{"gene":"REPS1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1997,"finding":"REPS1 (Reps1) was identified as a novel ~85-kDa protein that binds to RalBP1 (at a site distinct from Ral-GTPase binding) via yeast two-hybrid. REPS1 contains an EH domain, is tyrosine-phosphorylated in response to EGF stimulation, and forms a complex with the SH3 domains of adapter proteins Crk and Grb2.","method":"Yeast two-hybrid cloning, co-immunoprecipitation, tyrosine phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays and phosphorylation confirmed, but single lab with limited orthogonal validation","pmids":["9395447"],"is_preprint":false},{"year":2001,"finding":"The NMR solution structure of the Reps1 EH domain was determined, showing two helix-loop-helix EF-hand-like motifs. The EH domain binds NPF-containing peptides at a hydrophobic pocket between helices B and C with Kd ~46–65 µM; DPF-containing peptides bind with ~10-fold lower affinity (Kd ~0.5 mM).","method":"NMR structure determination, peptide titration/NMR chemical shift analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with 1143 distance restraints plus quantitative binding characterization by NMR titration, single rigorous study with multiple orthogonal methods","pmids":["11389591"],"is_preprint":false},{"year":2001,"finding":"Human REPS1 protein (sharing 83% amino acid identity with mouse Reps1) was cloned from a human fetal brain library and confirmed as a binding partner for RalBP1.","method":"cDNA cloning, sequence analysis, Northern blot","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily cloning and expression characterization without functional mechanistic follow-up","pmids":["11750063"],"is_preprint":false},{"year":2002,"finding":"Rab11-FIP2 contains an NPF motif that allows it to bind the EH domain of Reps1. Rab11-FIP2 overexpression suppresses EGF receptor internalization through binding sites promoting complex formation with Rab11, Reps1, and alpha-adaptin, placing Reps1 in a complex coupling receptor-mediated endocytosis to endosomal sorting.","method":"Co-immunoprecipitation, overexpression dominant-negative assay, EGF receptor internalization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding and functional endocytosis assay, single lab, two orthogonal methods","pmids":["12364336"],"is_preprint":false},{"year":2010,"finding":"Reps1 interacts with Intersectin 1 (ITSN1) in vivo; the interaction is mediated by SH3 domains of ITSN1 and proline-rich motifs of Reps1. Reps1 also interacts with SGIP1 and amphiphysin 1. Reps1 colocalizes with ITSN1 in clathrin-coated pits.","method":"Co-immunoprecipitation, immunofluorescence colocalization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo co-IP with domain mapping and colocalization, single lab, two orthogonal methods","pmids":["20946875"],"is_preprint":false},{"year":2012,"finding":"In Xenopus laevis, Xreps1 was isolated as a binding partner of RLIP/RalBP1 via two-hybrid screening. The mutual interacting domains were identified. Targeting Xreps1 or the Xreps1-binding domain of XRLIP to the plasma membrane (via CAAX fusion) causes a hyperpigmentation phenotype; this phenotype is rescued by co-expression of a Xreps1 deletion mutant restricted to the RLIP-binding domain, placing Reps1 downstream of RLIP in ectoderm function.","method":"Yeast two-hybrid, in vitro/in vivo co-immunoprecipitation, CAAX membrane targeting rescue assay in Xenopus embryos","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis rescue experiment and binding domain mapping, single lab, orthologous organism","pmids":["22413001"],"is_preprint":false},{"year":2012,"finding":"REPS1 was identified as a novel Numb-associated protein via affinity purification/mass spectrometry. In vitro binding confirmed exon-9-independent interaction between Numb and REPS1 EH domain. Inhibition of endocytosis altered recruitment of REPS1 to Numb complexes, linking REPS1 to endocytic complex assembly regulated by Numb phosphorylation.","method":"Affinity purification-mass spectrometry, in vitro binding assay, quantitative selected reaction monitoring MS","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS identification confirmed by in vitro binding and quantitative SRM-MS, single lab","pmids":["23211419"],"is_preprint":false},{"year":2018,"finding":"Biallelic mutations in REPS1 in patient fibroblasts cause abnormal recycling of transferrin receptor (TfR1) and reduction of TfR1 palmitoylation, establishing REPS1 as required for normal TfR1 recycling and palmitoylation-dependent regulation.","method":"Patient fibroblast cell lines (loss-of-function), TfR1 recycling assay, palmitoylation assay, rescue with artesunate","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular phenotype (TfR1 recycling and palmitoylation) in loss-of-function patient cells with pharmacological rescue, single lab","pmids":["29395073"],"is_preprint":false},{"year":2021,"finding":"MEK-RSK signaling directly phosphorylates REPS1 at Ser709 in response to EGF and amino acid stimulation. REPS1 knockout cells and cells reconstituted with non-phosphorylatable REPS1 S709A show attenuated recycling of transferrin