{"gene":"MCRIP1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2015,"finding":"MCRIP1 is a direct substrate of ERK kinase; when phosphorylated by ERK, MCRIP1 dissociates from the transcriptional co-repressor CtBP, allowing CtBP to interact with the DNA-binding repressor ZEB1 and be recruited to the E-cadherin promoter, resulting in chromatin modifications that silence E-cadherin expression during epithelial-mesenchymal transition.","method":"ERK substrate identification, co-immunoprecipitation, competitive binding assays, phosphorylation assays, chromatin immunoprecipitation, promoter-reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, phosphorylation assays, ChIP, and functional promoter assays in a single focused study establishing the full mechanistic pathway","pmids":["25728771"],"is_preprint":false},{"year":2015,"finding":"In the absence of ERK signaling, MCRIP1 binds to CtBP and competitively inhibits the CtBP–ZEB1 interaction, thereby preventing assembly of the CtBP co-repressor complex on target gene promoters.","method":"Co-immunoprecipitation, competitive binding/pulldown assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and competitive binding assays in same study establishing the inhibitory mechanism","pmids":["25728771"],"is_preprint":false},{"year":2019,"finding":"MCRIP1 promotes lung surfactant protein B (SP-B) and SP-C expression in alveolar epithelial cells by interfering with interactions between CtBP and the lung-enriched transcriptional repressors Foxp1 and Foxp2, thereby preventing recruitment of the CtBP co-repressor complex to SP-B and SP-C promoters and maintaining them in an active chromatin state. Homozygous Mcrip1 knockout mice die from respiratory distress due to abnormal repression of these surfactant proteins.","method":"Mcrip1 knockout mouse model (homozygous), co-immunoprecipitation (CtBP–Foxp1/Foxp2 interaction), chromatin immunoprecipitation (promoter occupancy), chromatin state analysis","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with clear lethal phenotype plus Co-IP and ChIP establishing molecular mechanism in same study","pmids":["31240265"],"is_preprint":false},{"year":2015,"finding":"FAM195B (GRAN2/MCRIP1) interacts with the RNA helicase DDX6 in an RNA-independent manner and re-localizes from the cytoplasm to stress granules upon cellular stress exposure, suggesting a role in translation repression during the stress response.","method":"Immunoprecipitation–mass spectrometry (DDX6 as bait), RNase treatment to confirm RNA-independence, fluorescence microscopy for stress granule localization","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — validated interaction by IP-MS with RNA-independent confirmation and microscopy, but functional consequence of the DDX6 interaction not fully characterized","pmids":["26184334"],"is_preprint":false},{"year":2020,"finding":"In Drosophila, depletion of the MCRIP ortholog (dMCRIP) in mxc mutant hemocytes phenocopies MAPK cascade activation by reducing DE-cadherin levels and enhancing lymph gland hyperplasia, placing dMCRIP downstream of MAPK signaling in cadherin gene silencing in vivo.","method":"Genetic epistasis — RNAi-mediated depletion of Drosophila MCRIP in mxcmbn1 mutant background, quantification of DE-cadherin levels and lymph gland phenotype","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Drosophila ortholog model with clear phenotypic readout, single lab, consistent with mammalian mechanism","pmids":["33012036"],"is_preprint":false}],"current_model":"MCRIP1 is an ERK-phosphorylated regulator of the CtBP transcriptional co-repressor: in its unphosphorylated state it binds CtBP and blocks CtBP's interaction with DNA-binding repressors (ZEB1, Foxp1, Foxp2), keeping target gene promoters active; upon ERK-mediated phosphorylation, MCRIP1 releases CtBP, enabling assembly of the CtBP co-repressor complex at target promoters (e.g., E-cadherin during EMT) to induce chromatin modifications and gene silencing, while in the lung its constitutive CtBP-inhibitory activity maintains surfactant protein B and C expression essential for neonatal survival."