaved at the ER, with fatty acids tuning protease activity and p97/VCP completing membrane extraction, establishing RHBDD1 as a lipogenic regulator.","evidence":"In vitro cleavage, knockout mice on Western diet, lipogenic gene expression analysis, biochemical fractionation/p97 complex analysis","pmids":["37954160"],"confidence":"High","gaps":["Molecular basis of fatty-acid sensing by the protease not defined","Relationship between metabolic and oncogenic functions unexplored"]},{"year":2025,"claim":"Showed RHBDD1 directs ERAD of mutant p53 and DNA-PKcs in TP53-mutant cells, coupling its activity to cell cycle arrest and apoptosis suppression for survival.","evidence":"shRNA/overexpression in TP53-mutant vs wild-type NSCLC, immunofluorescence co-localization, ER stress markers, flow cytometry, pharmacological rescue with p53 activators and DNA-PKcs inhibitor","pmids":["41013641"],"confidence":"Medium","gaps":["No in vitro reconstitution of RHBDD1-mediated ERAD of p53/DNA-PKcs","Direct versus indirect substrate engagement unresolved"]},{"year":2026,"claim":"Demonstrated a direct physical RHBDD1–EGFR association driving EGFR/PI3K/AKT-dependent oncogenicity in cervical cancer, reinforcing EGFR as a recurring effector.","evidence":"Co-immunoprecipitation, knockdown/overexpression, pharmacological epistasis (gefitinib, LY294002, SC79), western blot, xenograft model","pmids":["41759697"],"confidence":"Medium","gaps":["Whether EGFR is a proteolytic substrate or scaffold partner not determined","Reciprocal/structural validation of the interaction lacking"]},{"year":null,"claim":"How RHBDD1's catalytic proteolytic activity mechanistically connects to its many downstream signaling outputs (EGFR, Wnt, PI3K/AKT, ERAD) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","Unclear which signaling roles require catalytic activity versus scaffolding","Integration of metabolic and oncogenic functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,7]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,4,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["EGFR","BIK","TSAP6","SREBF1","TP53","PRKDC","VCP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TEB9","full_name":"Rhomboid-related protein 4","aliases":["Rhomboid domain-containing protein 1","Rhomboid-like protein 4"],"length_aa":315,"mass_kda":35.8,"function":"Intramembrane-cleaving serine protease that cleaves single transmembrane or multi-pass membrane proteins in the hydrophobic plane of the membrane, luminal loops and juxtamembrane regions. Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors. Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded membrane proteins. Required for the degradation process of some specific misfolded endoplasmic reticulum (ER) luminal proteins. Participates in the transfer of misfolded proteins from the ER to the cytosol, where they are destroyed by the proteasome in a ubiquitin-dependent manner. Functions in BIK, MPZ, PKD1, PTCRA, RHO, STEAP3 and TRAC processing. Involved in the regulation of exosomal secretion; inhibits the TSAP6-mediated secretion pathway. Involved in the regulation of apoptosis; modulates BIK-mediated apoptotic activity. Also plays a role in the regulation of spermatogenesis; inhibits apoptotic activity in spermatogonia","subcellular_location":"Endoplasmic reticulum membrane; Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q8TEB9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RHBDD1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RHBDD1","total_profiled":1310},"omim":[{"mim_id":"617515","title":"RHOMBOID DOMAIN-CONTAINING 1; RHBDD1","url":"https://www.omim.org/entry/617515"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RHBDD1"},"hgnc":{"alias_symbol":["DKFZp547E052","RHBDL4"],"prev_symbol":[]},"alphafold":{"accession":"Q8TEB9","domains":[{"cath_id":"1.20.1540.10","chopping":"11-219","consensus_level":"high","plddt":92.2679,"start":11,"end":219}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TEB9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TEB9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TEB9-F1-predicted_aligned_error_v6.png","plddt_mean":79.