{"gene":"TSC22D4","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2013,"finding":"TSC22D4 functions as a hepatic transcription factor that inhibits VLDL secretion and lipogenic gene expression; elevated hepatic TSC22D4 in cancer cachexia drives reduced systemic VLDL levels, while liver-specific ablation triggers hypertriglyceridemia through induction of hepatic VLDL secretion.","method":"Liver-specific overexpression and ablation (loss-of-function) in mice with metabolic phenotyping (VLDL secretion, lipogenic gene expression)","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic manipulation (OE and KO) in vivo with defined metabolic phenotype, replicated across normal and high-fat dietary conditions","pmids":["23307490"],"is_preprint":false},{"year":2016,"finding":"Hepatic TSC22D4 directly transcriptionally regulates the small secretory protein lipocalin 13 (LCN13) to control systemic glucose homeostasis; hepatic TSC22D4 inhibition prevents and reverses hyperglycemia, glucose intolerance, and insulin resistance in diabetic mouse models.","method":"Hepatic loss-of-function in vivo, direct transcriptional regulation of LCN13 established, correlation with human diabetic patient data","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — clean hepatic KD/KO with defined metabolic phenotype plus identification of direct transcriptional target LCN13","pmids":["27827363"],"is_preprint":false},{"year":2012,"finding":"TSC22D4 subcellular localization shifts from nuclear/cytoplasmic in undifferentiated cerebellar granule neurons (CGNs) to somatodendritic/synaptic compartments upon maturation; TSC22D4 silencing with siRNAs blocks CGN differentiation and inhibits neurite elongation.","method":"In vivo and in vitro localization during CGN differentiation, siRNA knockdown with neurite elongation readout in N1E-115 neuroblastoma cells","journal":"Cerebellum (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence (KD + differentiation phenotype), single lab","pmids":["20878296"],"is_preprint":false},{"year":2013,"finding":"TSC22D4 exists as multiple iso- and phospho-glycoforms with distinct subcellular localizations and interacting partners during CGN differentiation: the 42 kDa form is cytosolic and associates with TSC22D1.2 only in undifferentiated CGNs; the 55 kDa form associates with the nuclear matrix in differentiated CGNs; the 67 kDa form enters mitochondria in differentiated CGNs and associates with apoptosis-inducing factor; the 72 kDa form is O-GlcNAcylated and phosphorylated and is constitutively chromatin-associated.","method":"Biochemical fractionation, co-immunoprecipitation, mass spectrometry identification of post-translational modifications (O-GlcNAcylation, phosphorylation)","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple orthogonal biochemical methods (fractionation, Co-IP, PTM identification) but single lab","pmids":["23305244"],"is_preprint":false},{"year":2019,"finding":"TSC22D4 (THG-1) knockout induces cellular senescence through activation of the JUNB pathway, which drives transcription of the CDK inhibitor P21(CDKN1A); siRNA-mediated knockdown of JUNB reduces P21 mRNA and cellular senescence in TSC22D4 KO cells, placing TSC22D4 upstream of JUNB–P21 in senescence suppression.","method":"CRISPR/Cas9 knockout, siRNA knockdown of JUNB, mRNA quantification of P21","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis established by KO + downstream KD with defined pathway placement, single lab","pmids":["31806366"],"is_preprint":false},{"year":2019,"finding":"TSC22D4 (THG-1) binds NRBP1 and competitively inhibits NRBP1-mediated ubiquitination and degradation of SALL4, thereby stabilizing SALL4 protein and inducing stemness genes (NANOG, OCT4) to promote tumorsphere formation in esophageal squamous cell carcinoma cells.","method":"Co-immunoprecipitation (TSC22D4–NRBP1 interaction), ubiquitination assay, rescue experiment with exogenous SALL4 expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP, ubiquitination assay, and functional rescue experiment, single lab","pmids":["31864704"],"is_preprint":false},{"year":2022,"finding":"TSC22D4 directly interacts with Akt1 via its intrinsically disordered D2 domain; this interaction is promoted by energy deprivation and oxidative stress and impaired by refeeding/glucose/insulin. The TSC22D4–Akt1 interaction reduces basal Akt phosphorylation and downstream signaling during starvation, promoting insulin sensitivity. Liver-specific reconstitution experiments confirm the interaction improves glucose handling in vivo.","method":"Co-immunoprecipitation, domain mapping (D2 domain), liver-specific genetic reconstitution in mice, phosphorylation assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with domain mapping, physiological regulation of interaction, and in vivo reconstitution with defined metabolic phenotype","pmids":["36269831"],"is_preprint":false},{"year":2022,"finding":"Hepatocyte-specific deletion of TSC22D4 upregulates mitochondrial-related processes (TCA cycle, mitochondrial organization, triglyceride metabolism), reduces liver lipid accumulation, improves steatosis/inflammation, and decreases apoptosis in NASH