id: P13569 gene_symbol: CFTR aliases: - ABCC7 - ABC35 - CF - MRP7 - TNR-CFTR - dJ760C5.1 taxon: id: NCBITaxon:9606 label: Homo sapiens description: CFTR is a membrane anion channel of the ATP-binding cassette protein family. Phosphorylation and ATP-dependent conformational cycling regulate its pore, which conducts chloride and bicarbonate down their electrochemical gradients. Its ATPase activity controls gating rather than pumping anions against a gradient. At epithelial apical membranes, CFTR supports salt, fluid and bicarbonate transport; tissue-specific consequences include airway surface hydration, pancreatic and intestinal secretion, and sweat-duct salt handling. Cytosolic terminal and regulatory regions engage trafficking adaptors, chaperones and regulatory proteins. The channel cycles through biosynthetic and endosomal compartments, and misfolded forms can be retained in the endoplasmic reticulum and eliminated through quality-control pathways. Pathogenic variants cause cystic fibrosis; the common F508del variant disrupts folding and cell-surface delivery, reducing epithelial anion secretion. existing_annotations: - term: id: GO:0005260 label: intracellularly ATP-gated chloride channel activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: ATP-gated chloride conduction is the conserved core activity. action: ACCEPT reason: The PAINT assertion agrees with purified CFTR ATPase/gating measurements and human epithelial chloride transport. The historical ancestral placement was not reconstructed; target evidence independently supports the activity without criticizing donor count or target self-evidence. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:8910473 - reference_id: PMID:19621064 - term: id: GO:0005254 label: chloride channel activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: The combined electronic annotation correctly identifies chloride channel activity. action: ACCEPT reason: Direct channel measurements support passive chloride conductance through CFTR. ATP regulates gating; this does not turn chloride movement into primary active transport. supported_by: - reference_id: GO_REF:0000120 - reference_id: PMID:19019741 - reference_id: PMID:8910473 - term: id: GO:0000166 label: nucleotide binding evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: enables review: summary: Specify the experimentally established nucleotide ligand. action: MODIFY reason: CFTR binds ATP at its nucleotide-binding domains, and purified-protein experiments measure ATP hydrolysis coupled to gating. ATP binding is more informative than the original generic nucleotide-binding keyword inference. supported_by: - reference_id: GO_REF:0000043 - reference_id: PMID:8910473 proposed_replacement_terms: - id: GO:0005524 label: ATP binding - term: id: GO:0005260 label: intracellularly ATP-gated chloride channel activity evidence_type: IEA original_reference_id: GO_REF:0000003 qualifier: enables review: summary: The enzyme mapping correctly identifies ATP-gated channel activity. action: ACCEPT reason: Official EC 5.6.1.6 concerns ATP-dependent conformational control of CFTR conductance. Direct hydrolysis/gating evidence supports this channel activity while ions move passively. supported_by: - reference_id: GO_REF:0000003 - reference_id: PMID:8910473 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12369822 qualifier: enables review: summary: The actual source pair supports PDZ-domain binding. action: MODIFY reason: The preserved GOA partner is NHERF2/E3KARP Q15599. The primary abstract describes direct in-vitro binding to its second PDZ domain, with CFTR as the affinity comparator. This refines the target association; the DRA-centered title does not make DRA the preserved CFTR partner. supported_by: - reference_id: PMID:12369822 supporting_text: affinity being comparable to that of the known ligand CFTR - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:12471024 qualifier: enables review: summary: Retain the source-specific PDZ-organized protein associations. action: KEEP_AS_NON_CORE reason: Exact positive records include NHERF1, ClC-3B, PDZK1 and GOPC, using CFTR-tail pull-downs and cellular co-IP. Some contacts are within PDZ-organized complexes; a single binary PDZ-binding claim would not describe every preserved partner. No CFTR-mediated ClC-3B trafficking mechanism is inferred. supported_by: - reference_id: PMID:12471024 supporting_text: only PDZK1 was found to promote interaction between the two channels - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14679199 qualifier: enables review: summary: The Shank interaction is specifically PDZ-dependent. action: MODIFY reason: The primary reports yeast-two-hybrid and co-IP association and loss of binding after mutation of the Shank PDZ domain. The source partner is rat Shank Q9QX74; cellular functional corroboration includes mammalian expression and human T84 antisense experiments. This is domain-binding evidence, not proof of a native human binary affinity. supported_by: - reference_id: PMID:14679199 supporting_text: this interaction was abolished by mutations in the PDZ domain of Shank2 - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16203867 qualifier: enables review: summary: Retain CFTR association with the LPA-receptor regulatory complex. action: KEEP_AS_NON_CORE reason: Exact records separate CFTR/NHERF2 fragment pull-down from LPAR2-containing co-IP/crosslinking complexes. The association and receptor-dependent regulation are real source findings, but they do not confer receptor or scaffold activity on CFTR or establish all contacts as binary. supported_by: - reference_id: PMID:16203867 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16546175 qualifier: enables review: summary: Retain the calnexin association in the tested folding context. action: KEEP_AS_NON_CORE reason: The authentic abstract reports loss of the F508del-CFTR/calnexin interaction after miglustat treatment, alongside mutant rescue. Retain the experimentally curated association with explicit mutant/quality-control scope; do not generalize it into a constitutive mature-channel interaction or assign CFTR chaperone activity. supported_by: - reference_id: PMID:16546175 supporting_text: prevents delF508-CFTR/calnexin interaction - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16901789 qualifier: enables review: summary: Retain associations with the ER quality-control machinery. action: KEEP_AS_NON_CORE reason: Exact human 293T records support CFTR association with RNF5 and DERL1 under wild-type/mutant expression conditions. CFTR is a quality-control client; these associations do not establish intrinsic ubiquitin-ligase or retrotranslocase activity. supported_by: - reference_id: PMID:16901789 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17110338 qualifier: enables review: summary: Retain the actual source partner set rather than the title-level regulator alone. action: KEEP_AS_NON_CORE reason: The preserved six-partner set is supported by exact co-IP records, including endogenous human epithelial assays. The paper foregrounds proteostasis remodeling, but the original partners are not interchangeable