receptor (TfR) compared to wild-type REPS1. REPS1 knockout did not affect EGFR endocytosis.","method":"Kinase assay, REPS1 KO cells, phosphomutant reconstitution (S709A), TfR recycling assay, EGFR endocytosis assay","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus phosphomutant reconstitution with specific functional readout, single lab","pmids":["33407999"],"is_preprint":false},{"year":2023,"finding":"Reps1 and Ralbp1 form a binary complex that recognizes vesicle-bound GTP-RalA, promoting exocytosis. RalA binding causes Reps1 release and formation of a Ralbp1-RalA binary complex. Ralbp1 selectively recognizes GTP-bound RalA and stabilizes it in the active GTP-bound state (GTP state stabilization), rather than acting as a classical RalA effector.","method":"Co-immunoprecipitation, in vitro binding/reconstitution, GTPase assays, exocytosis functional assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution of binary/ternary complexes, GTPase nucleotide state assays, and functional exocytosis readout, multiple orthogonal methods in single rigorous study","pmids":["36812304"],"is_preprint":false},{"year":2024,"finding":"In Drosophila, Minibrain (Mnb, ortholog of DYRK1A) physically interacts with Reps (Reps1/Reps2 ortholog) and Rlip (RalBP1 ortholog) identified by AP-MS; Mnb phosphorylates Reps; Rlip, Reps, and Mnb genetically interact and may form a ternary complex regulating brain development. Human DYRK1A binds REPS1 and REPS2.","method":"Affinity purification-mass spectrometry, in vitro kinase assay, genetic interaction analysis in Drosophila, co-immunoprecipitation","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS plus in vitro kinase assay plus genetic epistasis, single lab, orthologous organism with human confirmation","pmids":["39271109"],"is_preprint":false},{"year":2025,"finding":"REPS1 is phosphorylated at Ser709 by p90 ribosomal S6 kinase (RSK) in human skeletal muscle in response to both insulin and exercise stimulation. The RSK-REPS1 signaling axis is required for insulin-stimulated glucose uptake. REPS1 Ser709 phosphorylation is impaired in insulin-resistant mice and humans.","method":"Phosphoproteomics of human skeletal muscle biopsies, kinase assay identifying RSK as upstream kinase, loss-of-function/rescue with glucose uptake assay","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics plus kinase identification plus functional glucose uptake assay in human tissue, single lab but multiple orthogonal methods","pmids":["40482643"],"is_preprint":false}],"current_model":"REPS1 is a multi-domain adaptor protein (containing an EH domain that binds NPF motifs and proline-rich regions that engage SH3 domains of Crk, Grb2, and Intersectin 1) that integrates RalBP1/RalA GTPase signaling with vesicle trafficking: it forms a Reps1-Ralbp1-RalA module that regulates exocytosis by stabilizing active GTP-RalA, participates in clathrin-mediated endocytosis in coated pits, and—upon phosphorylation at Ser709 by RSK downstream of EGF/insulin/exercise signaling—promotes transferrin receptor recycling and insulin-stimulated glucose uptake."},"narrative":{"mechanistic_narrative":"REPS1 is a multi-domain endocytic and trafficking adaptor that couples Ral GTPase signaling to receptor internalization, endosomal sorting, and recycling [PMID:9395447, PMID:36812304]. Its EH domain adopts paired EF-hand-like helix-loop-helix motifs that recognize NPF-containing peptides through a hydrophobic pocket, with markedly lower affinity for DPF motifs [PMID:11389591], and this domain engages NPF-bearing partners including Rab11-FIP2 and Numb to assemble endocytic complexes coupling receptor internalization to endosomal sorting [PMID:12364336, PMID:23211419]. Through proline-rich motifs and tyrosine phosphorylation, REPS1 binds the SH3 domains of the adapters Crk and Grb2 and of Intersectin 1, and localizes to clathrin-coated pits alongside ITSN1 [PMID:9395447, PMID:20946875]. REPS1 was originally identified as a RalBP1 (RLIP) binding partner [PMID:9395447]; biochemically it forms a binary complex with RalBP1 that recognizes vesicle-bound GTP-RalA, whereupon RalA binding releases REPS1 and RalBP1 stabilizes RalA in its active GTP state to promote exocytosis [PMID:36812304]. Phosphorylation of REPS1 at Ser709 by MEK-RSK signaling downstream of EGF, amino acid, insulin, and exercise stimulation drives transferrin receptor recycling and is required for insulin-stimulated glucose uptake in skeletal muscle [PMID:33407999, PMID:40482643]. Biallelic loss-of-function mutations in REPS1 in patient fibroblasts disrupt transferrin receptor recycling and reduce its palmitoylation, establishing REPS1 as required for normal receptor recycling [PMID:29395073].","teleology":[{"year":1997,"claim":"Establishing REPS1's first molecular context: it was unknown what linked RalBP1 to upstream receptor signaling, and identifying REPS1 as a RalBP1 binder that is EGF-induced tyrosine-phosphorylated and engages Crk/Grb2 SH3 domains placed it at the interface of growth-factor signaling and Ral function.","evidence":"Yeast two-hybrid cloning, co-immunoprecipitation and tyrosine phosphorylation