mouse models, establishing TSC22D4 as a repressor of hepatocyte mitochondrial function.","method":"Hepatocyte-specific knockout (TSC22D4-HepaKO), single-nuclei RNA sequencing, NASH diet models","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean hepatocyte-specific KO with transcriptomic mechanistic readout and multiple NASH model validation","pmids":["35378329"],"is_preprint":false},{"year":2022,"finding":"TSC22D4 promotes TGFβ1-mediated activation, proliferation, and migration of hepatic stellate cells (HSCs), initiating transcriptional programs associated with HSC activation as revealed by RNA-seq.","method":"Loss-of-function in HSCs, RNA sequencing, migration and proliferation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2/3 — KD with defined cellular phenotype and transcriptomic pathway mapping, single lab","pmids":["35714570"],"is_preprint":false},{"year":2023,"finding":"TSC22D4 (THG-1) is phosphorylated by the RTK-RAS-ERK pathway, promoting oncogene-mediated tumorigenesis and SCC proliferation/invasiveness; TSC22D4 also regulates alternative splicing of CD44 variants downstream of RTK signaling.","method":"Phosphorylation assay with specific antibody, knockdown/overexpression in SCC cells, xenograft formation, CD44 splicing analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2/3 — phosphorylation by identified kinase pathway with functional consequences shown in vitro and in vivo, single lab","pmids":["37607779"],"is_preprint":false},{"year":2025,"finding":"TSC22D4 (THG-1) binds NRBP1 and suppresses NRBP1's E3 ubiquitin ligase activity toward TRAF6, preventing TRAF6 degradation; this stabilizes TRAF6 and sustains NF-κB nuclear translocation and IL-1-mediated inflammatory signaling in squamous cell carcinoma cells.","method":"Co-immunoprecipitation (THG-1–NRBP1), ubiquitination assay (TRAF6), siRNA knockdown, NF-κB nuclear translocation assay","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP, ubiquitination assay, and functional pathway readout, single lab","pmids":["39869046"],"is_preprint":false},{"year":2025,"finding":"TSC22D4 directly binds glucose; UV-crosslinking mass spectrometry maps glucose binding to the C-terminal leucine zipper region, and the I322W mutation abolishes glucose binding. Glucose binding increases accessibility of the leucine zipper and promotes intra-protein contacts between the C-terminal zipper and N-terminal intrinsically disordered domain; under high glucose, TSC22D4 associates with fatty acid metabolism machinery proteins.","method":"Thermal proteome profiling (PISA), microscale thermophoresis (MST) confirming direct glucose-protein interaction, UV-crosslinking mass spectrometry, site-directed mutagenesis (I322W), chemo-proteomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — direct binding confirmed by MST, binding site mapped by crosslinking-MS, abolished by mutagenesis; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.05.06.651509"],"is_preprint":true},{"year":2024,"finding":"TSC22D4 acts as an adaptor protein in the WNK osmotic stress pathway; osmotic stress promotes association of TSC22D4 with WNK1 and NRBP1 pseudokinase, and AlphaFold-3 modeling predicts two TSC22D4 RΦ-motifs interact with the CCTL1 domain of WNK1 and the CCT domain of NRBP1 to form a multi-subunit complex required for WNK pathway activation.","method":"Proximity ligation, immunoprecipitation, mass spectrometry, AlphaFold-3 structural modeling","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP and proximity ligation confirmed but structural model is computational; preprint, WNK role of TSC22D4 not yet functionally dissected independently","pmids":["bio_10.1101_2024.12.12.628181"],"is_preprint":true}],"current_model":"TSC22D4 is a multifunctional leucine zipper transcription factor and adaptor protein that, in hepatocytes, directly binds Akt1 via its disordered D2 domain to modulate insulin signaling, transcriptionally regulates LCN13 and lipogenic/VLDL secretion genes to control glucose and lipid homeostasis, represses mitochondrial metabolism, and directly binds glucose at its C-terminal leucine zipper (I322W-sensitive); in non-hepatic contexts it stabilizes TRAF6 and SALL4 by competitively inhibiting NRBP1's E3 ubiquitin ligase activity, is phosphorylated by the RTK-RAS-ERK pathway to promote tumorigenesis, suppresses cellular senescence upstream of JUNB–P21, and serves as an adaptor for the WNK osmotic stress kinase complex."