with Aha1. Complex recovery is retained without claiming purified binary binding or a shared function for every partner. supported_by: - reference_id: PMID:17110338 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17244609 qualifier: enables review: summary: The measured terminal-peptide contacts are PDZ-domain binding. action: MODIFY reason: Exact surface-plasmon-resonance records test a GST CFTR C-terminal fragment against NHERF1 and rat Shank PDZ constructs. The direct domain-level interaction supports this refinement while fragment, tag and species limits remain explicit. supported_by: - reference_id: PMID:17244609 supporting_text: physical and physiological competition between EBP50-CFTR and Shank2-CFTR associations - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18555783 qualifier: enables review: summary: Retain BAP31 association during mutant-channel quality control. action: KEEP_AS_NON_CORE reason: Exact records include F508del CFTR and an N-terminal fragment in human expression systems. The association supports this non-core client-protein binding assertion, not a role for CFTR as an ER export factor. supported_by: - reference_id: PMID:18555783 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19465887 qualifier: enables review: summary: Retain USP19 association with the mutant quality-control substrate. action: KEEP_AS_NON_CORE reason: The normal cache omits relevant Results despite its full-text flag. Independently recovered original Results explicitly report Figure 5 co-IP of USP19 with GFP-F508del CFTR, separate from substrate-stabilization measurements. This supports a tagged mutant-containing complex, not a purified binary interface or universal mature wild-type association. supported_by: - reference_id: PMID:19465887 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19878303 qualifier: enables review: summary: Retain the source-scoped Hsc70 association. action: KEEP_AS_NON_CORE reason: The authentic abstract explicitly tests murine wild-type/F508del NBD1 with Hsc70 by surface plasmon resonance; the preserved partner is bovine Hsc70. Independent human CFTR chaperone-binding evidence supports the broad conserved association. This source is not presented as a full-length human-CFTR experiment. supported_by: - reference_id: PMID:19878303 supporting_text: F508del-murine (m)NBD1 binds Hsc70 with higher affinity - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21455491 qualifier: enables review: summary: The actual preserved partner is USP10. action: KEEP_AS_NON_CORE reason: Selected full Results and Figure 4A show CFTR co-IP with USP10 from early endosomes of human airway epithelial cells, reduced by Cif treatment. The seeded Q14694 pair is not CFTR binding to the bacterial Cif toxin. Retain complex association without calling the deubiquitinase activity CFTR intrinsic. supported_by: - reference_id: PMID:21455491 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21884936 qualifier: enables review: summary: GRASP55 binds the CFTR terminal PDZ-binding region. action: MODIFY reason: Exact fragment pull-down and HEK293 co-IP records resolve the GRASP55 PDZ domain and CFTR C terminus. The specific domain interaction is supported in the unconventional trafficking study; the channel itself is not assigned GRASP-mediated export machinery activity. supported_by: - reference_id: PMID:21884936 - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22038833 qualifier: enables review: summary: Retain the measured cytoskeletal associations. action: KEEP_AS_NON_CORE reason: Exact records support keratin-8 and actin association with wild-type/F508del CFTR in HeLa assays; direct SPR concerns keratin-8 and NBD1. These mixed assays support the original grouped binding assertion without converting co-IP into a purified actin interface or CFTR cytoskeletal-scaffold activity. supported_by: - reference_id: PMID:22038833 supporting_text: CFTR was immunoprecipitated from HeLa cells - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22121115 qualifier: enables review: summary: Retain SLC26A8 association and functional coupling. action: KEEP_AS_NON_CORE reason: The authentic abstract explicitly reports physical interaction and enhanced CFTR activity in oocyte/CHO expression assays, with mouse reproductive phenotypes. Retain the curated association while avoiding an unverified human-construct assignment based solely on the host cell. supported_by: - reference_id: PMID:22121115 supporting_text: 'TAT1 and CFTR physically interact' - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22768251 qualifier: enables review: summary: Retain calumenin association in the tested variant context. action: KEEP_AS_NON_CORE reason: Exact records support calumenin isoform 1 association with G551D CFTR in HeLa pull-down/co-IP assays; the authentic abstract additionally reports SPR. The reported folding-support hypothesis is not established as an intrinsic CFTR or calumenin catalytic mechanism by this association alone. supported_by: - reference_id: PMID:22768251 supporting_text: calumenin was present in the protein complex linked to G551D-CFTR - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25661196 qualifier: enables review: summary: Retain the SERCA2-containing CFTR complex. action: KEEP_AS_NON_CORE reason: Exact co-IP and proximity-ligation records in human airway-cell contexts support the preserved SERCA2 association. These are positive complex-level assays, not grounds to deny binding because calcium-pump regulation is discussed. They do not establish CFTR calcium-pump activity or a purified binary interface. supported_by: - reference_id: PMID:25661196 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25712891 qualifier: enables review: summary: Retain the actin association in wild-type and mutant expression contexts. action: KEEP_AS_NON_CORE reason: Exact records support actin recovery with CFTR in HeLa co-IP experiments. The source is appropriately retained as non-core association, without inferring that CFTR itself bundles actin or serves as a general cytoskeletal scaffold. supported_by: - reference_id: PMID:25712891 supporting_text: a higher amount of actin was bound onto G551D-CFTR than onto Wt-CFTR - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26618866 qualifier: enables review: summary: Human CFTR co-purifies with multiple proteins in wild-type, F508del and rescue/treatment contexts. action: KEEP_AS_NON_CORE reason: The original source is retained. PMID:26618866 uses anti-CFTR CoPIT in human bronchial epithelial cell lines, with CFTR-null and bead-only controls; complexes include indirect as well as direct associations. Exact publisher Table S1 contains 24 of the 31 original GOA partner accessions. Six further partners map through official human UniProt identities to CFTR-containing edges in Tables S7-S13 under temperature-shift, SAHA/TSA or HDAC7-depletion conditions; Q9P035 maps to HACD3/PTPLAD1, for which the main Results and Extended Data Figure 2 describe reciprocal co-IP. Therefore these are not 31 untreated wild-type binary interfaces. The heterogeneous partner set supports retained non-core protein association under the