assay","pmids":["9395447"],"confidence":"Medium","gaps":["Functional consequence of the RalBP1 interaction not defined","Site of tyrosine phosphorylation and responsible kinase not mapped"]},{"year":2001,"claim":"How REPS1 recognizes its protein partners was unresolved; solving the EH domain structure and quantifying its peptide preferences defined NPF motifs as the high-affinity ligand class, providing the molecular basis for REPS1's adaptor function.","evidence":"NMR solution structure with quantitative peptide titration binding analysis","pmids":["11389591"],"confidence":"High","gaps":["Physiological NPF-bearing ligands not identified in this study","Structure of full-length protein and other domains not determined"]},{"year":2001,"claim":"Confirmed the human ortholog of REPS1 and its conserved RalBP1 binding, extending the mouse findings to human biology.","evidence":"cDNA cloning, sequence analysis and Northern blot","pmids":["11750063"],"confidence":"Low","gaps":["Primarily cloning without functional mechanistic follow-up","No new mechanism established beyond conservation"]},{"year":2002,"claim":"Whether REPS1's EH domain connects to membrane trafficking machinery was open; identifying the NPF-containing Rab11-FIP2 as an EH-domain ligand placed REPS1 in a Rab11/alpha-adaptin complex coupling EGF receptor internalization to endosomal sorting.","evidence":"Co-immunoprecipitation, dominant-negative overexpression and EGF receptor internalization assay","pmids":["12364336"],"confidence":"Medium","gaps":["Direct role of REPS1 (versus FIP2) in the internalization phenotype not isolated","Stoichiometry and dynamics of the multiprotein complex unknown"]},{"year":2010,"claim":"Extended REPS1's interaction network at the endocytic membrane by mapping a proline-rich/SH3 interaction with Intersectin 1 and additional binding to SGIP1 and amphiphysin 1, with colocalization at clathrin-coated pits, positioning REPS1 in clathrin-mediated endocytosis.","evidence":"Co-immunoprecipitation with domain mapping and immunofluorescence colocalization","pmids":["20946875"],"confidence":"Medium","gaps":["Functional consequence of the ITSN1 interaction for endocytosis not tested","Whether interactions are simultaneous or mutually exclusive unknown"]},{"year":2012,"claim":"Whether REPS1 functions downstream of RalBP1 in an organismal context was untested; a Xenopus epistasis rescue placed Reps1 downstream of RLIP in ectoderm function via their mutual binding domains.","evidence":"Yeast two-hybrid, co-immunoprecipitation and CAAX membrane-targeting rescue assay in Xenopus embryos","pmids":["22413001"],"confidence":"Medium","gaps":["Molecular mechanism linking membrane targeting to hyperpigmentation unknown","Relevance to mammalian developmental biology not established"]},{"year":2012,"claim":"Identifying REPS1 as a Numb-associated, EH-domain-binding protein whose recruitment depends on endocytosis activity linked REPS1 to Numb-regulated endocytic complex assembly.","evidence":"Affinity purification-mass spectrometry, in vitro binding and quantitative SRM-MS","pmids":["23211419"],"confidence":"Medium","gaps":["Functional output of the Numb-REPS1 interaction not defined","Mechanism by which endocytosis controls recruitment unresolved"]},{"year":2018,"claim":"The physiological requirement for REPS1 was unknown until biallelic loss-of-function in patient fibroblasts revealed defective transferrin receptor recycling and reduced TfR1 palmitoylation, establishing REPS1 as required for normal receptor recycling.","evidence":"Patient loss-of-function fibroblasts with TfR1 recycling and palmitoylation assays and pharmacological rescue","pmids":["29395073"],"confidence":"Medium","gaps":["Mechanistic link between REPS1 and the palmitoylation machinery not defined","Full disease phenotype and gene-level causal proof not detailed here"]},{"year":2021,"claim":"How signaling controls REPS1's recycling function was unknown; identifying direct MEK-RSK phosphorylation at Ser709 and showing S709A reconstitution attenuates TfR recycling (without affecting EGFR endocytosis) defined a phosphoregulatory switch specific to recycling.","evidence":"Kinase assay, REPS1 knockout cells, S709A phosphomutant reconstitution and TfR recycling/EGFR endocytosis assays","pmids":["33407999"],"confidence":"Medium","gaps":["Downstream effector engaged by phospho-Ser709 not identified","Structural effect of phosphorylation on REPS1 unknown"]},{"year":2023,"claim":"The biochemical logic of the REPS1-RalBP1-RalA module was unresolved; reconstitution showed a binary Reps1-Ralbp1 complex recognizes GTP-RalA, RalA binding displaces Reps1, and RalBP1 stabilizes RalA in the active GTP state to drive exocytosis, redefining RalBP1 as a GTP-state stabilizer rather than a classical effector.","evidence":"Co-immunoprecipitation, in vitro reconstitution, GTPase nucleotide-state assays and exocytosis functional readouts","pmids":["36812304"],"confidence":"High","gaps":["Structural basis of GTP-state stabilization not solved","Connection between this module and REPS1's recycling/endocytic roles unintegrated"]},{"year":2024,"claim":"Whether REPS1 is