},"narrative":{"teleology":[{"year":2012,"claim":"TSC22D4 was shown to be functionally required for neuronal differentiation, establishing it as more than a passive transcription factor and revealing context-dependent subcellular redistribution during development.","evidence":"siRNA knockdown in CGNs and N1E-115 neuroblastoma cells with neurite elongation readout plus localization imaging during differentiation","pmids":["20878296"],"confidence":"Medium","gaps":["Single lab observation","Neuronal target genes unidentified","Mechanism linking TSC22D4 redistribution to differentiation unknown"]},{"year":2013,"claim":"Discovery that TSC22D4 exists as multiple differentially modified isoforms (42–72 kDa) with distinct subcellular localizations and binding partners revealed unexpected complexity, including mitochondrial entry and O-GlcNAcylation, suggesting post-translational regulation of its function.","evidence":"Biochemical fractionation, co-immunoprecipitation, and mass spectrometry of PTMs in CGNs","pmids":["23305244"],"confidence":"Medium","gaps":["Functional significance of each isoform not established","Mitochondrial role not independently validated","O-GlcNAcylation functional consequence unknown"]},{"year":2013,"claim":"Bidirectional hepatic manipulation established TSC22D4 as a transcriptional repressor of lipogenic and VLDL secretion programs, resolving how the liver controls systemic triglyceride availability and linking hepatic TSC22D4 to cancer cachexia-associated hypolipidemia.","evidence":"Liver-specific overexpression and ablation in mice with VLDL secretion and lipogenic gene quantification","pmids":["23307490"],"confidence":"High","gaps":["Direct transcriptional targets mediating VLDL repression not fully identified","Mechanism of TSC22D4 upregulation in cachexia unknown"]},{"year":2016,"claim":"Identification of LCN13 as a direct transcriptional target of hepatic TSC22D4 explained how a liver transcription factor controls systemic glucose homeostasis and insulin sensitivity, providing a therapeutic rationale for TSC22D4 inhibition in diabetes.","evidence":"Hepatic loss-of-function in diabetic mouse models, direct transcriptional regulation of LCN13, correlation with human diabetic data","pmids":["27827363"],"confidence":"High","gaps":["How LCN13 signals to peripheral tissues to improve glucose homeostasis unresolved","Whether TSC22D4 binds the LCN13 promoter directly or via co-factors not fully dissected"]},{"year":2019,"claim":"Two studies expanded TSC22D4's role beyond metabolism: knockout induced senescence via JUNB–P21, and TSC22D4 was found to stabilize SALL4 by competitively inhibiting NRBP1-mediated ubiquitination, revealing a non-transcriptional adaptor function that promotes cancer stemness.","evidence":"CRISPR KO with JUNB epistasis (siRNA rescue of P21); Co-IP of TSC22D4–NRBP1, ubiquitination assays, SALL4 rescue in ESCC cells","pmids":["31806366","31864704"],"confidence":"Medium","gaps":["How TSC22D4 suppresses JUNB transcription unknown","Whether NRBP1 inhibition is direct competition or allosteric not resolved","Single-lab findings for both observations"]},{"year":2022,"claim":"Direct binding of TSC22D4 to Akt1 through its disordered D2 domain under starvation conditions provided a mechanistic explanation for how TSC22D4 tunes insulin signaling: the interaction reduces basal Akt phosphorylation, and its release upon refeeding permits full insulin responsiveness.","evidence":"Co-immunoprecipitation, D2 domain mapping, liver-specific reconstitution in mice with glucose tolerance testing","pmids":["36269831"],"confidence":"High","gaps":["Structural basis of D2–Akt1 interaction unresolved","Whether TSC22D4–Akt interaction occurs in non-hepatic tissues unknown"]},{"year":2022,"claim":"Hepatocyte-specific TSC22D4 deletion upregulated mitochondrial TCA cycle and triglyceride metabolism programs and ameliorated NASH, establishing TSC22D4 as a tonic repressor of hepatic mitochondrial function and a candidate therapeutic target in fatty liver disease.","evidence":"Hepatocyte-specific KO, single-nuclei RNA-seq, multiple NASH diet models","pmids":["35378329"],"confidence":"High","gaps":["Direct transcriptional targets mediating mitochondrial repression not identified","Whether the benefit is hepatocyte-autonomous or involves stellate cell cross-talk not resolved"]},{"year":2022,"claim":"TSC22D4 was found to promote TGFβ1-mediated hepatic stellate cell activation, broadening its liver role from a hepatocyte-intrinsic factor to an activator of fibrogenic cell types.","evidence":"Loss-of-function in HSCs, RNA-seq, migration and proliferation assays","pmids":["35714570"],"confidence":"Medium","gaps":["Whether TSC22D4 acts cell-autonomously in HSCs or via paracrine signals unknown","Direct target genes in HSCs unidentified"]},{"year":2023,"claim":"Phosphorylation of TSC22D4 by the RTK-RAS-ERK pathway linked it to oncogene-driven tumorigenesis and CD44 alternative splicing, demonstrating that post-translational modification switches TSC22D4 into a pro-tumorigenic effector.","evidence":"Phospho-specific antibody, knockdown/overexpression in SCC cells, xenograft assays, CD44 splicing analysis","pmids":["37607779"],"confidence":"Medium","gaps":["Specific ERK phosphorylation sites on TSC22D4 not mapped","Mechanism linking TSC22D4 phosphorylation to CD44 splicing unknown","Single-lab study"]},{"year":2025,"claim":"TSC22D4 was shown to stabilize TRAF6 by inhibiting NRBP1-dependent ubiquitination, sustaining NF-κB signaling and IL-1-mediated inflammation in SCC, generalizing the NRBP1-inhibition mechanism to a second substrate beyond SALL4.","evidence":"Co-IP of TSC22D4–NRBP1, TRAF6 ubiquitination assay, NF-κB nuclear translocation readout","pmids":["39869046"],"confidence":"Medium","gaps":["Whether TRAF6 stabilization and SALL4 stabilization are concurrent or context-dependent unknown","Structural basis of NRBP1 inhibition unresolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis of TSC22D4's interaction with Akt1 and NRBP1, the identity of direct transcriptional targets mediating mitochondrial repression, whether direct glucose binding (mapped to the leucine zipper) serves a physiological sensing role, and how the adaptor function in the WNK osmotic stress complex integrates with metabolic signaling.