campaign instruction; it does not establish one narrower shared molecular activity. The original source object has no WITH field and is not backfilled. supported_by: - reference_id: PMID:26618866 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27092946 qualifier: enables review: summary: Retain CFTR association with KCa3.1. action: KEEP_AS_NON_CORE reason: Exact records include human-protein fragments in bacterial two-hybrid assays and co-IP from CFBE cells expressing wild-type or F508del CFTR. These support source-specific association; they do not make CFTR a potassium channel or establish a universal regulatory effect of KCa3.1. supported_by: - reference_id: PMID:27092946 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28360110 qualifier: enables review: summary: Retain the source-specific terminal-domain and complex associations. action: KEEP_AS_NON_CORE reason: The exact partner set includes PDZ-protein interactions and a channel-associated partner. Fragment fluorescence-polarization and complex assays have different resolution, so retain the grouped generic assertion rather than assign every partner a single PDZ interaction mechanism. supported_by: - reference_id: PMID:28360110 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29924966 qualifier: enables review: summary: Retain variant-dependent proteomic associations. action: KEEP_AS_NON_CORE reason: All 17 original partner accessions have exact positive source records in the ProVarA panel. Variant-dependent recoveries are not treated as independent wild-type positives, and pooled or feature-free records are not used to erase mutation context. supported_by: - reference_id: PMID:29924966 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0006695 label: cholesterol biosynthetic process evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: Retain the source-qualified upstream effect on cholesterol synthesis as non-core. action: KEEP_AS_NON_CORE reason: The preserved GOA qualifier is acts_upstream_of_or_within, also present on the mouse IMP donor. PMID:17085523 measures increased synthesis by deuterium incorporation/GC-MS after Cftr loss. This supports the broad upstream assertion, without assigning CFTR a sterol-synthetic reaction. The qualifier field now records the relationship already present in the preserved GOA. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:17085523 supporting_text: increased de novo cholesterol synthesis - reference_id: file:human/CFTR/CFTR-source-evidence.json qualifier: acts_upstream_of_or_within - term: id: GO:0030301 label: cholesterol transport evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: Retain the source-qualified upstream effect on cholesterol movement as non-core. action: KEEP_AS_NON_CORE reason: The preserved GOA and mouse donor use acts_upstream_of_or_within. PMID:17085523 reports abnormal cholesterol distribution and correction in cells expressing full-length wild-type CFTR. Retain that causal upstream scope; the molecular transport mechanism remains unresolved, and this is not evidence that CFTR translocates cholesterol through its pore. The qualifier field now records the relationship already present in the preserved GOA. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:17085523 supporting_text_fulltext: Correction of the cholesterol transport phenotype by expression of full-length CFTR in S9 cells - reference_id: file:human/CFTR/CFTR-source-evidence.json qualifier: acts_upstream_of_or_within - term: id: GO:0051649 label: establishment of localization in cell evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: The exact broad localization transfer remains unresolved. action: UNDECIDED reason: The original GOA qualifier is acts_upstream_of_or_within. Its historical Ensembl mapping to this broad localization term has not been reconstructed from the current mouse records. The cholesterol findings support upstream homeostasis but do not identify which localization assertion generated this transfer. Preserve the source while leaving that specific mapping unresolved; uncertainty is not limited to inaccessible publications. The qualifier field now records the relationship already present in the preserved GOA. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:17085523 - reference_id: file:human/CFTR/CFTR-source-evidence.json qualifier: acts_upstream_of_or_within - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29393851 qualifier: enables review: summary: Retain the ADGRG2-associated signaling complex. action: KEEP_AS_NON_CORE reason: Full Results show association in mouse efferent ductules and tagged HEK293 co-IP; beta-arrestin-1 is implicated in organizing the complex. This supports the original CFTR association without assigning the scaffolding activity to CFTR or treating mouse tissue as a human endogenous assay. supported_by: - reference_id: PMID:29393851 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23818989 qualifier: enables review: summary: Retain MARCH2 association through a trafficking complex. action: KEEP_AS_NON_CORE reason: Full Figure 7 and Results show HA-MARCH2 co-IP with GFP-CFTR in HEK293 cells, with terminal deletion affecting the interaction, and cellular colocalization. This is a supported substrate-containing complex; it does not confer ubiquitin-ligase activity on CFTR or resolve a purified binary MARCH2 interface. supported_by: - reference_id: PMID:23818989 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005254 label: chloride channel activity evidence_type: IDA original_reference_id: PMID:15010471 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: Oocyte channel measurements establish chloride permeation; the dynamic external-chloride selectivity interpretation belongs to this paper. supported_by: - reference_id: PMID:15010471 - reference_id: PMID:8910473 - term: id: GO:0005254 label: chloride channel activity evidence_type: IDA original_reference_id: PMID:19019741 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: Inside-out patches from BHK cells expressing human CFTR directly measure anion permeation. This paper finds stable selectivity under the tested conditions. supported_by: - reference_id: PMID:19019741 - reference_id: PMID:8910473 - term: id: GO:0005254 label: chloride channel activity evidence_type: IMP original_reference_id: PMID:19621064 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: Human CF airway-culture gene delivery restores chloride transport alongside epithelial fluid and sodium-transport phenotypes. supported_by: - reference_id: PMID:19621064 - reference_id: PMID:8910473 - term: id: GO:0005254 label: chloride channel activity evidence_type: IDA original_reference_id: PMID:11524016 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: The authentic primary abstract describes human CFTR channel and ATPase measurements; independent purified-protein evidence corroborates the activity. supported_by: - reference_id: PMID:11524016 - reference_id: PMID:8910473 - term: id: GO:0005260 label: intracellularly ATP-gated chloride channel activity evidence_type: IMP original_reference_id: PMID:8910473 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: Purified, reconstituted CFTR directly hydrolyzes ATP in a gating-coupled system. supported_by: - reference_id: PMID:8910473 - reference_id: PMID:8910473 - term: id: GO:0005254 label: chloride channel activity evidence_type: IDA original_reference_id: PMID:11707463 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: The source reports CFTR channel activity in its CAL/PDZ trafficking context; the partner-centered title does not negate the target functional assay. supported_by: - reference_id: PMID:11707463 - reference_id: PMID:8910473 - term: id: GO:0005254 label: chloride channel activity evidence_type: IMP original_reference_id: PMID:24885604 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: Full human/mouse beta-cell Results measure cAMP-dependent currents and their sensitivity to CFTR antagonists; pharmacological attribution is distinguished from a purified pore assay. supported_by: - reference_id: PMID:24885604 - reference_id: PMID:8910473 - term: id: GO:0005254 label: chloride channel activity evidence_type: IDA original_reference_id: PMID:18570918 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: The authentic recycling study supports channel function at the apical membrane alongside localization and trafficking measurements. supported_by: - reference_id: PMID:18570918 - reference_id: PMID:8910473 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19289574 qualifier: enables review: summary: Retain SLC26A9 co-association and functional coupling. action: KEEP_AS_NON_CORE reason: Selected full Results support co-IP and CFTR-dependent SLC26A9 conductance in expression systems. ER retention is offered as a possible explanation, not directly established. Association is not treated as a purified binary interaction or as evidence about ENaC. supported_by: - reference_id: PMID:19289574 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20658517 qualifier: enables review: summary: Retain the airway-cell SLC26A9 association. action: KEEP_AS_NON_CORE reason: The authentic abstract explicitly reports co-IP and apical functional association in bronchial epithelia. This corroborates a contextual channel complex, without assigning CFTR an intrinsic exchanger mechanism. supported_by: - reference_id: PMID:20658517 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005254 label: chloride channel activity evidence_type: IDA original_reference_id: PMID:22178883 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: The authentic abstract reports CFTR current and TMEM16A coupling; this supports CFTR channel activity without attributing all calcium-activated current to CFTR. supported_by: - reference_id: PMID:22178883 - reference_id: PMID:8910473 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22178883 qualifier: enables review: summary: Retain TMEM16A association in its measured regulatory context. action: KEEP_AS_NON_CORE reason: The authentic abstract reports co-IP and suppression of calcium-activated TMEM16A currents by CFTR. This is partner-specific complex/coupling evidence, not sodium-channel regulation or proof of an isolated binary interface. supported_by: - reference_id: PMID:22178883 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11707463 qualifier: enables review: summary: The CAL interaction is specifically PDZ-domain binding. action: MODIFY reason: The authentic source reports interaction between the CFTR terminal motif and the CAL/GOPC PDZ domain. This supports the more precise domain-binding activity already independently demonstrated for CFTR; preserve the source IPI assertion. supported_by: - reference_id: PMID:11707463 supporting_text: The PDZ domain of CAL binds to the C terminus of CFTR - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:15247260 qualifier: enables review: summary: Retain the human epithelial endocytic complex associations. action: KEEP_AS_NON_CORE reason: The authentic source reports CFTR in a complex with Dab2 and myosin VI in polarized Calu-3 cells. Co-complex recovery supports the grouped binding assertion; the motor and adaptor activities belong to the partners. supported_by: - reference_id: PMID:15247260 supporting_text: formed a complex with myosin VI - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005260 label: intracellularly ATP-gated chloride channel activity evidence_type: NAS original_reference_id: PMID:11707463 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: The NAS statement agrees with independently measured ATP-regulated CFTR conductance; the original citation is preserved without upgrading its evidence code. supported_by: - reference_id: PMID:11707463 - reference_id: PMID:8910473 - term: id: GO:0005254 label: chloride channel activity evidence_type: TAS original_reference_id: PMID:9931011 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: The original TAS channel statement is independently established by purified CFTR and human epithelial experiments; it is not treated as a new direct assay in this citation. supported_by: - reference_id: PMID:9931011 - reference_id: PMID:8910473 - term: id: GO:0005260 label: intracellularly ATP-gated chloride channel activity evidence_type: TAS original_reference_id: PMID:10581360 qualifier: enables review: summary: Retain the experimentally supported CFTR channel function. action: ACCEPT reason: The authentic NBD study supports differential nucleotide-domain contributions to CFTR gating, consistent with independent purified-channel evidence. supported_by: - reference_id: PMID:10581360 - reference_id: PMID:8910473 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31324722 qualifier: enables review: summary: Retain condition- and variant-dependent interactome recovery. action: KEEP_AS_NON_CORE reason: All 19 original partners join exact positive records from tagged CFTR proteomics in CFBE41o cells. Wild-type, rescued F508del and mutant-selective recovery are distinguished; CAPN1 is not promoted to a universal wild-type interaction. These are co-complex assays rather than purified binary affinities. supported_by: - reference_id: PMID:31324722 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35156780 qualifier: enables review: summary: Human wild-type and F508del CFTR show construct-dependent MaMTH associations with the original partner set. action: KEEP_AS_NON_CORE reason: 'The genuine publisher Dataset EV4 contains all 94 original GOA partner accessions with its MaMTH detection flag positive, and all 94 match the actual Dataset EV2 ORF/replicate rows: 32 wild-type-only, 44 F508del-only and 18 shared. The assay uses full-length human CFTR with C-terminal Cub-GAL4TF-P2A-tagBFP and N-terminal Nub-tagged human ORFeome preys in HEK293 reporters. These are cellular reporter associations, not purified binary affinities or proof of all endogenous tissues/isoforms. Dataset EV5 and Table EV2 independently within the same paper report mixed retest/co-IP outcomes; an HTS detection must not be described as universal orthogonal validation. Imported/predicted IID-only edges are excluded from this target support. Retain non-core association without forcing a single partner-class refinement across this diverse group.' supported_by: - reference_id: PMID:35156780 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0140359 label: ABC-type transporter activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: CFTR is not a primary-active ABC transporter under this term definition. action: REMOVE reason: Current GO:0140359 requires transport powered directly by ATP hydrolysis. Human CFTR instead uses ATP-dependent gating while anions move down an electrochemical gradient. This target-specific functional divergence challenges the inherited activity, not the family membership or number of PAINT donors; the historical node was not reconstructed. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:8910473 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json propagation_review: root_cause: PROPAGATION_BAD failure_modes: - FUNCTIONAL_DIVERGENCE source_entities: - source_id: PANTHER:PTN009085477 source_status: UNRESOLVED comment: The literal historical PAINT node is preserved; full IBD placement/alignment was not reconstructed. Target-specific passive CFTR conduction contradicts the primary-active-transport requirement, independently of donor count. - term: id: GO:0005886 label: plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Plasma-membrane localization supports the core channel role. action: ACCEPT reason: The PAINT location agrees with direct human epithelial localization and transport. No ancestral-node reconstruction or donor-count argument is required to recognize this independently established target location. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0016323 label: basolateral plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Basolateral association is supported in a specific epithelial context. action: KEEP_AS_NON_CORE reason: The authentic PMID:1720311 abstract reports human sweat-duct staining predominantly apically but also near the basolateral membrane using two CFTR peptide antibodies. Predominant apical function does not refute the broader IBA location. Preserve the historical source while keeping tissue and spatial-resolution limits explicit; no universal basolateral distribution is asserted. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:1720311 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0006833 label: water transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: CFTR contributes to epithelial water movement through ion transport. action: KEEP_AS_NON_CORE reason: Human airway rescue supports fluid homeostasis coupled to CFTR-mediated salt transport. Retain the broad existing biological process without claiming that the CFTR pore itself is an aquaporin or that water conduction was directly measured through the protein. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:19621064 - term: id: GO:0015701 label: bicarbonate transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Bicarbonate movement is a core channel process. action: ACCEPT reason: Human CFTR directly conducts bicarbonate in inside-out patch measurements. This positive target evidence supports the PAINT process without equating the inherited assertion with a freshly reconstructed ancestral node. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:19019741 - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: CFTR directly performs chloride transmembrane transport. action: ACCEPT reason: The pore carries chloride; it is not merely a substrate required by another chloride transporter. Purified and epithelial measurements support the conserved process. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:8910473 - reference_id: PMID:19621064 - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Cytosolic CFTR species occur during quality control. action: KEEP_AS_NON_CORE reason: The retained broad location is supported by retrotranslocation and cytosolic deglycosylated CFTR described in the Sec61 study. Cytosolic domains of an intact membrane protein alone would not establish this location. The PAINT history remains distinct from the independent trafficking evidence. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:9792704 - term: id: GO:0016324 label: apical plasma membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Apical plasma membrane is a principal site of channel activity. action: ACCEPT reason: Direct human epithelial localization and functional rescue support the PAINT location. Tissue-specific additional pools do not negate this major active compartment. supported_by: - reference_id: GO_REF:0000033 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: ATP binding is intrinsic to CFTR gating. action: ACCEPT reason: The electronic inference agrees with nucleotide-dependent gating and ATPase experiments. Binding and hydrolysis are distinct but both supported; no active-anion-pump mechanism follows. supported_by: - reference_id: GO_REF:0000120 - reference_id: PMID:8910473 - reference_id: PMID:11524016 - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Nuclear localization has a processed-product/ortholog context. action: KEEP_AS_NON_CORE reason: Full rat primary Methods/Results show Sertoli nuclear immunofluorescence, peptide-blocking and independent-antibody controls, and an approximately 85-kDa nuclear fraction band. The authors propose a processed CFTR fragment; nuclear gene regulation is untested. Retain this unscoped source conservatively as non-core ortholog/product context, not evidence that intact human CFTR is a nuclear anion channel. supported_by: - reference_id: GO_REF:0000044 - reference_id: PMID:29453757 supporting_text_fulltext: the nuclear fraction showed a very strong band - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Retain the broad cytoplasmic compartment as a non-core cellular pool. action: KEEP_AS_NON_CORE reason: The original electronic compartment is compatible with CFTR biosynthetic, endosomal and degradation-associated intracellular pools. It does not localize the intact active pore freely in cytosol or infer activity merely from exposed cytoplasmic domains. supported_by: - reference_id: GO_REF:0000117 - reference_id: PMID:9792704 - reference_id: PMID:18570918 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: CFTR occupies the ER membrane during biosynthesis and quality control. action: KEEP_AS_NON_CORE reason: This source location is consistent with folding, retention and ER-associated degradation of CFTR, including F508del. It is a trafficking/quality-control compartment distinct from the principal epithelial surface activity. supported_by: - reference_id: GO_REF:0000044 - reference_id: PMID:11707463 - reference_id: PMID:9792704 - term: id: GO:0005886 label: plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: The combined electronic plasma-membrane location is correct. action: ACCEPT reason: Human localization and electrophysiology independently place functional CFTR at the cell surface. Preserve the original mapping without claiming every cellular pool is surface active. supported_by: - reference_id: GO_REF:0000120 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0006811 label: monoatomic ion transport evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Ion transport is a correct broad description of the