{"gene":"CNKSR3","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2009,"finding":"CNKSR3 (CNK3) is a direct transcriptional target of the mineralocorticoid receptor (MR): the cnksr3 promoter contains two functional aldosterone-responsive regions bound by MR (confirmed by chromatin immunoprecipitation), and CNKSR3 mRNA is upregulated in response to physiological aldosterone concentrations. CNKSR3 is highly expressed in the renal cortical collecting duct (CCD). CCD cell lines stably overexpressing CNKSR3 showed increased ENaC-mediated transepithelial sodium transport, while CNKSR3 silencing reduced it, establishing that CNKSR3 expression is required for ENaC-mediated sodium transport. In parallel, CNKSR3 expression correlated with decreased MEK phosphorylation, suggesting it modulates MAPK pathway activity.","method":"Chromatin immunoprecipitation (ChIP) of MR at the cnksr3 promoter; stable overexpression and shRNA knockdown cell lines; electrophysiological measurement of transepithelial sodium transport; Western blot for MEK phosphorylation","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, gain- and loss-of-function, electrophysiology) in a single study; not independently replicated","pmids":["19567370"],"is_preprint":false},{"year":2011,"finding":"CNK3 (CNKSR3) and IPCEF1 encode a single fused protein in MDCK and CaCo-2 epithelial cells. This CNK3/IPCEF1 protein is required for HGF-induced Arf6 activation and cell migration: siRNA knockdown of CNK3/IPCEF1 impaired HGF-induced Arf6 activation and reduced cell migration in response to HGF treatment, placing CNK3 as a scaffold downstream of HGF signaling for Arf6-dependent epithelial motility.","method":"siRNA knockdown; Arf6 GTP-loading (activation) assay; migration assay; RT-PCR and Western blot confirming fused transcript/protein","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — clean knockdown with defined pathway phenotype (Arf6 activation and migration), single lab with multiple orthogonal methods","pmids":["22085542"],"is_preprint":false},{"year":2012,"finding":"CNKSR3 (CNK3) acts as a molecular scaffold that coordinates assembly of a large (~1.0–1.2 MDa) plasma membrane ENaC-regulatory complex in response to aldosterone. CNK3 physically interacts with ENaC, the E3 ubiquitin ligase Nedd4-2, and the kinase SGK1; it enhances interactions among these components; and it stimulates ENaC function in a PDZ domain-dependent, aldosterone-induced manner. Loss of the PDZ domain abolishes the stimulatory effect, demonstrating domain-specificity of the scaffold function.","method":"Co-immunoprecipitation; size-exclusion chromatography/native gel to define complex size; PDZ domain deletion mutagenesis; functional ENaC current measurements; aldosterone treatment of renal epithelial cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution of multiprotein complex, reciprocal co-IP, domain mutagenesis, and functional electrophysiological readout in a single study","pmids":["22851176"],"is_preprint":false}],"current_model":"CNKSR3 (CNK3) is an aldosterone/mineralocorticoid receptor-induced scaffold protein that coordinates assembly of a multiprotein ENaC-regulatory complex (containing ENaC, SGK1, and Nedd4-2) at the renal collecting duct plasma membrane via its PDZ domain to promote transepithelial sodium transport, while also suppressing MEK/MAPK phosphorylation; additionally, as the N-terminal half of a fused CNK3/IPCEF1 protein in epithelial cells, it is required for HGF-induced Arf6 activation and cell migration."},"narrative":{"teleology":[{"year":2009,"claim":"Establishing that CNKSR3 is a mineralocorticoid receptor target gene required for ENaC-mediated sodium transport answered how aldosterone transcriptionally controls ENaC activity through novel intermediaries, and simultaneously linked CNKSR3 to MAPK pathway suppression.","evidence":"ChIP of MR at the cnksr3 promoter, stable overexpression and shRNA knockdown in CCD cell lines, electrophysiology, and phospho-MEK Western blot","pmids":["19567370"],"confidence":"Medium","gaps":["Not independently replicated in a second laboratory or in vivo model","Mechanism by which CNKSR3 suppresses MEK phosphorylation is undefined","Direct physical interaction between CNKSR3 and ENaC pathway components was not demonstrated"]},{"year":2011,"claim":"Discovering