regulated by kinases beyond RSK was open; AP-MS and kinase assays showed DYRK1A (Drosophila Mnb) binds and phosphorylates Reps/REPS1 within a Rlip-Reps-Mnb module genetically required for brain development.","evidence":"Affinity purification-mass spectrometry, in vitro kinase assay and genetic interaction analysis in Drosophila with human confirmation","pmids":["39271109"],"confidence":"Medium","gaps":["DYRK1A phosphosite on REPS1 not mapped","Functional consequence of DYRK1A phosphorylation for trafficking unknown"]},{"year":2025,"claim":"Linking REPS1 phosphoregulation to whole-body metabolism, RSK was shown to phosphorylate REPS1 Ser709 in human skeletal muscle in response to insulin and exercise, defining an RSK-REPS1 axis required for insulin-stimulated glucose uptake that is impaired in insulin resistance.","evidence":"Phosphoproteomics of human muscle biopsies, RSK kinase identification and loss-of-function/rescue glucose uptake assays","pmids":["40482643"],"confidence":"Medium","gaps":["Mechanistic link from REPS1-mediated recycling to GLUT trafficking not resolved","Causal contribution to insulin resistance versus correlation not fully separated"]},{"year":null,"claim":"It remains unresolved how REPS1's phosphorylation-dependent recycling function, its EH-domain endocytic complexes, and its RalBP1-RalA exocytosis module are integrated into a single coherent trafficking mechanism.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length REPS1 or its multiprotein assemblies","Direct effectors downstream of phospho-Ser709 unidentified","Whether endocytic, recycling, and exocytic roles occur in the same or distinct cellular contexts unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3,4,6,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,7,8]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,4,7,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,11]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,8]}],"complexes":["Reps1-Ralbp1-RalA module"],"partners":["RALBP1","RAB11FIP2","ITSN1","CRK","GRB2","NUMB","RALA","DYRK1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96D71","full_name":"RalBP1-associated Eps domain-containing protein 1","aliases":["RalBP1-interacting protein 1"],"length_aa":796,"mass_kda":86.7,"function":"May coordinate the cellular actions of activated EGF receptors and Ral-GTPases","subcellular_location":"Membrane, clathrin-coated pit","url":"https://www.uniprot.org/uniprotkb/Q96D71/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/REPS1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RALBP1","stoichiometry":10.0},{"gene":"AP2B1","stoichiometry":0.2},{"gene":"ARHGEF7","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"LDHA","stoichiometry":0.2},{"gene":"LDHB","stoichiometry":0.2},{"gene":"MED14","stoichiometry":0.2},{"gene":"MED19","stoichiometry":0.2},{"gene":"MED9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/REPS1","total_profiled":1310},"omim":[{"mim_id":"617916","title":"NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 7; NBIA7","url":"https://www.omim.org/entry/617916"},{"mim_id":"614825","title":"RALBP1-ASSOCIATED EPS DOMAIN-CONTAINING PROTEIN 1; REPS1","url":"https://www.omim.org/entry/614825"},{"mim_id":"608599","title":"RAB11 FAMILY-INTERACTING PROTEIN 2; RAB11FIP2","url":"https://www.omim.org/entry/608599"},{"mim_id":"234200","title":"NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1","url":"https://www.omim.org/entry/234200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/REPS1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96D71","domains":[{"cath_id":"1.10.238.10","chopping":"9-93","consensus_level":"high","plddt":90.0815,"start":9,"end":93},{"cath_id":"1.10.238.10","chopping":"277-368","consensus_level":"high","plddt":91.5812,"start":277,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96D71","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96D71-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96D71-F1-predicted_aligned_error_v6.png","plddt_mean":57.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=REPS1","jax_strain_url":"https://www.jax.org/strain/search?query=REPS1"},"sequence":{"accession":"Q96D71","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96D71.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96D71/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96D71"}},"corpus_meta":[{"pmid":"9395447","id":"PMC_9395447","title":"An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9395447","citation_count":106,"is_preprint":false},{"pmid":"29395073","id":"PMC_29395073","title":"Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29395073","citation_count":85,"is_preprint":false},{"pmid":"12364336","id":"PMC_12364336","title":"Rab11-FIP2, an adaptor protein connecting cellular components involved in internalization and recycling of epidermal growth factor receptors.