core channel process. action: ACCEPT reason: CFTR directly moves chloride and bicarbonate across membranes. The broad electronic process is supported alongside its more specific source annotations. supported_by: - reference_id: GO_REF:0000120 - reference_id: PMID:19019741 - term: id: GO:0006821 label: chloride transport evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Chloride transport is directly performed by CFTR. action: ACCEPT reason: The channel mediates chloride flux; hydrolysis controls gating rather than providing uphill transport energy. supported_by: - reference_id: GO_REF:0000120 - reference_id: PMID:8910473 - reference_id: PMID:19621064 - term: id: GO:0015701 label: bicarbonate transport evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: The bicarbonate-transport inference agrees with direct target experiments. action: ACCEPT reason: Human CFTR bicarbonate permeation is directly resolved in membrane-patch assays. The ARBA source is retained without manufacturing a separate mechanistic donor chain. supported_by: - reference_id: GO_REF:0000117 - reference_id: PMID:19019741 - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: located_in review: summary: Membrane insertion is integral to the channel function. action: ACCEPT reason: The InterPro membrane assertion agrees with the genuine multipass UniProt record and functional membrane-reconstituted CFTR. Membrane association is not inferred solely from a partner. supported_by: - reference_id: GO_REF:0000002 - reference_id: PMID:8910473 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0016324 label: apical plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Apical localization is independently established. action: ACCEPT reason: Human epithelial localization and CF airway surface rescue support the combined electronic location, with tissue-dependent distribution acknowledged. supported_by: - reference_id: GO_REF:0000120 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0016853 label: isomerase activity evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: enables review: summary: Use the specific ATP-hydrolysis activity within the valid EC classification. action: MODIFY reason: GO:0016853 explicitly includes EC class 5 enzymes, and EC 5.6.1.6 classifies CFTR ATP-dependent conformational control. Thus the old broad isomerase mapping is not fabricated or biologically impossible. ATP hydrolysis is the experimentally measured, more informative molecular activity; passive ion flow remains distinct from pumping. supported_by: - reference_id: GO_REF:0000043 - reference_id: PMID:8910473 - reference_id: PMID:11524016 - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0016887 label: ATP hydrolysis activity - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: CFTR directly hydrolyzes ATP. action: ACCEPT reason: Purified reconstituted CFTR measurements establish the catalytic activity. Its purpose here is conformational gating, not chemical transformation of chloride or primary active anion transport. supported_by: - reference_id: GO_REF:0000120 - reference_id: PMID:8910473 - reference_id: PMID:11524016 - term: id: GO:0031901 label: early endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Early-endosome membrane is a recycling compartment for CFTR. action: KEEP_AS_NON_CORE reason: The original location mapping agrees with the USP10 and Cif trafficking studies. CFTR is the membrane cargo regulated in these experiments, not the deubiquitinase. supported_by: - reference_id: GO_REF:0000044 - reference_id: PMID:19398555 - reference_id: PMID:21455491 - term: id: GO:0034220 label: monoatomic ion transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Ion movement across a membrane is the core transport process. action: ACCEPT reason: Chloride and bicarbonate permeation through the CFTR pore supports this broad electronic term; the direction follows electrochemical conditions. supported_by: - reference_id: GO_REF:0000120 - reference_id: PMID:19019741 - term: id: GO:0034707 label: chloride channel complex evidence_type: IEA original_reference_id: GO_REF:0000043 qualifier: part_of review: summary: CFTR is a functional component of chloride-channel assemblies. action: ACCEPT reason: The keyword-derived complex term is concordant with membrane CFTR and documented regulatory complexes. It does not require an unverified fixed oligomeric stoichiometry or make all recovered partners obligatory pore subunits. supported_by: - reference_id: GO_REF:0000043 - reference_id: PMID:8910473 - reference_id: PMID:11707463 - term: id: GO:0055038 label: recycling endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Recycling-endosome membrane is a supported trafficking location. action: KEEP_AS_NON_CORE reason: The endosomal SNARE and USP10 studies support CFTR cycling through recycling compartments. The original location does not assign recycling-machinery activity to the cargo. supported_by: - reference_id: GO_REF:0000044 - reference_id: PMID:18570918 - reference_id: PMID:19398555 - term: id: GO:0055085 label: transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: The broad transmembrane-transport process is correct. action: ACCEPT reason: The membrane pore directly performs anion translocation. This broad process is compatible with passive channel conductance and does not inherit an ATP-driven pump mechanism from the ABC fold. supported_by: - reference_id: GO_REF:0000002 - reference_id: PMID:19019741 - term: id: GO:0098660 label: obsolete inorganic ion transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Retain the ion-transport meaning with the current supported process term. action: MODIFY reason: The official current response marks the original ID obsolete, but the original machine term is preserved. Independently measured monatomic-ion movement supports GO:0034220; this is a semantic update, not evidence that CFTR lacks the old process. supported_by: - reference_id: GO_REF:0000117 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0034220 label: monoatomic ion transmembrane transport - term: id: GO:0140359 label: ABC-type transporter activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: The ABC-family domain mapping overextends to primary active transport. action: REMOVE reason: IPR011527 supports ABC-family architecture; the current GO activity additionally requires ATP-powered primary active transport. CFTR-specific passive conduction with ATP-dependent gating fails that mechanistic requirement. Retain the original domain/source fields while rejecting this activity inference. supported_by: - reference_id: GO_REF:0000002 - reference_id: PMID:8910473 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36012204 qualifier: enables review: summary: The source reports CFTR-centered proximity labeling, which does not by itself resolve the original protein-binding assertion. action: UNDECIDED reason: PMID:36012204 uses N-terminal APEX2/TurboID-CFTR in transfected human HEK293 cells, including wild-type, G551D and W1282X/truncated constructs. The central exact IntAct join recovers 148 positive records for 66 of the 70 original GOA partners, but every matched record is