that the CNKSR3 locus produces a fused CNK3/IPCEF1 protein in epithelial cells revealed a second signaling axis — HGF/Arf6-dependent cell migration — broadening the functional scope of CNKSR3 beyond sodium transport.","evidence":"siRNA knockdown of CNK3/IPCEF1 in MDCK and CaCo-2 cells, Arf6-GTP pull-down assay, Transwell migration assay, RT-PCR and Western blot confirming fused transcript","pmids":["22085542"],"confidence":"Medium","gaps":["Single-study finding not independently confirmed","Relative contributions of the CNK3 versus IPCEF1 moieties to Arf6 activation are unresolved","Whether the fused protein operates in the renal collecting duct context is unknown"]},{"year":2012,"claim":"Demonstrating that CNKSR3 physically scaffolds ENaC, SGK1, and Nedd4-2 into a large membrane complex via its PDZ domain resolved the molecular mechanism through which it promotes aldosterone-stimulated sodium transport.","evidence":"Reciprocal co-immunoprecipitation, size-exclusion chromatography/native gel analysis, PDZ domain deletion mutagenesis, and functional ENaC current measurements in aldosterone-treated renal epithelial cells","pmids":["22851176"],"confidence":"High","gaps":["No in vivo knockout or knockin model confirming physiological relevance","Structural basis of PDZ-mediated interactions with each partner is unknown","Whether scaffold assembly is dynamically regulated beyond aldosterone induction is unresolved"]},{"year":null,"claim":"Key unresolved questions include the in vivo renal phenotype of CNKSR3 loss, the structural details of PDZ-mediated complex assembly, how CNKSR3 suppresses MEK phosphorylation, and whether the CNK3/IPCEF1 fusion protein and the ENaC-scaffold function operate in the same or distinct cell types.","evidence":"","pmids":[],"confidence":"Low","gaps":["No animal model phenotype reported","No structural data for CNKSR3 or its complexes","Relationship between the ENaC-scaffold and Arf6/migration functions is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["SCNN1A","SGK1","NEDD4L","ARF6"],"other_free_text":[]},"mechanistic_narrative":"CNKSR3 (CNK3) is an aldosterone-induced scaffold protein that coordinates epithelial sodium channel (ENaC) regulation in the renal cortical collecting duct. It is a direct transcriptional target of the mineralocorticoid receptor, with its promoter containing two functional aldosterone-responsive elements bound by MR [PMID:19567370]. CNKSR3 assembles a ~1.0–1.2 MDa plasma membrane complex containing ENaC, SGK1, and the E3 ubiquitin ligase Nedd4-2 in a PDZ domain–dependent manner, thereby enhancing ENaC-mediated transepithelial sodium transport and concurrently suppressing MEK/MAPK phosphorylation [PMID:22851176, PMID:19567370]. In epithelial cells, the CNKSR3 locus encodes a fused CNK3/IPCEF1 protein that is required for HGF-induced Arf6 activation and cell migration [PMID:22085542]."},"prefetch_data":{"uniprot":{"accession":"Q6P9H4","full_name":"Connector enhancer of kinase suppressor of ras 3","aliases":["CNK homolog protein 3","CNK3","CNKSR family member 3","Maguin-like protein"],"length_aa":555,"mass_kda":61.9,"function":"Involved in transepithelial sodium transport. Regulates aldosterone-induced and epithelial sodium channel (ENaC)-mediated sodium transport through regulation of ENaC cell surface expression. Acts as a scaffold protein coordinating the assembly of an ENaC-regulatory complex (ERC)","subcellular_location":"Cytoplasm; Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/Q6P9H4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNKSR3","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":"TJP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CNKSR3","total_profiled":1310},"omim":[{"mim_id":"619948","title":"INTERACTION PROTEIN FOR CYTOHESIN EXCHANGE FACTORS 1; IPCEF1","url":"https://www.omim.org/entry/619948"},{"mim_id":"617476","title":"CNKSR FAMILY, MEMBER 3; CNKSR3","url":"https://www.omim.org/entry/617476"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CNKSR3"},"hgnc":{"alias_symbol":["FLJ31349"],"prev_symbol":["MAGI1"]},"alphafold":{"accession":"Q6P9H4","domains":[{"cath_id":"1.10.150.50","chopping":"5-77","consensus_level":"high","plddt":93.0833,"start":5,"end":77},{"cath_id":"1.20.120,1.20.120","chopping":"82-205","consensus_level":"high","plddt":85.4388,"start":82,"end":205},{"cath_id":"2.30.42.10","chopping":"210-291","consensus_level":"high","plddt":89.3006,"start":210,"end":291}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P9H4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P9H4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P9H4-F1-predicted_aligned_error_v6.png","plddt_mean":64.