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of TSC22D4 or its complexes","Glucose-binding functional consequence not established in vivo","WNK pathway role awaits independent confirmation and functional dissection"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]}],"complexes":[],"partners":["AKT1","NRBP1","SALL4","TRAF6","TSC22D1","JUNB","LCN13"],"other_free_text":[]},"mechanistic_narrative":"TSC22D4 is a leucine zipper transcription factor and protein adaptor that integrates metabolic, inflammatory, and oncogenic signaling across multiple cell types. In hepatocytes, TSC22D4 transcriptionally represses lipogenic and VLDL secretion genes and the hepatokine LCN13 to control systemic lipid and glucose homeostasis, and directly binds Akt1 via its intrinsically disordered D2 domain under energy deprivation to dampen basal Akt phosphorylation and promote insulin sensitivity [PMID:23307490, PMID:27827363, PMID:36269831]. Hepatocyte-specific deletion derepresses mitochondrial metabolism and ameliorates NASH-associated steatosis and inflammation [PMID:35378329]. In squamous cell carcinoma, TSC22D4 competitively inhibits NRBP1's E3 ubiquitin ligase activity to stabilize SALL4 and TRAF6, thereby sustaining stemness gene expression and NF-κB–driven inflammatory signaling, and is phosphorylated by the RTK-RAS-ERK pathway to promote tumorigenesis and regulate CD44 alternative splicing [PMID:31864704, PMID:39869046, PMID:37607779]."},"prefetch_data":{"uniprot":{"accession":"Q9Y3Q8","full_name":"TSC22 domain family protein 4","aliases":["TSC22-related-inducible leucine zipper protein 2"],"length_aa":395,"mass_kda":41.0,"function":"Binds DNA and acts as a transcriptional repressor (PubMed:10488076). Involved in the regulation of systematic glucose homeostasis and insulin sensitivity, via transcriptional repression of downstream insulin signaling targets such as OBP2A/LCN13 (By similarity). Acts as a negative regulator of lipogenic gene expression in hepatocytes and thereby mediates the control of very low-density lipoprotein release (PubMed:23307490). May play a role in neurite elongation and survival (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Cell projection, dendrite; Synapse","url":"https://www.uniprot.org/uniprotkb/Q9Y3Q8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TSC22D4","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NRBP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TSC22D4","total_profiled":1310},"omim":[{"mim_id":"611914","title":"TSC22 DOMAIN FAMILY, MEMBER 4; TSC22D4","url":"https://www.omim.org/entry/611914"},{"mim_id":"607715","title":"TSC22 DOMAIN FAMILY, MEMBER 1; TSC22D1","url":"https://www.omim.org/entry/607715"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":851.2}],"url":"https://www.proteinatlas.org/search/TSC22D4"},"hgnc":{"alias_symbol":["THG-1","TILZ2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y3Q8","domains":[{"cath_id":"1.20.5","chopping":"329-355","consensus_level":"medium","plddt":97.2926,"start":329,"end":355}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3Q8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3Q8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3Q8-F1-predicted_aligned_error_v6.png","plddt_mean":56.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TSC22D4","jax_strain_url":"https://www.jax.org/strain/search?query=TSC22D4"},"sequence":{"accession":"Q9Y3Q8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3Q8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3Q8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3Q8"}},"corpus_meta":[{"pmid":"23307490","id":"PMC_23307490","title":"TSC22D4 is a molecular output of hepatic wasting metabolism.","date":"2013","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23307490","citation_count":53,"is_preprint":false},{"pmid":"27827363","id":"PMC_27827363","title":"Control of diabetic hyperglycaemia and insulin resistance through TSC22D4.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27827363","citation_count":30,"is_preprint":false},{"pmid":"20878296","id":"PMC_20878296","title":"Subcellular TSC22D4 localization in cerebellum granule neurons of the mouse depends on development and differentiation.","date":"2012","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20878296","citation_count":23,"is_preprint":false},{"pmid":"36269831","id":"PMC_36269831","title":"TSC22D4 interacts with Akt1 to regulate glucose metabolism.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36269831","citation_count":17,"is_preprint":false},{"pmid":"31806366","id":"PMC_31806366","title":"Promotion of cellular senescence by THG-1/TSC22D4 knockout through activation of JUNB.