},"narrative":{"mechanistic_narrative":"MCRIP1 is an ERK-responsive regulator of the CtBP transcriptional co-repressor that gates whether CtBP-dependent gene silencing occurs [PMID:25728771]. In its unphosphorylated state, MCRIP1 binds CtBP and competitively blocks CtBP's interaction with DNA-binding repressors, preventing assembly of the CtBP co-repressor complex on target promoters [PMID:25728771]. ERK directly phosphorylates MCRIP1, causing it to dissociate from CtBP; freed CtBP then binds the DNA-binding repressor ZEB1 and is recruited to the E-cadherin promoter, driving chromatin modifications that silence E-cadherin during epithelial-mesenchymal transition [PMID:25728771]. This switch is conserved in vivo: in Drosophila, depletion of the MCRIP ortholog phenocopies MAPK activation by reducing DE-cadherin, placing MCRIP downstream of MAPK in cadherin silencing [PMID:33012036]. The same CtBP-inhibitory activity operates in a developmental context, where MCRIP1 interferes with CtBP interactions with the lung-enriched repressors Foxp1 and Foxp2 to keep the surfactant protein B and C promoters active; Mcrip1-null mice die of neonatal respiratory distress from aberrant surfactant gene repression [PMID:31240265]. Independently of its CtBP role, MCRIP1 (FAM195B/GRAN2) binds the RNA helicase DDX6 in an RNA-independent manner and relocalizes to stress granules upon cellular stress [PMID:26184334].","teleology":[{"year":2015,"claim":"Established the core mechanism by which MCRIP1 couples ERK signaling to transcriptional repression: it answered how a kinase signal is converted into CtBP-dependent gene silencing.","evidence":"ERK substrate identification, reciprocal Co-IP, competitive binding and phosphorylation assays, ChIP and promoter-reporter assays in mammalian cells","pmids":["25728771"],"confidence":"High","gaps":["The phosphorylation site(s) and the structural basis of the MCRIP1-CtBP interaction are not defined","Whether MCRIP1 regulates CtBP at promoters beyond E-cadherin in EMT is not established here"]},{"year":2015,"claim":"Defined the unphosphorylated-state function as a competitive inhibitor, showing MCRIP1 acts by occluding CtBP's binding to DNA-bound repressors rather than by altering CtBP levels.","evidence":"Co-immunoprecipitation and competitive pulldown assays","pmids":["25728771"],"confidence":"High","gaps":["The binding interface that overlaps between MCRIP1 and ZEB1 on CtBP is not mapped"]},{"year":2015,"claim":"Identified a CtBP-independent activity by showing MCRIP1 binds the RNA helicase DDX6 and partitions into stress granules, raising a possible role in translational control during stress.","evidence":"IP-mass spectrometry with DDX6 bait, RNase treatment for RNA-independence, fluorescence microscopy of stress granule localization","pmids":["26184334"],"confidence":"Medium","gaps":["Functional consequence of the DDX6 interaction is not characterized","Whether stress granule recruitment intersects with the CtBP/ERK axis is unknown"]},{"year":2019,"claim":"Extended the CtBP-inhibitory model to a physiological, essential context, demonstrating that MCRIP1 keeps surfactant genes active by blocking CtBP-Foxp1/Foxp2 interactions, and that its loss is neonatally lethal.","evidence":"Homozygous Mcrip1 knockout mouse model, Co-IP of CtBP-Foxp1/Foxp2, ChIP and chromatin state analysis at SP-B/SP-C promoters","pmids":["31240265"],"confidence":"High","gaps":["Whether surfactant gene repression in vivo is ERK-regulated is not tested","Tissue contexts beyond lung where MCRIP1 is required are not addressed"]},{"year":2020,"claim":"Provided in vivo genetic confirmation that MCRIP function lies downstream of MAPK in cadherin silencing, validating the mammalian biochemical model in a whole-organism epistasis setting.","evidence":"RNAi depletion of Drosophila MCRIP ortholog in mxc mutant hemocytes with DE-cadherin and lymph gland phenotype readouts","pmids":["33012036"],"confidence":"Medium","gaps":["Single-lab ortholog study; direct CtBP involvement in the fly phenotype not biochemically confirmed","Phosphorylation-dependence of the fly phenotype not tested"]},{"year":null,"claim":"How the two activities of MCRIP1 — CtBP regulation and DDX6/stress-granule association — are mechanistically related, and whether they are coordinated by ERK signaling, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of MCRIP1 or its binding interfaces","Functional role of DDX6 binding undefined","Phosphosite mapping on MCRIP1 absent from the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["CTBP1","DDX6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"C9JLW8","full_name":"Mapk-regulated corepressor-interacting protein 1","aliases":["Granulin-2","Protein FAM195B"],"length_aa":97,"mass_kda":10.9,"function":"The phosphorylation status of MCRIP1 functions as a molecular switch to regulate epithelial-mesenchymal