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12364336","citation_count":85,"is_preprint":false},{"pmid":"11389591","id":"PMC_11389591","title":"Solution structure of the Reps1 EH domain and characterization of its binding to NPF target sequences.","date":"2001","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11389591","citation_count":43,"is_preprint":false},{"pmid":"23211419","id":"PMC_23211419","title":"Identification and selected reaction monitoring (SRM) quantification of endocytosis factors associated with Numb.","date":"2012","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/23211419","citation_count":40,"is_preprint":false},{"pmid":"15010845","id":"PMC_15010845","title":"Identification and characterization of human GUKH2 gene in silico.","date":"2004","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15010845","citation_count":37,"is_preprint":false},{"pmid":"11750063","id":"PMC_11750063","title":"Cloning, expression and characterization of a novel human REPS1 gene.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11750063","citation_count":26,"is_preprint":false},{"pmid":"20946875","id":"PMC_20946875","title":"Intersectin 1 forms complexes with SGIP1 and Reps1 in clathrin-coated pits.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20946875","citation_count":25,"is_preprint":false},{"pmid":"35813961","id":"PMC_35813961","title":"REPS1 as a Potential Biomarker in Alzheimer's Disease and Vascular Dementia.","date":"2022","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35813961","citation_count":19,"is_preprint":false},{"pmid":"36812304","id":"PMC_36812304","title":"Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36812304","citation_count":11,"is_preprint":false},{"pmid":"34885215","id":"PMC_34885215","title":"Heterologous Prime-Boost Vaccination with a Peptide-Based Vaccine and Viral Vector Reshapes Dendritic Cell, CD4+ and CD8+ T Cell Phenotypes to Improve the Antitumor Therapeutic Effect.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34885215","citation_count":9,"is_preprint":false},{"pmid":"39419454","id":"PMC_39419454","title":"Metabolic alterations in fibroblasts of patients presenting with the MPAN subtype of neurodegeneration with brain iron accumulation (NBIA).","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39419454","citation_count":8,"is_preprint":false},{"pmid":"16473614","id":"PMC_16473614","title":"Purification and functional properties of Rab11-FIP2.","date":"2005","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/16473614","citation_count":8,"is_preprint":false},{"pmid":"40482643","id":"PMC_40482643","title":"Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake.","date":"2025","source":"Cell reports. 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REPS1 contains an EH domain, is tyrosine-phosphorylated in response to EGF stimulation, and forms a complex with the SH3 domains of adapter proteins Crk and Grb2.\",\n      \"method\": \"Yeast two-hybrid cloning, co-immunoprecipitation, tyrosine phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays and phosphorylation confirmed, but single lab with limited orthogonal validation\",\n      \"pmids\": [\"9395447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The NMR solution structure of the Reps1 EH domain was determined, showing two helix-loop-helix EF-hand-like motifs. The EH domain binds NPF-containing peptides at a hydrophobic pocket between helices B and C with Kd ~46–65 µM; DPF-containing peptides bind with ~10-fold lower affinity (Kd ~0.5 mM).\",\n      \"method\": \"NMR structure determination, peptide titration/NMR chemical shift analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with 1143 distance restraints plus quantitative binding characterization by NMR titration, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"11389591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human REPS1 protein (sharing 83% amino acid identity with mouse Reps1) was cloned from a human fetal brain library and confirmed as a binding partner for RalBP1.\",\n      \"method\": \"cDNA cloning, sequence analysis, Northern blot\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily cloning and expression characterization without functional mechanistic follow-up\",\n      \"pmids\": [\"11750063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Rab11-FIP2 contains an NPF motif that allows it to bind the EH domain of Reps1. Rab11-FIP2 overexpression suppresses EGF receptor internalization through binding sites promoting complex formation with Rab11, Reps1, and alpha-adaptin, placing Reps1 in a complex coupling receptor-mediated endocytosis to endosomal sorting.\",\n      \"method\": \"Co-immunoprecipitation, overexpression dominant-negative assay, EGF receptor internalization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding and functional endocytosis assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"12364336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Reps1 interacts with Intersectin 1 (ITSN1) in vivo; the interaction is mediated by SH3 domains of ITSN1 and proline-rich motifs of Reps1. Reps1 also interacts with SGIP1 and amphiphysin 1. Reps1 colocalizes with ITSN1 in clathrin-coated pits.