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31806366","citation_count":13,"is_preprint":false},{"pmid":"31864704","id":"PMC_31864704","title":"THG-1 suppresses SALL4 degradation to induce stemness genes and tumorsphere formation through antagonizing NRBP1 in squamous cell carcinoma cells.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31864704","citation_count":11,"is_preprint":false},{"pmid":"23305244","id":"PMC_23305244","title":"Multiple TSC22D4 iso-/phospho-glycoforms display idiosyncratic subcellular localizations and interacting protein partners.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/23305244","citation_count":10,"is_preprint":false},{"pmid":"35378329","id":"PMC_35378329","title":"Hepatocyte-specific activity of TSC22D4 triggers progressive NAFLD by impairing mitochondrial function.","date":"2022","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35378329","citation_count":7,"is_preprint":false},{"pmid":"35714570","id":"PMC_35714570","title":"TSC22D4 promotes TGFβ1-induced activation of hepatic stellate cells.","date":"2022","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35714570","citation_count":7,"is_preprint":false},{"pmid":"37607779","id":"PMC_37607779","title":"Promotion of squamous cell carcinoma tumorigenesis by oncogene-mediated THG-1/TSC22D4 phosphorylation.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/37607779","citation_count":5,"is_preprint":false},{"pmid":"39869046","id":"PMC_39869046","title":"THG-1/TSC22D4 Promotes IL-1 Signaling through Stabilization of TRAF6 in Squamous Cell Carcinoma.","date":"2025","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/39869046","citation_count":1,"is_preprint":false},{"pmid":"39906612","id":"PMC_39906612","title":"Nanomolecular silencing of TSC22D4 mRNA via a DNAsome-siRNA for enhancing insulin sensitization in hepatocytes.","date":"2025","source":"Iranian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39906612","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.06.651509","title":"Thermal proteome profiling identifies glucose binding proteins involved in metabolic disease","date":"2025-05-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.06.651509","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.12.628181","title":"NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress","date":"2024-12-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.12.628181","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8360,"output_tokens":3348,"usd":0.03765},"stage2":{"model":"claude-opus-4-6","input_tokens":6735,"output_tokens":2810,"usd":0.155888},"total_usd":0.193538,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"TSC22D4 functions as a hepatic transcription factor that inhibits VLDL secretion and lipogenic gene expression; elevated hepatic TSC22D4 in cancer cachexia drives reduced systemic VLDL levels, while liver-specific ablation triggers hypertriglyceridemia through induction of hepatic VLDL secretion.\",\n      \"method\": \"Liver-specific overexpression and ablation (loss-of-function) in mice with metabolic phenotyping (VLDL secretion, lipogenic gene expression)\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation (OE and KO) in vivo with defined metabolic phenotype, replicated across normal and high-fat dietary conditions\",\n      \"pmids\": [\"23307490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hepatic TSC22D4 directly transcriptionally regulates the small secretory protein lipocalin 13 (LCN13) to control systemic glucose homeostasis; hepatic TSC22D4 inhibition prevents and reverses hyperglycemia, glucose intolerance, and insulin resistance in diabetic mouse models.\",\n      \"method\": \"Hepatic loss-of-function in vivo, direct transcriptional regulation of LCN13 established, correlation with human diabetic patient data\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean hepatic KD/KO with defined metabolic phenotype plus identification of direct transcriptional target LCN13\",\n      \"pmids\": [\"27827363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TSC22D4 subcellular localization shifts from nuclear/cytoplasmic in undifferentiated cerebellar granule neurons (CGNs) to somatodendritic/synaptic compartments upon maturation; TSC22D4 silencing with siRNAs blocks CGN differentiation and inhibits neurite elongation.\",\n      \"method\": \"In vivo and in vitro localization during CGN differentiation, siRNA knockdown with neurite elongation readout in N1E-115 neuroblastoma cells\",\n      \"journal\": \"Cerebellum (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence (KD + differentiation phenotype), single lab\",\n      \"pmids\": [\"20878296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TSC22D4 exists as multiple iso- and phospho-glycoforms with distinct subcellular localizations and interacting partners during CGN differentiation: the 42 kDa form is cytosolic and associates with TSC22D1.2 only in undifferentiated CGNs; the 55 kDa form associates with the nuclear matrix in differentiated CGNs; the 67 kDa form enters mitochondria in differentiated CGNs and associates with apoptosis-inducing factor; the 72 kDa form is O-GlcNAcylated and phosphorylated and is constitutively chromatin-associated.