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNKSR3","jax_strain_url":"https://www.jax.org/strain/search?query=CNKSR3"},"sequence":{"accession":"Q6P9H4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P9H4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P9H4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P9H4"}},"corpus_meta":[{"pmid":"11077444","id":"PMC_11077444","title":"Interactions 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The CNKSR3 promoter contains two functional aldosterone-responsive regions bound by MR (confirmed by ChIP). CNKSR3 expression is required for ENaC-mediated transepithelial sodium transport in renal cortical collecting duct cells, and its expression correlates with decreased MEK phosphorylation, placing it in MAPK pathway regulation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), electrophysiological analysis of CCD cell lines stably overexpressing or silencing CNKSR3, promoter analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, stable overexpression, siRNA knockdown, electrophysiology) in a single study with clear functional readout\",\n      \"pmids\": [\"19567370\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNKSR3 is a direct transcriptional target of the mineralocorticoid receptor (activated by aldosterone), is highly expressed in renal cortical collecting duct cells, and is required for ENaC-mediated transepithelial sodium transport, likely acting as a scaffold protein that suppresses MEK/MAPK signaling to permit sodium channel activity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to classify papers carefully:\n\n- Papers [1]-[15] (main corpus), [17]-[53], [55]-[85]: These are about **MAGI-1/MAGI1** (membrane-associated guanylate kinase with inverted domain structure-1), which is a completely different gene from **CNKSR3** (Connector Enhancer of Kinase Suppressor of Ras 3). MAGI1 is the product of the *MAGI1* gene; CNKSR3 is a scaffold protein in the CNK/KSR family. These are EXCLUDE (alias collision - MAGI1 papers dominate the corpus).\n\n- Paper [16] (main corpus): \"Cnksr3 is a direct mineralocorticoid receptor target gene...\" — KEEP, explicitly about CNKSR3.\n- Paper [34] (main corpus): \"Single nucleotide polymorphism array analysis of uveal melanomas reveals that amplification of CNKSR3 is correlated with improved patient survival\" — mentions CNKSR3 protein expression but is primarily a survival/prognostic study. No mechanistic findings about how CNKSR3 works. EXCLUDE from discoveries.\n\nGene2pubmed papers:\n- [18]: \"CNK3 and IPCEF1 produce a single protein that is required for HGF dependent Arf6 activation and migration\" — CNK3/CNKSR3, KEEP.\n- [19]: \"Scaffold protein connector enhancer of kinase suppressor of Ras isoform 3 (CNK3) coordinates assembly of a multiprotein epithelial sodium channel (ENaC)-regulatory complex\" — CNK3 = CNKSR3, KEEP.\n- [21]: \"Significance of miR-15a-5p and CNKSR3 as Novel Prognostic Biomarkers...\" — expression/biomarker study, no mechanism. EXCLUDE.\n- [25]: \"The Association of a Genetic Variant in SCAF8-CNKSR3 with Diabetic Kidney Disease...\" — GWAS association, no mechanism. EXCLUDE.\n- Others: general interactome/GWAS/sequence papers with no specific CNKSR3 mechanistic findings. EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"CNKSR3 (CNK3) is a direct transcriptional target of the mineralocorticoid receptor (MR): the cnksr3 promoter contains two functional aldosterone-responsive regions bound by MR (confirmed by chromatin immunoprecipitation), and CNKSR3 mRNA is upregulated in response to physiological aldosterone concentrations. CNKSR3 is highly expressed in the renal cortical collecting duct (CCD). CCD cell lines stably overexpressing CNKSR3 showed increased ENaC-mediated transepithelial sodium transport, while CNKSR3 silencing reduced it, establishing that CNKSR3 expression is required for ENaC-mediated sodium transport. In parallel, CNKSR3 expression correlated with decreased MEK phosphorylation, suggesting it modulates MAPK pathway activity.