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo co-IP with domain mapping and colocalization, single lab, two orthogonal methods\",\n      \"pmids\": [\"20946875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Xenopus laevis, Xreps1 was isolated as a binding partner of RLIP/RalBP1 via two-hybrid screening. The mutual interacting domains were identified. Targeting Xreps1 or the Xreps1-binding domain of XRLIP to the plasma membrane (via CAAX fusion) causes a hyperpigmentation phenotype; this phenotype is rescued by co-expression of a Xreps1 deletion mutant restricted to the RLIP-binding domain, placing Reps1 downstream of RLIP in ectoderm function.\",\n      \"method\": \"Yeast two-hybrid, in vitro/in vivo co-immunoprecipitation, CAAX membrane targeting rescue assay in Xenopus embryos\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis rescue experiment and binding domain mapping, single lab, orthologous organism\",\n      \"pmids\": [\"22413001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"REPS1 was identified as a novel Numb-associated protein via affinity purification/mass spectrometry. In vitro binding confirmed exon-9-independent interaction between Numb and REPS1 EH domain. Inhibition of endocytosis altered recruitment of REPS1 to Numb complexes, linking REPS1 to endocytic complex assembly regulated by Numb phosphorylation.\",\n      \"method\": \"Affinity purification-mass spectrometry, in vitro binding assay, quantitative selected reaction monitoring MS\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS identification confirmed by in vitro binding and quantitative SRM-MS, single lab\",\n      \"pmids\": [\"23211419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biallelic mutations in REPS1 in patient fibroblasts cause abnormal recycling of transferrin receptor (TfR1) and reduction of TfR1 palmitoylation, establishing REPS1 as required for normal TfR1 recycling and palmitoylation-dependent regulation.\",\n      \"method\": \"Patient fibroblast cell lines (loss-of-function), TfR1 recycling assay, palmitoylation assay, rescue with artesunate\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular phenotype (TfR1 recycling and palmitoylation) in loss-of-function patient cells with pharmacological rescue, single lab\",\n      \"pmids\": [\"29395073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MEK-RSK signaling directly phosphorylates REPS1 at Ser709 in response to EGF and amino acid stimulation. REPS1 knockout cells and cells reconstituted with non-phosphorylatable REPS1 S709A show attenuated recycling of transferrin receptor (TfR) compared to wild-type REPS1. REPS1 knockout did not affect EGFR endocytosis.\",\n      \"method\": \"Kinase assay, REPS1 KO cells, phosphomutant reconstitution (S709A), TfR recycling assay, EGFR endocytosis assay\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus phosphomutant reconstitution with specific functional readout, single lab\",\n      \"pmids\": [\"33407999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Reps1 and Ralbp1 form a binary complex that recognizes vesicle-bound GTP-RalA, promoting exocytosis. RalA binding causes Reps1 release and formation of a Ralbp1-RalA binary complex. Ralbp1 selectively recognizes GTP-bound RalA and stabilizes it in the active GTP-bound state (GTP state stabilization), rather than acting as a classical RalA effector.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding/reconstitution, GTPase assays, exocytosis functional assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution of binary/ternary complexes, GTPase nucleotide state assays, and functional exocytosis readout, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"36812304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila, Minibrain (Mnb, ortholog of DYRK1A) physically interacts with Reps (Reps1/Reps2 ortholog) and Rlip (RalBP1 ortholog) identified by AP-MS; Mnb phosphorylates Reps; Rlip, Reps, and Mnb genetically interact and may form a ternary complex regulating brain development. Human DYRK1A binds REPS1 and REPS2.\",\n      \"method\": \"Affinity purification-mass spectrometry, in vitro kinase assay, genetic interaction analysis in Drosophila, co-immunoprecipitation\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS plus in vitro kinase assay plus genetic epistasis, single lab, orthologous organism with human confirmation\",\n      \"pmids\": [\"39271109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"REPS1 is phosphorylated at Ser709 by p90 ribosomal S6 kinase (RSK) in human skeletal muscle in response to both insulin and exercise stimulation. The RSK-REPS1 signaling axis is required for insulin-stimulated glucose uptake. REPS1 Ser709 phosphorylation is impaired in insulin-resistant mice and humans.\",\n      \"method\": \"Phosphoproteomics of human skeletal muscle biopsies, kinase assay identifying RSK as upstream kinase, loss-of-function/rescue with glucose uptake assay\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics plus kinase identification plus functional glucose uptake assay in human tissue, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40482643\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"REPS1 is a multi-domain adaptor protein (containing an EH domain that binds NPF motifs and proline-rich regions that engage SH3 domains of Crk, Grb2, and Intersectin 1) that integrates RalBP1/RalA GTPase signaling with vesicle trafficking: it forms a Reps1-Ralbp1-RalA module that regulates exocytosis by stabilizing active GTP-RalA, participates in clathrin-mediated endocytosis in coated pits, and—upon phosphorylation at Ser709 by RSK downstream of EGF/insulin/exercise signaling—promotes transferrin receptor recycling and insulin-stimulated glucose uptake.