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, mass spectrometry identification of post-translational modifications (O-GlcNAcylation, phosphorylation)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple orthogonal biochemical methods (fractionation, Co-IP, PTM identification) but single lab\",\n      \"pmids\": [\"23305244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSC22D4 (THG-1) knockout induces cellular senescence through activation of the JUNB pathway, which drives transcription of the CDK inhibitor P21(CDKN1A); siRNA-mediated knockdown of JUNB reduces P21 mRNA and cellular senescence in TSC22D4 KO cells, placing TSC22D4 upstream of JUNB–P21 in senescence suppression.\",\n      \"method\": \"CRISPR/Cas9 knockout, siRNA knockdown of JUNB, mRNA quantification of P21\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis established by KO + downstream KD with defined pathway placement, single lab\",\n      \"pmids\": [\"31806366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSC22D4 (THG-1) binds NRBP1 and competitively inhibits NRBP1-mediated ubiquitination and degradation of SALL4, thereby stabilizing SALL4 protein and inducing stemness genes (NANOG, OCT4) to promote tumorsphere formation in esophageal squamous cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (TSC22D4–NRBP1 interaction), ubiquitination assay, rescue experiment with exogenous SALL4 expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP, ubiquitination assay, and functional rescue experiment, single lab\",\n      \"pmids\": [\"31864704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TSC22D4 directly interacts with Akt1 via its intrinsically disordered D2 domain; this interaction is promoted by energy deprivation and oxidative stress and impaired by refeeding/glucose/insulin. The TSC22D4–Akt1 interaction reduces basal Akt phosphorylation and downstream signaling during starvation, promoting insulin sensitivity. Liver-specific reconstitution experiments confirm the interaction improves glucose handling in vivo.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping (D2 domain), liver-specific genetic reconstitution in mice, phosphorylation assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping, physiological regulation of interaction, and in vivo reconstitution with defined metabolic phenotype\",\n      \"pmids\": [\"36269831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hepatocyte-specific deletion of TSC22D4 upregulates mitochondrial-related processes (TCA cycle, mitochondrial organization, triglyceride metabolism), reduces liver lipid accumulation, improves steatosis/inflammation, and decreases apoptosis in NASH mouse models, establishing TSC22D4 as a repressor of hepatocyte mitochondrial function.\",\n      \"method\": \"Hepatocyte-specific knockout (TSC22D4-HepaKO), single-nuclei RNA sequencing, NASH diet models\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean hepatocyte-specific KO with transcriptomic mechanistic readout and multiple NASH model validation\",\n      \"pmids\": [\"35378329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TSC22D4 promotes TGFβ1-mediated activation, proliferation, and migration of hepatic stellate cells (HSCs), initiating transcriptional programs associated with HSC activation as revealed by RNA-seq.\",\n      \"method\": \"Loss-of-function in HSCs, RNA sequencing, migration and proliferation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — KD with defined cellular phenotype and transcriptomic pathway mapping, single lab\",\n      \"pmids\": [\"35714570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TSC22D4 (THG-1) is phosphorylated by the RTK-RAS-ERK pathway, promoting oncogene-mediated tumorigenesis and SCC proliferation/invasiveness; TSC22D4 also regulates alternative splicing of CD44 variants downstream of RTK signaling.\",\n      \"method\": \"Phosphorylation assay with specific antibody, knockdown/overexpression in SCC cells, xenograft formation, CD44 splicing analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — phosphorylation by identified kinase pathway with functional consequences shown in vitro and in vivo, single lab\",\n      \"pmids\": [\"37607779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TSC22D4 (THG-1) binds NRBP1 and suppresses NRBP1's E3 ubiquitin ligase activity toward TRAF6, preventing TRAF6 degradation; this stabilizes TRAF6 and sustains NF-κB nuclear translocation and IL-1-mediated inflammatory signaling in squamous cell carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (THG-1–NRBP1), ubiquitination assay (TRAF6), siRNA knockdown, NF-κB nuclear translocation assay\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP, ubiquitination assay, and functional pathway readout, single lab\",\n      \"pmids\": [\"39869046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TSC22D4 directly binds glucose; UV-crosslinking mass spectrometry maps glucose binding to the C-terminal leucine zipper region, and the I322W mutation abolishes glucose binding. Glucose binding increases accessibility of the leucine zipper and promotes intra-protein contacts between the C-terminal zipper and N-terminal intrinsically disordered domain; under high glucose, TSC22D4 associates with fatty acid metabolism machinery proteins.