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of MR at the cnksr3 promoter; stable overexpression and shRNA knockdown cell lines; electrophysiological measurement of transepithelial sodium transport; Western blot for MEK phosphorylation\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, gain- and loss-of-function, electrophysiology) in a single study; not independently replicated\",\n      \"pmids\": [\"19567370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CNK3 (CNKSR3) and IPCEF1 encode a single fused protein in MDCK and CaCo-2 epithelial cells. This CNK3/IPCEF1 protein is required for HGF-induced Arf6 activation and cell migration: siRNA knockdown of CNK3/IPCEF1 impaired HGF-induced Arf6 activation and reduced cell migration in response to HGF treatment, placing CNK3 as a scaffold downstream of HGF signaling for Arf6-dependent epithelial motility.\",\n      \"method\": \"siRNA knockdown; Arf6 GTP-loading (activation) assay; migration assay; RT-PCR and Western blot confirming fused transcript/protein\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with defined pathway phenotype (Arf6 activation and migration), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22085542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CNKSR3 (CNK3) acts as a molecular scaffold that coordinates assembly of a large (~1.0–1.2 MDa) plasma membrane ENaC-regulatory complex in response to aldosterone. CNK3 physically interacts with ENaC, the E3 ubiquitin ligase Nedd4-2, and the kinase SGK1; it enhances interactions among these components; and it stimulates ENaC function in a PDZ domain-dependent, aldosterone-induced manner. Loss of the PDZ domain abolishes the stimulatory effect, demonstrating domain-specificity of the scaffold function.\",\n      \"method\": \"Co-immunoprecipitation; size-exclusion chromatography/native gel to define complex size; PDZ domain deletion mutagenesis; functional ENaC current measurements; aldosterone treatment of renal epithelial cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution of multiprotein complex, reciprocal co-IP, domain mutagenesis, and functional electrophysiological readout in a single study\",\n      \"pmids\": [\"22851176\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNKSR3 (CNK3) is an aldosterone/mineralocorticoid receptor-induced scaffold protein that coordinates assembly of a multiprotein ENaC-regulatory complex (containing ENaC, SGK1, and Nedd4-2) at the renal collecting duct plasma membrane via its PDZ domain to promote transepithelial sodium transport, while also suppressing MEK/MAPK phosphorylation; additionally, as the N-terminal half of a fused CNK3/IPCEF1 protein in epithelial cells, it is required for HGF-induced Arf6 activation and cell migration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CNKSR3 is a direct transcriptional target of the mineralocorticoid receptor, upregulated by aldosterone via two functional aldosterone-responsive regions in its promoter that are bound by MR [PMID:19567370]. In renal cortical collecting duct cells, CNKSR3 functions as a scaffold protein required for ENaC-mediated transepithelial sodium transport, acting through suppression of MEK/MAPK signaling to permit sodium channel activity [PMID:19567370].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"The identification of CNKSR3 as a direct aldosterone/MR target gene that controls ENaC-mediated sodium transport via MAPK pathway suppression established its core function as a scaffolding link between hormonal signaling and epithelial ion transport.\",\n      \"evidence\": \"ChIP demonstrating MR binding to CNKSR3 promoter regions, electrophysiology in CCD cells with stable overexpression and siRNA knockdown of CNKSR3, promoter analysis\",\n      \"pmids\": [\"19567370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct physical interaction partners mediating the scaffold function have not been identified\",\n        \"The precise mechanism by which CNKSR3 suppresses MEK phosphorylation is unknown\",\n        \"In vivo role in renal sodium handling and blood pressure regulation has not been demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of CNKSR3 scaffolding, the identity of its direct MAPK pathway binding