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RHBDD1","jax_strain_url":"https://www.jax.org/strain/search?query=RHBDD1"},"sequence":{"accession":"Q8TEB9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TEB9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TEB9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TEB9"}},"corpus_meta":[{"pmid":"29426364","id":"PMC_29426364","title":"RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/29426364","citation_count":78,"is_preprint":false},{"pmid":"31243644","id":"PMC_31243644","title":"MicroRNA-138-5p inhibits cell migration, invasion and EMT in breast cancer by directly targeting RHBDD1.","date":"2019","source":"Breast cancer (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/31243644","citation_count":59,"is_preprint":false},{"pmid":"18953687","id":"PMC_18953687","title":"A novel member of the Rhomboid family, RHBDD1, regulates BIK-mediated apoptosis.","date":"2008","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/18953687","citation_count":49,"is_preprint":false},{"pmid":"31693935","id":"PMC_31693935","title":"miR-145-5p restrained cell growth, invasion, migration and tumorigenesis via modulating RHBDD1 in colorectal cancer via the EGFR-associated signaling pathway.","date":"2019","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31693935","citation_count":39,"is_preprint":false},{"pmid":"22624035","id":"PMC_22624035","title":"Exosome-related multi-pass transmembrane protein TSAP6 is a target of rhomboid protease RHBDD1-induced proteolysis.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22624035","citation_count":33,"is_preprint":false},{"pmid":"32528541","id":"PMC_32528541","title":"Silibinin suppresses epithelial-mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1.","date":"2020","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32528541","citation_count":22,"is_preprint":false},{"pmid":"33041671","id":"PMC_33041671","title":"MiR-924 as a tumor suppressor inhibits non-small cell lung cancer by inhibiting RHBDD1/Wnt/β-catenin signaling pathway.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33041671","citation_count":21,"is_preprint":false},{"pmid":"23883433","id":"PMC_23883433","title":"Lentiviral vector mediated delivery of RHBDD1 shRNA down regulated the proliferation of human glioblastoma cells.","date":"2013","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/23883433","citation_count":18,"is_preprint":false},{"pmid":"38072968","id":"PMC_38072968","title":"Circular RNA RHBDD1 regulates tumorigenicity and ferroptosis in colorectal cancer by mediating the ELAVL1/SCD mRNA interaction.","date":"2023","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38072968","citation_count":15,"is_preprint":false},{"pmid":"28445956","id":"PMC_28445956","title":"RHBDD1 upregulates EGFR via the AP-1 pathway in colorectal cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28445956","citation_count":12,"is_preprint":false},{"pmid":"33515112","id":"PMC_33515112","title":"RHBDD1 silencing inhibited cell growth and invasion of non-small cell lung cancer by mediating ZEB1/PI3K/AKT signaling pathway.","date":"2021","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/33515112","citation_count":11,"is_preprint":false},{"pmid":"37954160","id":"PMC_37954160","title":"Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids.","date":"2023","source":"PNAS nexus","url":"https://pubmed.ncbi.nlm.nih.gov/37954160","citation_count":10,"is_preprint":false},{"pmid":"29548344","id":"PMC_29548344","title":"Correction to: RHBDD1 promotes colorectal cancer metastasis through the Wnt signaling pathway and its downstream target ZEB1.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/29548344","citation_count":10,"is_preprint":false},{"pmid":"34581421","id":"PMC_34581421","title":"RHBDD1 promotes proliferation, migration, invasion and EMT in renal cell carcinoma via the EGFR/AKT signaling pathway.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34581421","citation_count":9,"is_preprint":false},{"pmid":"23484682","id":"PMC_23484682","title":"[Expression of RHBDD1 gene in patients with chronic myeloid leukemia and its clinical significance].","date":"2013","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/23484682","citation_count":5,"is_preprint":false},{"pmid":"37861049","id":"PMC_37861049","title":"RHBDD1 Promotes the Growth and Stemness Characteristics of Gastric Cancer Cells by Activating Wnt/β-catenin Signaling Pathway.","date":"2024","source":"Current stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37861049","citation_count":4,"is_preprint":false},{"pmid":"35950472","id":"PMC_35950472","title":"Effects of miR-211-3p/RHBDD1 axis on cell proliferation, cell cycle progression, and epithelial-mesenchymal transition in glioma.","date":"2022","source":"Folia neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/35950472","citation_count":3,"is_preprint":false},{"pmid":"36825753","id":"PMC_36825753","title":"MiR-5195-3p functions as a tumor suppressor by targeting RHBDD1 in ovarian cancer.","date":"2023","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/36825753","citation_count":3,"is_preprint":false},{"pmid":"40787199","id":"PMC_40787199","title":"Regulation of RHBDD1 in the invasion of esophageal cancer cells via ELK3/Wnt/β-catenin signaling pathway.","date":"2025","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/40787199","citation_count":1,"is_preprint":false},{"pmid":"41013641","id":"PMC_41013641","title":"RHBDD1 induces cell cycle arrest in TP53-mutant NSCLC cells by promoting endoplasmic reticulum-associated degradation of p53 and DNA-PKcs.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41013641","citation_count":0,"is_preprint":false},{"pmid":"41759697","id":"PMC_41759697","title":"RHBDD1 promotes cervical cancer progression by activating the EGFR/PI3K/AKT signaling pathway.","date":"2026","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/41759697","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13700,"output_tokens":3278,"usd":0.045135,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10771,"output_tokens":3392,"usd":0.069328,"stage2_stop_reason":"end_turn"},"total_usd":0.114463,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"RHBDD1 is a serine protease (rhomboid family member) that cleaves BIK, a pro-apoptotic Bcl-2 family protein, at a site located in BIK's transmembrane region; glycine142 and serine144 of RHBDD1 are catalytically critical residues. Overexpression of RHBDD1 reduces BIK-mediated apoptosis, while knockdown enhances it, placing RHBDD1 upstream of BIK protein degradation.\",\n      \"method\": \"In vitro cleavage assay, active-site mutagenesis (G142, S144), overexpression and knockdown in HEK 293T cells with apoptosis readout\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro proteolytic activity established, active-site mutagenesis with functional validation, gain- and loss-of-function in cells with specific apoptosis readout\",\n      \"pmids\": [\"18953687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RHBDD1 cleaves the multi-pass transmembrane protein TSAP6 in a dose- and activity-dependent manner; the major cleavage site is in the C-terminal portion of TSAP6's third transmembrane domain, identified by mass spectrometry and mutagenesis. Genetic inactivation of endogenous RHBDD1 in HCT116 and RKO colon cancer cells significantly elevated exosome secretion (detected via exosomal markers Tsg101, Tf-R, FasL, Trail); this elevation was reduced when TSAP6 was knocked down, establishing a TSAP6-dependent mechanism by which RHBDD1 restricts non-classical exosomal secretion.\",\n      \"method\": \"In vitro proteolysis assay, mass spectrometry, site-directed mutagenesis, somatic cell knock-in for endogenous RHBDD1 inactivation, TSAP6 knockdown rescue experiment, exosome quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cleavage site identified by MS and mutagenesis, genetic inactivation with functional exosome phenotype, epistasis via TSAP6 knockdown rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22624035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RHBDD1 upregulates EGFR expression via the AP-1 pathway in colorectal cancer: RHBDD1 knockdown or inactivation decreases c-Jun and EGFR protein levels; c-Jun overexpression in RHBDD1-inactivated cells rescues EGFR expression dose-dependently; conversely, c-Jun knockdown blocks RHBDD1-mediated EGFR restoration, placing c-Jun/AP-1 between RHBDD1 and EGFR transcriptional regulation.\",\n      \"method\": \"RHBDD1 knockdown/inactivation, c-Jun overexpression and knockdown rescue experiments, western blot, animal tumor models, tissue microarray\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via c-Jun rescue and c-Jun knockdown counter-rescue, replicated in cells and animal models, single lab\",\n      \"pmids\": [\"28445956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RHBDD1 promotes CRC metastasis by activating the Wnt/β-catenin signaling pathway, specifically by regulating phosphorylation of β-catenin at Ser552 and Ser675; rescue of these phosphorylation events restores Wnt pathway activity, migration, and invasion in RHBDD1-knockdown cells. RHBDD1 also promotes EMT and a stem-like phenotype, and regulates the Wnt/β-catenin target ZEB1 at both mRNA and protein levels.