transition. Unphosphorylated MCRIP1 binds to and inhibits the transcriptional corepressor CTBP(s). When phosphorylated by MAPK/ERK, MCRIP1 releases CTBP(s) resulting in transcriptional silencing of the E-cadherin gene and induction of epithelial-mesenchymal transition (PubMed:25728771)","subcellular_location":"Nucleus; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/C9JLW8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MCRIP1","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATXN2L","stoichiometry":10.0},{"gene":"DDX6","stoichiometry":10.0},{"gene":"EIF3B","stoichiometry":0.2},{"gene":"METAP2","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"RTCB","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MCRIP1","total_profiled":1310},"omim":[{"mim_id":"616514","title":"FAMILY WITH SEQUENCE SIMILARITY 195, MEMBER B; FAM195B","url":"https://www.omim.org/entry/616514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MCRIP1"},"hgnc":{"alias_symbol":["GRAN2","MCRIP"],"prev_symbol":["FAM195B"]},"alphafold":{"accession":"C9JLW8","domains":[{"cath_id":"1.20.5","chopping":"30-55","consensus_level":"medium","plddt":89.92,"start":30,"end":55}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/C9JLW8","model_url":"https://alphafold.ebi.ac.uk/files/AF-C9JLW8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-C9JLW8-F1-predicted_aligned_error_v6.png","plddt_mean":75.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MCRIP1","jax_strain_url":"https://www.jax.org/strain/search?query=MCRIP1"},"sequence":{"accession":"C9JLW8","fasta_url":"https://rest.uniprot.org/uniprotkb/C9JLW8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/C9JLW8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/C9JLW8"}},"corpus_meta":[{"pmid":"25728771","id":"PMC_25728771","title":"MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/25728771","citation_count":68,"is_preprint":false},{"pmid":"2607151","id":"PMC_2607151","title":"Measurement of antibody affinity for cell surface antigens using an enzyme-linked immunosorbent assay.","date":"1989","source":"Journal of immunological methods","url":"https://pubmed.ncbi.nlm.nih.gov/2607151","citation_count":28,"is_preprint":false},{"pmid":"26184334","id":"PMC_26184334","title":"Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins.","date":"2015","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/26184334","citation_count":28,"is_preprint":false},{"pmid":"36730645","id":"PMC_36730645","title":"Shear Stress Markedly Alters the Proteomic Response to Hypoxia in Human Pulmonary Endothelial Cells.","date":"2023","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36730645","citation_count":19,"is_preprint":false},{"pmid":"37662857","id":"PMC_37662857","title":"Fecal microbiota transplantation alleviates experimental colitis through the Toll-like receptor 4 signaling pathway.","date":"2023","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/37662857","citation_count":16,"is_preprint":false},{"pmid":"27096246","id":"PMC_27096246","title":"EXPERIMENTAL OBSERVATIONS ON THE INFLUENCE OF TEMPERATURE, LIGHT, AND SALINITY ON CELL DIVISION OF THE MARINE DIATOM, DETONULA CONFERVACEA (CLEVE) GRAN(2).","date":"1969","source":"Journal of phycology","url":"https://pubmed.ncbi.nlm.nih.gov/27096246","citation_count":10,"is_preprint":false},{"pmid":"31240265","id":"PMC_31240265","title":"MCRIP1 promotes the expression of lung-surfactant proteins in mice by disrupting CtBP-mediated epigenetic gene silencing.","date":"2019","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/31240265","citation_count":5,"is_preprint":false},{"pmid":"33012036","id":"PMC_33012036","title":"Enhancement of leukemia-like phenotypes in Drosophila mxc mutant larvae due to activation of the RAS-MAP kinase cascade possibly via down-regulation of DE-cadherin.","date":"2020","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/33012036","citation_count":4,"is_preprint":false},{"pmid":"42012768","id":"PMC_42012768","title":"Culture-dependent baseline states and drug response programs in myxofibrosarcoma models across 2D and 3D systems.","date":"2026","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/42012768","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6918,"output_tokens":1412,"usd":0.020967,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8108,"output_tokens":2365,"usd":0.049833,"stage2_stop_reason":"end_turn"},"total_usd":0.0708,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"MCRIP1 is a direct substrate of ERK kinase; when phosphorylated by ERK, MCRIP1 dissociates from the transcriptional co-repressor CtBP, allowing CtBP to interact with the DNA-binding repressor ZEB1 and be recruited to the E-cadherin promoter, resulting in chromatin modifications that silence E-cadherin expression during epithelial-mesenchymal transition.