partners, and its in vivo physiological role in sodium homeostasis remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical reconstitution of CNKSR3 scaffold complexes\",\n        \"No animal model phenotyping reported\",\n        \"Relationship to other CNK family scaffold proteins in MAPK signaling is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NR3C2\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"CNKSR3 (CNK3) is an aldosterone-induced scaffold protein that coordinates epithelial sodium channel (ENaC) regulation in the renal cortical collecting duct. It is a direct transcriptional target of the mineralocorticoid receptor, with its promoter containing two functional aldosterone-responsive elements bound by MR [PMID:19567370]. CNKSR3 assembles a ~1.0–1.2 MDa plasma membrane complex containing ENaC, SGK1, and the E3 ubiquitin ligase Nedd4-2 in a PDZ domain–dependent manner, thereby enhancing ENaC-mediated transepithelial sodium transport and concurrently suppressing MEK/MAPK phosphorylation [PMID:22851176, PMID:19567370]. In epithelial cells, the CNKSR3 locus encodes a fused CNK3/IPCEF1 protein that is required for HGF-induced Arf6 activation and cell migration [PMID:22085542].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that CNKSR3 is a mineralocorticoid receptor target gene required for ENaC-mediated sodium transport answered how aldosterone transcriptionally controls ENaC activity through novel intermediaries, and simultaneously linked CNKSR3 to MAPK pathway suppression.\",\n      \"evidence\": \"ChIP of MR at the cnksr3 promoter, stable overexpression and shRNA knockdown in CCD cell lines, electrophysiology, and phospho-MEK Western blot\",\n      \"pmids\": [\"19567370\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not independently replicated in a second laboratory or in vivo model\",\n        \"Mechanism by which CNKSR3 suppresses MEK phosphorylation is undefined\",\n        \"Direct physical interaction between CNKSR3 and ENaC pathway components was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovering that the CNKSR3 locus produces a fused CNK3/IPCEF1 protein in epithelial cells revealed a second signaling axis — HGF/Arf6-dependent cell migration — broadening the functional scope of CNKSR3 beyond sodium transport.\",\n      \"evidence\": \"siRNA knockdown of CNK3/IPCEF1 in MDCK and CaCo-2 cells, Arf6-GTP pull-down assay, Transwell migration assay, RT-PCR and Western blot confirming fused transcript\",\n      \"pmids\": [\"22085542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-study finding not independently confirmed\",\n        \"Relative contributions of the CNK3 versus IPCEF1 moieties to Arf6 activation are unresolved\",\n        \"Whether the fused protein operates in the renal collecting duct context is unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that CNKSR3 physically scaffolds ENaC, SGK1, and Nedd4-2 into a large membrane complex via its PDZ domain resolved the molecular mechanism through which it promotes aldosterone-stimulated sodium transport.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, size-exclusion chromatography/native gel analysis, PDZ domain deletion mutagenesis, and functional ENaC current measurements in aldosterone-treated renal epithelial cells\",\n      \"pmids\": [\"22851176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo knockout or knockin model confirming physiological relevance\",\n        \"Structural basis of PDZ-mediated interactions with each partner is unknown\",\n        \"Whether scaffold assembly is dynamically regulated beyond aldosterone induction is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the in vivo renal phenotype of CNKSR3 loss, the structural details of PDZ-mediated complex assembly, how CNKSR3 suppresses MEK phosphorylation, and whether the CNK3/IPCEF1 fusion protein and the ENaC-scaffold function operate in the same or distinct cell types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No animal model phenotype reported\",\n        \"No structural data for CNKSR3 or its complexes\",\n        \"Relationship between the ENaC-scaffold and Arf6/migration functions is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SCNN1A\",\n      \"SGK1\",\n      \"NEDD4L\",\n      \"ARF6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}