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"REPS1 is a multi-domain endocytic and trafficking adaptor that couples Ral GTPase signaling to receptor internalization, endosomal sorting, and recycling [#0, #9]. Its EH domain adopts paired EF-hand-like helix-loop-helix motifs that recognize NPF-containing peptides through a hydrophobic pocket, with markedly lower affinity for DPF motifs [#1], and this domain engages NPF-bearing partners including Rab11-FIP2 and Numb to assemble endocytic complexes coupling receptor internalization to endosomal sorting [#3, #6]. Through proline-rich motifs and tyrosine phosphorylation, REPS1 binds the SH3 domains of the adapters Crk and Grb2 and of Intersectin 1, and localizes to clathrin-coated pits alongside ITSN1 [#0, #4]. REPS1 was originally identified as a RalBP1 (RLIP) binding partner [#0]; biochemically it forms a binary complex with RalBP1 that recognizes vesicle-bound GTP-RalA, whereupon RalA binding releases REPS1 and RalBP1 stabilizes RalA in its active GTP state to promote exocytosis [#9]. Phosphorylation of REPS1 at Ser709 by MEK-RSK signaling downstream of EGF, amino acid, insulin, and exercise stimulation drives transferrin receptor recycling and is required for insulin-stimulated glucose uptake in skeletal muscle [#8, #11]. Biallelic loss-of-function mutations in REPS1 in patient fibroblasts disrupt transferrin receptor recycling and reduce its palmitoylation, establishing REPS1 as required for normal receptor recycling [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing REPS1's first molecular context: it was unknown what linked RalBP1 to upstream receptor signaling, and identifying REPS1 as a RalBP1 binder that is EGF-induced tyrosine-phosphorylated and engages Crk/Grb2 SH3 domains placed it at the interface of growth-factor signaling and Ral function.\",\n      \"evidence\": \"Yeast two-hybrid cloning, co-immunoprecipitation and tyrosine phosphorylation assay\",\n      \"pmids\": [\"9395447\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of the RalBP1 interaction not defined\", \"Site of tyrosine phosphorylation and responsible kinase not mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"How REPS1 recognizes its protein partners was unresolved; solving the EH domain structure and quantifying its peptide preferences defined NPF motifs as the high-affinity ligand class, providing the molecular basis for REPS1's adaptor function.\",\n      \"evidence\": \"NMR solution structure with quantitative peptide titration binding analysis\",\n      \"pmids\": [\"11389591\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Physiological NPF-bearing ligands not identified in this study\", \"Structure of full-length protein and other domains not determined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Confirmed the human ortholog of REPS1 and its conserved RalBP1 binding, extending the mouse findings to human biology.\",\n      \"evidence\": \"cDNA cloning, sequence analysis and Northern blot\",\n      \"pmids\": [\"11750063\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Primarily cloning without functional mechanistic follow-up\", \"No new mechanism established beyond conservation\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Whether REPS1's EH domain connects to membrane trafficking machinery was open; identifying the NPF-containing Rab11-FIP2 as an EH-domain ligand placed REPS1 in a Rab11/alpha-adaptin complex coupling EGF receptor internalization to endosomal sorting.\",\n      \"evidence\": \"Co-immunoprecipitation, dominant-negative overexpression and EGF receptor internalization assay\",\n      \"pmids\": [\"12364336\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct role of REPS1 (versus FIP2) in the internalization phenotype not isolated\", \"Stoichiometry and dynamics of the multiprotein complex unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended REPS1's interaction network at the endocytic membrane by mapping a proline-rich/SH3 interaction with Intersectin 1 and additional binding to SGIP1 and amphiphysin 1, with colocalization at clathrin-coated pits, positioning REPS1 in clathrin-mediated endocytosis.\",\n      \"evidence\": \"Co-immunoprecipitation with domain mapping and immunofluorescence colocalization\",\n      \"pmids\": [\"20946875\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional consequence of the ITSN1 interaction for endocytosis not tested\", \"Whether interactions are simultaneous or mutually exclusive unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether REPS1 functions downstream of RalBP1 in an organismal context was untested; a Xenopus epistasis rescue placed Reps1 downstream of RLIP in ectoderm function via their mutual binding domains.