\",\n      \"method\": \"Thermal proteome profiling (PISA), microscale thermophoresis (MST) confirming direct glucose-protein interaction, UV-crosslinking mass spectrometry, site-directed mutagenesis (I322W), chemo-proteomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct binding confirmed by MST, binding site mapped by crosslinking-MS, abolished by mutagenesis; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.06.651509\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TSC22D4 acts as an adaptor protein in the WNK osmotic stress pathway; osmotic stress promotes association of TSC22D4 with WNK1 and NRBP1 pseudokinase, and AlphaFold-3 modeling predicts two TSC22D4 RΦ-motifs interact with the CCTL1 domain of WNK1 and the CCT domain of NRBP1 to form a multi-subunit complex required for WNK pathway activation.\",\n      \"method\": \"Proximity ligation, immunoprecipitation, mass spectrometry, AlphaFold-3 structural modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and proximity ligation confirmed but structural model is computational; preprint, WNK role of TSC22D4 not yet functionally dissected independently\",\n      \"pmids\": [\"bio_10.1101_2024.12.12.628181\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TSC22D4 is a multifunctional leucine zipper transcription factor and adaptor protein that, in hepatocytes, directly binds Akt1 via its disordered D2 domain to modulate insulin signaling, transcriptionally regulates LCN13 and lipogenic/VLDL secretion genes to control glucose and lipid homeostasis, represses mitochondrial metabolism, and directly binds glucose at its C-terminal leucine zipper (I322W-sensitive); in non-hepatic contexts it stabilizes TRAF6 and SALL4 by competitively inhibiting NRBP1's E3 ubiquitin ligase activity, is phosphorylated by the RTK-RAS-ERK pathway to promote tumorigenesis, suppresses cellular senescence upstream of JUNB–P21, and serves as an adaptor for the WNK osmotic stress kinase complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TSC22D4 is a leucine zipper transcription factor and protein adaptor that integrates metabolic, inflammatory, and oncogenic signaling across multiple cell types. In hepatocytes, TSC22D4 transcriptionally represses lipogenic and VLDL secretion genes and the hepatokine LCN13 to control systemic lipid and glucose homeostasis, and directly binds Akt1 via its intrinsically disordered D2 domain under energy deprivation to dampen basal Akt phosphorylation and promote insulin sensitivity [PMID:23307490, PMID:27827363, PMID:36269831]. Hepatocyte-specific deletion derepresses mitochondrial metabolism and ameliorates NASH-associated steatosis and inflammation [PMID:35378329]. In squamous cell carcinoma, TSC22D4 competitively inhibits NRBP1's E3 ubiquitin ligase activity to stabilize SALL4 and TRAF6, thereby sustaining stemness gene expression and NF-κB–driven inflammatory signaling, and is phosphorylated by the RTK-RAS-ERK pathway to promote tumorigenesis and regulate CD44 alternative splicing [PMID:31864704, PMID:39869046, PMID:37607779].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"TSC22D4 was shown to be functionally required for neuronal differentiation, establishing it as more than a passive transcription factor and revealing context-dependent subcellular redistribution during development.\",\n      \"evidence\": \"siRNA knockdown in CGNs and N1E-115 neuroblastoma cells with neurite elongation readout plus localization imaging during differentiation\",\n      \"pmids\": [\"20878296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab observation\", \"Neuronal target genes unidentified\", \"Mechanism linking TSC22D4 redistribution to differentiation unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that TSC22D4 exists as multiple differentially modified isoforms (42–72 kDa) with distinct subcellular localizations and binding partners revealed unexpected complexity, including mitochondrial entry and O-GlcNAcylation, suggesting post-translational regulation of its function.\",\n      \"evidence\": \"Biochemical fractionation, co-immunoprecipitation, and mass spectrometry of PTMs in CGNs\",\n      \"pmids\": [\"23305244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of each isoform not established\", \"Mitochondrial role not independently validated\", \"O-GlcNAcylation functional consequence unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Bidirectional hepatic manipulation established TSC22D4 as a transcriptional repressor of lipogenic and VLDL secretion programs, resolving how the liver controls systemic triglyceride availability and linking hepatic TSC22D4 to cancer cachexia-associated hypolipidemia.\",\n      \"evidence\": \"Liver-specific overexpression and ablation in mice with VLDL secretion and lipogenic gene quantification\",\n      \"pmids\": [\"23307490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating VLDL repression not fully identified\", \"Mechanism of TSC22D4 upregulation in cachexia unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of LCN13 as a direct transcriptional target of hepatic TSC22D4 explained how a liver transcription factor controls systemic glucose homeostasis and insulin sensitivity, providing a therapeutic rationale for TSC22D4 inhibition in diabetes.