\",\n      \"method\": \"RNA-seq, TOP/FOP flash reporter assay, western blot (phospho-β-catenin), Transwell assay, phosphorylation rescue experiments, Transwell in vitro and pleural metastasis in vivo\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Wnt pathway activity measured by TOP/FOP reporter, phospho-specific rescue demonstrates mechanistic link, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29426364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RHBDD1 (also designated RHBDL4) directly cleaves SREBP-1c at the ER; the p97/VCP AAA-ATPase complex then extracts the remaining ER-embedded SREBP-1c fragment. The enzymatic activity of RHBDD1 is enhanced by saturated fatty acids (SFAs) and inhibited by polyunsaturated fatty acids (PUFAs). Genetic deletion of RHBDD1 in mice fed a Western diet prevents SREBP-1c-driven induction of lipogenic genes (especially for PUFA synthesis and incorporation) and lipoprotein secretion.\",\n      \"method\": \"In vitro cleavage assay, genetic deletion (knockout mice), Western diet feeding experiment, gene expression analysis of lipogenic targets, biochemical fractionation/p97 complex analysis\",\n      \"journal\": \"PNAS nexus\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct cleavage demonstrated in vitro, genetic KO in mice with defined metabolic phenotype, fatty acid regulation of enzymatic activity established, multiple orthogonal methods\",\n      \"pmids\": [\"37954160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RHBDD1 promotes NSCLC cell growth and invasion via the ZEB1/PI3K/AKT signaling pathway: RHBDD1 silencing reduces ZEB1 mRNA and protein levels, decreases PI3K and AKT phosphorylation, and inhibits proliferation/invasion; overexpression of ZEB1 or activated AKT reverses these effects, placing RHBDD1 upstream of ZEB1 and PI3K/AKT in NSCLC.\",\n      \"method\": \"RNAi knockdown, ZEB1/AKT overexpression rescue, western blot (phospho-PI3K, phospho-AKT), cell proliferation and invasion assays\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via ZEB1/AKT rescue, knockdown with defined phospho-signaling readouts, single lab\",\n      \"pmids\": [\"33515112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RHBDD1 promotes proliferation, migration, invasion, and EMT in renal cell carcinoma via activation of the EGFR/AKT signaling pathway; EGFR inhibitor gefitinib partially reverses the pro-tumorigenic effects of RHBDD1 overexpression.\",\n      \"method\": \"RHBDD1 knockdown and overexpression in RCC cell lines, CCK-8, wound healing and Transwell assays, western blot for EGFR/AKT phosphorylation, gefitinib pharmacological rescue\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological rescue with EGFR inhibitor links RHBDD1 to EGFR/AKT, single lab, no structural or in vitro enzymatic data\",\n      \"pmids\": [\"34581421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In TP53-mutant NSCLC cells, RHBDD1 promotes endoplasmic reticulum-associated degradation (ERAD) of mutant p53 and DNA-PKcs (encoded by PRKDC); co-localization of p53 with RHBDD1 and DNA-PKcs is observed specifically in TP53-mutant cells. RHBDD1-mediated ERAD of these substrates causes S-phase cell cycle arrest, while simultaneously inhibiting DNA-PKcs-regulated apoptosis, thereby enhancing cell survival.\",\n      \"method\": \"shRNA knockdown and overexpression of RHBDD1 in TP53-mutant vs. wild-type NSCLC cells, immunofluorescence co-localization, western blot for p53/DNA-PKcs/ER stress markers, flow cytometry cell cycle analysis, pharmacological rescue with p53 activators (Nutlin-3a, HBX41108) and DNA-PKcs inhibitor (STL127705)\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-localization and pharmacological rescue support ERAD mechanism, multiple readouts, but single lab and no direct in vitro reconstitution of RHBDD1-mediated ERAD of p53/DNA-PKcs\",\n      \"pmids\": [\"41013641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RHBDD1 physically associates with EGFR (confirmed by co-immunoprecipitation) and activates EGFR/PI3K/AKT signaling to promote proliferation, EMT (including Snail upregulation), migration, and invasion in cervical cancer cells; gefitinib and LY294002 mitigate RHBDD1-induced oncogenicity, while AKT activator SC79 partially reverses RHBDD1-knockdown suppression.