\",\n      \"method\": \"ERK substrate identification, co-immunoprecipitation, competitive binding assays, phosphorylation assays, chromatin immunoprecipitation, promoter-reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, phosphorylation assays, ChIP, and functional promoter assays in a single focused study establishing the full mechanistic pathway\",\n      \"pmids\": [\"25728771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In the absence of ERK signaling, MCRIP1 binds to CtBP and competitively inhibits the CtBP–ZEB1 interaction, thereby preventing assembly of the CtBP co-repressor complex on target gene promoters.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding/pulldown assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and competitive binding assays in same study establishing the inhibitory mechanism\",\n      \"pmids\": [\"25728771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MCRIP1 promotes lung surfactant protein B (SP-B) and SP-C expression in alveolar epithelial cells by interfering with interactions between CtBP and the lung-enriched transcriptional repressors Foxp1 and Foxp2, thereby preventing recruitment of the CtBP co-repressor complex to SP-B and SP-C promoters and maintaining them in an active chromatin state. Homozygous Mcrip1 knockout mice die from respiratory distress due to abnormal repression of these surfactant proteins.\",\n      \"method\": \"Mcrip1 knockout mouse model (homozygous), co-immunoprecipitation (CtBP–Foxp1/Foxp2 interaction), chromatin immunoprecipitation (promoter occupancy), chromatin state analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with clear lethal phenotype plus Co-IP and ChIP establishing molecular mechanism in same study\",\n      \"pmids\": [\"31240265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FAM195B (GRAN2/MCRIP1) interacts with the RNA helicase DDX6 in an RNA-independent manner and re-localizes from the cytoplasm to stress granules upon cellular stress exposure, suggesting a role in translation repression during the stress response.\",\n      \"method\": \"Immunoprecipitation–mass spectrometry (DDX6 as bait), RNase treatment to confirm RNA-independence, fluorescence microscopy for stress granule localization\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — validated interaction by IP-MS with RNA-independent confirmation and microscopy, but functional consequence of the DDX6 interaction not fully characterized\",\n      \"pmids\": [\"26184334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Drosophila, depletion of the MCRIP ortholog (dMCRIP) in mxc mutant hemocytes phenocopies MAPK cascade activation by reducing DE-cadherin levels and enhancing lymph gland hyperplasia, placing dMCRIP downstream of MAPK signaling in cadherin gene silencing in vivo.\",\n      \"method\": \"Genetic epistasis — RNAi-mediated depletion of Drosophila MCRIP in mxcmbn1 mutant background, quantification of DE-cadherin levels and lymph gland phenotype\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Drosophila ortholog model with clear phenotypic readout, single lab, consistent with mammalian mechanism\",\n      \"pmids\": [\"33012036\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MCRIP1 is an ERK-phosphorylated regulator of the CtBP transcriptional co-repressor: in its unphosphorylated state it binds CtBP and blocks CtBP's interaction with DNA-binding repressors (ZEB1, Foxp1, Foxp2), keeping target gene promoters active; upon ERK-mediated phosphorylation, MCRIP1 releases CtBP, enabling assembly of the CtBP co-repressor complex at target promoters (e.g., E-cadherin during EMT) to induce chromatin modifications and gene silencing, while in the lung its constitutive CtBP-inhibitory activity maintains surfactant protein B and C expression essential for neonatal survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MCRIP1 is an ERK-responsive regulator of the CtBP transcriptional co-repressor that gates whether CtBP-dependent gene silencing occurs [#0, #1]. In its unphosphorylated state, MCRIP1 binds CtBP and competitively blocks CtBP's interaction with DNA-binding repressors, preventing assembly of the CtBP