\",\n      \"evidence\": \"Hepatic loss-of-function in diabetic mouse models, direct transcriptional regulation of LCN13, correlation with human diabetic data\",\n      \"pmids\": [\"27827363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LCN13 signals to peripheral tissues to improve glucose homeostasis unresolved\", \"Whether TSC22D4 binds the LCN13 promoter directly or via co-factors not fully dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies expanded TSC22D4's role beyond metabolism: knockout induced senescence via JUNB–P21, and TSC22D4 was found to stabilize SALL4 by competitively inhibiting NRBP1-mediated ubiquitination, revealing a non-transcriptional adaptor function that promotes cancer stemness.\",\n      \"evidence\": \"CRISPR KO with JUNB epistasis (siRNA rescue of P21); Co-IP of TSC22D4–NRBP1, ubiquitination assays, SALL4 rescue in ESCC cells\",\n      \"pmids\": [\"31806366\", \"31864704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TSC22D4 suppresses JUNB transcription unknown\", \"Whether NRBP1 inhibition is direct competition or allosteric not resolved\", \"Single-lab findings for both observations\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Direct binding of TSC22D4 to Akt1 through its disordered D2 domain under starvation conditions provided a mechanistic explanation for how TSC22D4 tunes insulin signaling: the interaction reduces basal Akt phosphorylation, and its release upon refeeding permits full insulin responsiveness.\",\n      \"evidence\": \"Co-immunoprecipitation, D2 domain mapping, liver-specific reconstitution in mice with glucose tolerance testing\",\n      \"pmids\": [\"36269831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of D2–Akt1 interaction unresolved\", \"Whether TSC22D4–Akt interaction occurs in non-hepatic tissues unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Hepatocyte-specific TSC22D4 deletion upregulated mitochondrial TCA cycle and triglyceride metabolism programs and ameliorated NASH, establishing TSC22D4 as a tonic repressor of hepatic mitochondrial function and a candidate therapeutic target in fatty liver disease.\",\n      \"evidence\": \"Hepatocyte-specific KO, single-nuclei RNA-seq, multiple NASH diet models\",\n      \"pmids\": [\"35378329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating mitochondrial repression not identified\", \"Whether the benefit is hepatocyte-autonomous or involves stellate cell cross-talk not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TSC22D4 was found to promote TGFβ1-mediated hepatic stellate cell activation, broadening its liver role from a hepatocyte-intrinsic factor to an activator of fibrogenic cell types.\",\n      \"evidence\": \"Loss-of-function in HSCs, RNA-seq, migration and proliferation assays\",\n      \"pmids\": [\"35714570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TSC22D4 acts cell-autonomously in HSCs or via paracrine signals unknown\", \"Direct target genes in HSCs unidentified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Phosphorylation of TSC22D4 by the RTK-RAS-ERK pathway linked it to oncogene-driven tumorigenesis and CD44 alternative splicing, demonstrating that post-translational modification switches TSC22D4 into a pro-tumorigenic effector.\",\n      \"evidence\": \"Phospho-specific antibody, knockdown/overexpression in SCC cells, xenograft assays, CD44 splicing analysis\",\n      \"pmids\": [\"37607779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific ERK phosphorylation sites on TSC22D4 not mapped\", \"Mechanism linking TSC22D4 phosphorylation to CD44 splicing unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TSC22D4 was shown to stabilize TRAF6 by inhibiting NRBP1-dependent ubiquitination, sustaining NF-κB signaling and IL-1-mediated inflammation in SCC, generalizing the NRBP1-inhibition mechanism to a second substrate beyond SALL4.\",\n      \"evidence\": \"Co-IP of TSC22D4–NRBP1, TRAF6 ubiquitination assay, NF-κB nuclear translocation readout\",\n      \"pmids\": [\"39869046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TRAF6 stabilization and SALL4 stabilization are concurrent or context-dependent unknown\", \"Structural basis of NRBP1 inhibition unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of TSC22D4's interaction with Akt1 and NRBP1, the identity of direct transcriptional targets mediating mitochondrial repression, whether direct glucose binding (mapped to the leucine zipper) serves a physiological sensing role, and how the adaptor function in the WNK osmotic stress complex integrates with metabolic signaling.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of TSC22D4 or its complexes\", \"Glucose-binding functional consequence not established in vivo\", \"WNK pathway role awaits independent confirmation and functional dissection\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AKT1\", \"NRBP1\", \"SALL4\", \"TRAF6\", \"TSC22D1\", \"JUNB\", \"LCN13\"],\n    \"other_free_text\": []\n  }\n}\n```"}