\",\n      \"method\": \"Co-immunoprecipitation (RHBDD1–EGFR), RHBDD1 knockdown and overexpression, pharmacological pathway inhibitors (gefitinib, LY294002) and activator (SC79), western blot for AKT phosphorylation and EMT markers, xenograft mouse model\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP establishes physical RHBDD1–EGFR interaction, pharmacological epistasis with multiple inhibitors/activators, single lab\",\n      \"pmids\": [\"41759697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lentiviral shRNA-mediated silencing of RHBDD1 in glioblastoma cell lines (U251 and U87MG) inhibited cell proliferation by >50% and completely abolished colony formation, with cell cycle arrest identified as the mechanism; this establishes RHBDD1 as required for cell cycle progression in glioblastoma cells.\",\n      \"method\": \"Lentiviral shRNA knockdown, proliferation assay, colony formation assay, cell cycle analysis\",\n      \"journal\": \"Technology in cancer research & treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown with proliferation and cell cycle phenotype, single lab, no pathway placement or molecular mechanism identified\",\n      \"pmids\": [\"23883433\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RHBDD1 is an ER-resident serine protease (rhomboid family) whose catalytic residues G142 and S144 cleave transmembrane substrates including the pro-apoptotic protein BIK (dampening BIK-driven apoptosis), the exosome regulator TSAP6 (suppressing non-classical exosome secretion in a TSAP6-dependent manner), and the lipogenic transcription factor SREBP-1c (a cleavage enhanced by saturated fatty acids and inhibited by PUFAs, with residual ER-embedded fragment extracted by the p97/VCP complex); beyond direct proteolysis, RHBDD1 activates the EGFR signaling axis (physically associating with EGFR and promoting AP-1/c-Jun-dependent EGFR transcription) and the Wnt/β-catenin pathway (via β-catenin Ser552/Ser675 phosphorylation and ZEB1 induction), and in TP53-mutant cells promotes ERAD-dependent degradation of mutant p53 and DNA-PKcs to induce S-phase arrest while suppressing apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RHBDD1 is an ER-resident rhomboid-family serine protease that controls cell fate by cleaving transmembrane substrates and, in cancer, by potentiating growth-signaling pathways [#0, #4]. Its proteolytic activity depends on the catalytic residues Gly142 and Ser144, which it uses to cleave the pro-apoptotic Bcl-2 protein BIK within its transmembrane region, thereby restraining BIK-driven apoptosis [#0]. The same activity cleaves the multi-pass membrane protein TSAP6 in its third transmembrane domain, and loss of RHBDD1 elevates non-classical exosome secretion in a TSAP6-dependent manner [#1]. RHBDD1 (also designated RHBDL4) further cleaves the lipogenic transcription factor SREBP-1c at the ER, with the residual membrane-embedded fragment extracted by the p97/VCP complex; this cleavage is enhanced by saturated fatty acids and inhibited by polyunsaturated fatty acids, and its genetic deletion in mice blunts SREBP-1c-driven lipogenic gene induction [#4]. Beyond direct proteolysis, RHBDD1 acts as a pro-tumorigenic regulator across multiple carcinomas: it physically associates with EGFR and drives c-Jun/AP-1-dependent EGFR transcription and EGFR/PI3K/AKT signaling [#2, #8], and it activates Wnt/\\u03b2-catenin signaling through \\u03b2-catenin Ser552/Ser675 phosphorylation while inducing ZEB1 to promote EMT and invasion [#3, #5]. In TP53-mutant cells RHBDD1 promotes ERAD-dependent degradation of mutant p53 and DNA-PKcs, producing S-phase arrest while suppressing apoptosis to favor survival [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established RHBDD1 as a catalytically active rhomboid protease and identified its first substrate, linking it to apoptotic control.\",\n      \"evidence\": \"In vitro cleavage assay with active-site mutagenesis (G142, S144) and gain/loss-of-function apoptosis readout in HEK293T cells\",\n      \"pmids\": [\"18953687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of BIK cleavage in tissues not defined\", \"No structural model of the protease-substrate interaction\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed RHBDD1 cleaves a second transmembrane substrate (TSAP6) and thereby restrains non-classical exosome secretion, broadening its substrate repertoire and physiological output.\",\n      \"evidence\": \"In vitro proteolysis, MS-mapped cleavage site, endogenous genetic inactivation, and TSAP6-knockdown epistasis with exosome quantification in colon cancer cells\",\n      \"pmids\": [\"22624035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of altered exosome flux in vivo unresolved\", \"Whether TSAP6 cleavage is regulated remains unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicated RHBDD1 as required for cell cycle progression in glioblastoma, the first link to a proliferative phenotype.