co-repressor complex on target promoters [#1]. ERK directly phosphorylates MCRIP1, causing it to dissociate from CtBP; freed CtBP then binds the DNA-binding repressor ZEB1 and is recruited to the E-cadherin promoter, driving chromatin modifications that silence E-cadherin during epithelial-mesenchymal transition [#0]. This switch is conserved in vivo: in Drosophila, depletion of the MCRIP ortholog phenocopies MAPK activation by reducing DE-cadherin, placing MCRIP downstream of MAPK in cadherin silencing [#4]. The same CtBP-inhibitory activity operates in a developmental context, where MCRIP1 interferes with CtBP interactions with the lung-enriched repressors Foxp1 and Foxp2 to keep the surfactant protein B and C promoters active; Mcrip1-null mice die of neonatal respiratory distress from aberrant surfactant gene repression [#2]. Independently of its CtBP role, MCRIP1 (FAM195B/GRAN2) binds the RNA helicase DDX6 in an RNA-independent manner and relocalizes to stress granules upon cellular stress [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the core mechanism by which MCRIP1 couples ERK signaling to transcriptional repression: it answered how a kinase signal is converted into CtBP-dependent gene silencing.\",\n      \"evidence\": \"ERK substrate identification, reciprocal Co-IP, competitive binding and phosphorylation assays, ChIP and promoter-reporter assays in mammalian cells\",\n      \"pmids\": [\"25728771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The phosphorylation site(s) and the structural basis of the MCRIP1-CtBP interaction are not defined\", \"Whether MCRIP1 regulates CtBP at promoters beyond E-cadherin in EMT is not established here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the unphosphorylated-state function as a competitive inhibitor, showing MCRIP1 acts by occluding CtBP's binding to DNA-bound repressors rather than by altering CtBP levels.\",\n      \"evidence\": \"Co-immunoprecipitation and competitive pulldown assays\",\n      \"pmids\": [\"25728771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The binding interface that overlaps between MCRIP1 and ZEB1 on CtBP is not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a CtBP-independent activity by showing MCRIP1 binds the RNA helicase DDX6 and partitions into stress granules, raising a possible role in translational control during stress.\",\n      \"evidence\": \"IP-mass spectrometry with DDX6 bait, RNase treatment for RNA-independence, fluorescence microscopy of stress granule localization\",\n      \"pmids\": [\"26184334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the DDX6 interaction is not characterized\", \"Whether stress granule recruitment intersects with the CtBP/ERK axis is unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the CtBP-inhibitory model to a physiological, essential context, demonstrating that MCRIP1 keeps surfactant genes active by blocking CtBP-Foxp1/Foxp2 interactions, and that its loss is neonatally lethal.\",\n      \"evidence\": \"Homozygous Mcrip1 knockout mouse model, Co-IP of CtBP-Foxp1/Foxp2, ChIP and chromatin state analysis at SP-B/SP-C promoters\",\n      \"pmids\": [\"31240265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether surfactant gene repression in vivo is ERK-regulated is not tested\", \"Tissue contexts beyond lung where MCRIP1 is required are not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided in vivo genetic confirmation that MCRIP function lies downstream of MAPK in cadherin silencing, validating the mammalian biochemical model in a whole-organism epistasis setting.\",\n      \"evidence\": \"RNAi depletion of Drosophila MCRIP ortholog in mxc mutant hemocytes with DE-cadherin and lymph gland phenotype readouts\",\n      \"pmids\": [\"33012036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab ortholog study; direct CtBP involvement in the fly phenotype not biochemically confirmed\", \"Phosphorylation-dependence of the fly phenotype not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the two activities of MCRIP1 — CtBP regulation and DDX6/stress-granule association — are mechanistically related, and whether they are coordinated by ERK signaling, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of MCRIP1 or its binding interfaces\", \"Functional role of DDX6 binding undefined\", \"Phosphosite mapping on MCRIP1 absent from the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTBP1\", \"DDX6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}