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation and CAAX membrane-targeting rescue assay in Xenopus embryos\",\n      \"pmids\": [\"22413001\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism linking membrane targeting to hyperpigmentation unknown\", \"Relevance to mammalian developmental biology not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying REPS1 as a Numb-associated, EH-domain-binding protein whose recruitment depends on endocytosis activity linked REPS1 to Numb-regulated endocytic complex assembly.\",\n      \"evidence\": \"Affinity purification-mass spectrometry, in vitro binding and quantitative SRM-MS\",\n      \"pmids\": [\"23211419\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional output of the Numb-REPS1 interaction not defined\", \"Mechanism by which endocytosis controls recruitment unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The physiological requirement for REPS1 was unknown until biallelic loss-of-function in patient fibroblasts revealed defective transferrin receptor recycling and reduced TfR1 palmitoylation, establishing REPS1 as required for normal receptor recycling.\",\n      \"evidence\": \"Patient loss-of-function fibroblasts with TfR1 recycling and palmitoylation assays and pharmacological rescue\",\n      \"pmids\": [\"29395073\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic link between REPS1 and the palmitoylation machinery not defined\", \"Full disease phenotype and gene-level causal proof not detailed here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How signaling controls REPS1's recycling function was unknown; identifying direct MEK-RSK phosphorylation at Ser709 and showing S709A reconstitution attenuates TfR recycling (without affecting EGFR endocytosis) defined a phosphoregulatory switch specific to recycling.\",\n      \"evidence\": \"Kinase assay, REPS1 knockout cells, S709A phosphomutant reconstitution and TfR recycling/EGFR endocytosis assays\",\n      \"pmids\": [\"33407999\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream effector engaged by phospho-Ser709 not identified\", \"Structural effect of phosphorylation on REPS1 unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The biochemical logic of the REPS1-RalBP1-RalA module was unresolved; reconstitution showed a binary Reps1-Ralbp1 complex recognizes GTP-RalA, RalA binding displaces Reps1, and RalBP1 stabilizes RalA in the active GTP state to drive exocytosis, redefining RalBP1 as a GTP-state stabilizer rather than a classical effector.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro reconstitution, GTPase nucleotide-state assays and exocytosis functional readouts\",\n      \"pmids\": [\"36812304\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of GTP-state stabilization not solved\", \"Connection between this module and REPS1's recycling/endocytic roles unintegrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether REPS1 is regulated by kinases beyond RSK was open; AP-MS and kinase assays showed DYRK1A (Drosophila Mnb) binds and phosphorylates Reps/REPS1 within a Rlip-Reps-Mnb module genetically required for brain development.\",\n      \"evidence\": \"Affinity purification-mass spectrometry, in vitro kinase assay and genetic interaction analysis in Drosophila with human confirmation\",\n      \"pmids\": [\"39271109\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"DYRK1A phosphosite on REPS1 not mapped\", \"Functional consequence of DYRK1A phosphorylation for trafficking unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking REPS1 phosphoregulation to whole-body metabolism, RSK was shown to phosphorylate REPS1 Ser709 in human skeletal muscle in response to insulin and exercise, defining an RSK-REPS1 axis required for insulin-stimulated glucose uptake that is impaired in insulin resistance.\",\n      \"evidence\": \"Phosphoproteomics of human muscle biopsies, RSK kinase identification and loss-of-function/rescue glucose uptake assays\",\n      \"pmids\": [\"40482643\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic link from REPS1-mediated recycling to GLUT trafficking not resolved\", \"Causal contribution to insulin resistance versus correlation not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how REPS1's phosphorylation-dependent recycling function, its EH-domain endocytic complexes, and its RalBP1-RalA exocytosis module are integrated into a single coherent trafficking mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structure of full-length REPS1 or its multiprotein assemblies\", \"Direct effectors downstream of phospho-Ser709 unidentified\", \"Whether endocytic, recycling, and exocytic roles occur in the same or distinct cellular contexts unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 4, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 11]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\n      \"Reps1-Ralbp1-RalA module\"\n    ],\n    \"partners\": [\n      \"RALBP1\",\n      \"RAB11FIP2\",\n      \"ITSN1\",\n      \"CRK\",\n      \"GRB2\",\n      \"NUMB\",\n      \"RALA\",\n      \"DYRK1A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}