\",\n      \"evidence\": \"Lentiviral shRNA knockdown with proliferation, colony formation, and cell cycle assays in U251/U87MG cells\",\n      \"pmids\": [\"23883433\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular mechanism or pathway placement identified\", \"Single lab, descriptive phenotype only\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a non-proteolytic transcriptional axis whereby RHBDD1 drives EGFR expression through c-Jun/AP-1 in colorectal cancer.\",\n      \"evidence\": \"Knockdown/inactivation with c-Jun overexpression and knockdown rescue, western blot, tumor models, tissue microarray\",\n      \"pmids\": [\"28445956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether protease activity is needed for AP-1/EGFR regulation not tested\", \"Direct molecular link between RHBDD1 and c-Jun unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected RHBDD1 to Wnt/\\u03b2-catenin signaling and EMT via \\u03b2-catenin phosphorylation and ZEB1 induction, explaining its pro-metastatic role.\",\n      \"evidence\": \"RNA-seq, TOP/FOP reporter, phospho-\\u03b2-catenin western blot, phosphorylation rescue, Transwell and in vivo pleural metastasis\",\n      \"pmids\": [\"29426364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase mediating \\u03b2-catenin Ser552/Ser675 phosphorylation not identified\", \"Mechanism linking protease to Wnt activation unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the RHBDD1\\u2013ZEB1 and EGFR/AKT oncogenic axes to NSCLC and renal cell carcinoma, indicating these signaling roles generalize across tumor types.\",\n      \"evidence\": \"RNAi knockdown with ZEB1/AKT and gefitinib pharmacological rescue, phospho-signaling western blots, proliferation/invasion assays in NSCLC and RCC cells\",\n      \"pmids\": [\"33515112\", \"34581421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect engagement of EGFR/AKT not distinguished\", \"No in vitro enzymatic or structural data in these contexts\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified SREBP-1c as a metabolically regulated substrate cleaved at the ER, with fatty acids tuning protease activity and p97/VCP completing membrane extraction, establishing RHBDD1 as a lipogenic regulator.\",\n      \"evidence\": \"In vitro cleavage, knockout mice on Western diet, lipogenic gene expression analysis, biochemical fractionation/p97 complex analysis\",\n      \"pmids\": [\"37954160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of fatty-acid sensing by the protease not defined\", \"Relationship between metabolic and oncogenic functions unexplored\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed RHBDD1 directs ERAD of mutant p53 and DNA-PKcs in TP53-mutant cells, coupling its activity to cell cycle arrest and apoptosis suppression for survival.\",\n      \"evidence\": \"shRNA/overexpression in TP53-mutant vs wild-type NSCLC, immunofluorescence co-localization, ER stress markers, flow cytometry, pharmacological rescue with p53 activators and DNA-PKcs inhibitor\",\n      \"pmids\": [\"41013641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of RHBDD1-mediated ERAD of p53/DNA-PKcs\", \"Direct versus indirect substrate engagement unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a direct physical RHBDD1\\u2013EGFR association driving EGFR/PI3K/AKT-dependent oncogenicity in cervical cancer, reinforcing EGFR as a recurring effector.\",\n      \"evidence\": \"Co-immunoprecipitation, knockdown/overexpression, pharmacological epistasis (gefitinib, LY294002, SC79), western blot, xenograft model\",\n      \"pmids\": [\"41759697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EGFR is a proteolytic substrate or scaffold partner not determined\", \"Reciprocal/structural validation of the interaction lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RHBDD1's catalytic proteolytic activity mechanistically connects to its many downstream signaling outputs (EGFR, Wnt, PI3K/AKT, ERAD) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"Unclear which signaling roles require catalytic activity versus scaffolding\", \"Integration of metabolic and oncogenic functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 4, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EGFR\", \"BIK\", \"TSAP6\", \"SREBF1\", \"TP53\", \"PRKDC\", \"VCP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}