explicitly MI:1314 proximity-dependent biotin identification with MI:2364 proximity. The full primary Discussion states that the method also labels noninteracting nearby proteins. This is an assay-resolution uncertainty, not absence of target data or proof that these proteins cannot bind. The four unmatched accessions are O60869, O75127, P07099 and P60709; an empty query result is not negative evidence. Preserve all original assertions and source fields, keep the positive proximity findings, and leave the source-specific binding claim unresolved. Independent binding evidence from other publications remains separately valid and is not silently substituted for this paper. supported_by: - reference_id: PMID:36012204 supporting_text: both direct binding partners and proximal non-interacting proteins - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:39009827 qualifier: enables review: summary: Retain engineered fragment-level positive interactions. action: KEEP_AS_NON_CORE reason: Exact positive records concern a CFTR peptide with an engineered CASK kinase-domain construct and a separate CFTR peptide/PTBP1 RRM experiment with mutation features. These support contextual binding capability, not intact wild-type CFTR association with both partners in native cells; no partner enzymatic or RNA-binding activity is transferred. supported_by: - reference_id: PMID:39009827 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9671706 qualifier: enables review: summary: The CFTR C-terminal sequence directly engages an NHERF PDZ domain. action: MODIFY reason: Full Results and Figure 4 show terminal-fusion overlays and in-vitro translated full-length CFTR binding to NHERF; N-terminal and truncated-terminal controls distinguish the site. This directly supports PDZ-domain binding rather than generic binding alone. supported_by: - reference_id: PMID:9671706 supporting_text: NHERF also binds to the tail of the cystic fibrosis transmembrane conductance regulator - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0030165 label: PDZ domain binding - term: id: GO:0055085 label: transmembrane transport evidence_type: TAS original_reference_id: Reactome:R-HSA-382556 qualifier: involved_in review: summary: Retain transmembrane transport with the CFTR channel mechanism. action: ACCEPT reason: The Reactome parent pathway broadly describes ABC transporters. Its generic active-transport prose is not evidence that CFTR pumps anions; independent CFTR pore measurements establish the sound broad transport annotation. supported_by: - reference_id: Reactome:R-HSA-382556 - reference_id: PMID:19019741 - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Retain the orthology-based cytosolic quality-control pool. action: KEEP_AS_NON_CORE reason: The source is a mouse transfer, not an independent human localization assay. Human CFTR retrotranslocation and deglycosylated cytosolic species support the broad location; exposed domains alone are not the rationale. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:9792704 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0015106 label: bicarbonate transmembrane transporter activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Specify bicarbonate movement by a channel. action: MODIFY reason: The preserved mouse-derived transporter annotation has a correct transported ion. Direct human CFTR patch assays establish a conductive pore rather than a bicarbonate pump or exchanger, supporting the more precise activity. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0160133 label: bicarbonate channel activity - term: id: GO:0015108 label: chloride transmembrane transporter activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Chloride transmembrane transport activity is correct. action: ACCEPT reason: The mouse-derived broad activity agrees with direct human channel assays. The original source remains untouched; passive channel conduction supplies the molecular mechanism. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0048240 label: sperm capacitation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Retain the reproductive context of CFTR-dependent sperm capacitation. action: KEEP_AS_NON_CORE reason: The source transfer is grounded in mouse CFTR-dependent chloride/pH/electrical responses during capacitation. The accessed primary material reports pharmacological perturbations and transporter cooperation, not a human purified assay or an additional autonomous sperm-development mechanism. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:21976599 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0051454 label: intracellular pH elevation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Retain the sperm-context intracellular alkalinization role. action: KEEP_AS_NON_CORE reason: The mouse source links CFTR-dependent anion handling to capacitation-associated pH change. Keep the physiological process as a contextual consequence of channel participation; this does not establish direct proton transport through CFTR or universal pH regulation in every compartment. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:21976599 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0060081 label: membrane hyperpolarization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Retain context-dependent membrane hyperpolarization. action: KEEP_AS_NON_CORE reason: Selected mouse primary Discussion reports reduced capacitation-associated hyperpolarization after CFTR inhibition alongside chloride-pathway interactions. The channel can contribute to an electrical response without becoming the sole voltage-determining transporter. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:21976599 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0070175 label: positive regulation of enamel mineralization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Retain the mouse-supported enamel mineralization role. action: KEEP_AS_NON_CORE reason: Full mouse knockout Methods/Results measure hypomineralized incisors and altered chloride, sodium and potassium profiles, with fluoride context. This supports the transferred enamel process while CFTR remains an anion channel, not a calcium transporter or mineral-deposition enzyme. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:26403673 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0071320 label: cellular response to cAMP evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: cAMP-dependent channel regulation is a core cellular response. action: ACCEPT reason: PKA-dependent CFTR phosphorylation and gating connect elevated cAMP to anion conductance. This is a channel response to signaling, not intrinsic adenylate-cyclase or kinase activity. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:15010471 - reference_id: PMID:19621064 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0097186 label: amelogenesis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Retain the developmental enamel context. action: KEEP_AS_NON_CORE reason: The source mouse knockout and elemental/ultrastructural readouts support CFTR participation in enamel physiology. Preserve the IEA/ISS provenance and avoid upgrading the mouse result to a direct human ameloblast assay. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:26403673 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Retain the conserved chloride-transport process. action: ACCEPT reason: The orthology-based assertion is independently supported by human CFTR electrophysiology and epithelial transport. The donor fields are preserved rather than replaced with a new evidence code. supported_by: - reference_id: GO_REF:0000107 - reference_id: PMID:19019741 - reference_id: PMID:19621064 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: IDA original_reference_id: PMID:22006324 qualifier: involved_in review: summary: The target chloride-transport assertion remains supported. action: ACCEPT reason: The ANO6-focused authentic abstract also reports CFTR-related transport measurements. Do not reject a target assay merely because another channel is foregrounded; independent CFTR electrophysiology confirms the same process. supported_by: - reference_id: PMID:22006324 - reference_id: PMID:19019741 - term: id: GO:0071889 label: 14-3-3 protein binding evidence_type: EXP original_reference_id: PMID:26888287 qualifier: enables review: summary: Retain phosphorylation-dependent 14-3-3 association. action: KEEP_AS_NON_CORE reason: Full primary peptide-binding, structural and mutational results establish CFTR regulatory-region engagement by 14-3-3. Assays use phosphorylated fragments and engineered crystallographic linkers as specified; beta binding is distinguished from zeta/gamma structures. The activity is an ancillary trafficking/regulatory contact, not CFTR adaptor catalysis. supported_by: - reference_id: PMID:26888287 - term: id: GO:0071889 label: 14-3-3 protein binding evidence_type: IMP original_reference_id: PMID:26888287 qualifier: enables review: summary: Retain phosphorylation-dependent 14-3-3 association. action: KEEP_AS_NON_CORE reason: Full primary peptide-binding, structural and mutational results establish CFTR regulatory-region engagement by 14-3-3. Assays use phosphorylated fragments and engineered crystallographic linkers as specified; beta binding is distinguished from zeta/gamma structures. The activity is an ancillary trafficking/regulatory contact, not CFTR adaptor catalysis. supported_by: - reference_id: PMID:26888287 supporting_text: The key binding site of CFTR (pS768) occupies one groove - term: id: GO:0071889 label: 14-3-3 protein binding evidence_type: IPI original_reference_id: PMID:26888287 qualifier: enables review: summary: Retain phosphorylation-dependent 14-3-3 association. action: KEEP_AS_NON_CORE reason: Full primary peptide-binding, structural and mutational results establish CFTR regulatory-region engagement by 14-3-3. Assays use phosphorylated fragments and engineered crystallographic linkers as specified; beta binding is distinguished from zeta/gamma structures. The activity is an ancillary trafficking/regulatory contact, not CFTR adaptor catalysis. supported_by: - reference_id: PMID:26888287 - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:32487539 qualifier: located_in review: summary: The apical location is correct in the human epithelial context. action: ACCEPT reason: Retain the experimental source location, independently corroborated by human CFTR localization and surface-rescue studies. The source is not discarded because its broader physiological topic differs from channel biophysics. supported_by: - reference_id: PMID:32487539 - reference_id: PMID:28130590 - reference_id: PMID:19621064 - term: id: GO:0070175 label: positive regulation of enamel mineralization evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Retain the mouse-supported enamel mineralization role. action: KEEP_AS_NON_CORE reason: Full mouse knockout Methods/Results measure hypomineralized incisors and altered chloride, sodium and potassium profiles, with fluoride context. This supports the transferred enamel process while CFTR remains an anion channel, not a calcium transporter or mineral-deposition enzyme. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:26403673 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0097186 label: amelogenesis evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Retain the developmental enamel context. action: KEEP_AS_NON_CORE reason: The source mouse knockout and elemental/ultrastructural readouts support CFTR participation in enamel physiology. Preserve the IEA/ISS provenance and avoid upgrading the mouse result to a direct human ameloblast assay. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:26403673 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Retain the conserved chloride-transport process. action: ACCEPT reason: The orthology-based assertion is independently supported by human CFTR electrophysiology and epithelial transport. The donor fields are preserved rather than replaced with a new evidence code. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:19019741 - reference_id: PMID:19621064 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0017081 label: chloride channel regulator activity evidence_type: TAS original_reference_id: Reactome:R-HSA-383190 qualifier: enables review: summary: Retain contextual regulation of another chloride conductance. action: KEEP_AS_NON_CORE reason: The original Reactome summary mainly describes CFTR bicarbonate/channel activity and does not itself resolve ORCC or ClC regulation. Independent SLC26A9 co-IP and functional coupling support a bounded regulatory role. Its proposed ER-retention explanation remains hypothetical; no general regulation of every chloride channel is asserted. supported_by: - reference_id: Reactome:R-HSA-383190 - reference_id: PMID:19289574 - reference_id: PMID:20658517 - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IDA original_reference_id: PMID:11524016 qualifier: enables review: summary: Retain directly assayed ATP hydrolysis. action: ACCEPT reason: The authentic human CFTR primary study measures ATPase activity alongside channel behavior. This is enzyme activity in the gating cycle, not ATP-driven solute pumping. supported_by: - reference_id: PMID:11524016 supporting_text: purified, reconstituted CFTR monomers are sufficient to mediate regulated chloride conduction and ATPase activity - reference_id: PMID:8910473 - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IDA original_reference_id: PMID:8910473 qualifier: enables review: summary: Purified reconstituted CFTR directly hydrolyzes ATP. action: ACCEPT reason: The original experiment measures ATP turnover by purified CFTR and relates it to gating. Preserve the IDA assertion and distinguish hydrolysis from passive anion permeation. supported_by: - reference_id: PMID:8910473 supporting_text: ATP hydrolysis by purified, reconstituted CFTR - term: id: GO:0015108 label: chloride transmembrane transporter activity evidence_type: TAS original_reference_id: Reactome:R-HSA-5678822 qualifier: enables review: summary: The normal chloride-transport activity remains correct despite disease-event context. action: ACCEPT reason: The source event describes defective CFTR failure to transport chloride, so it is variant/pathway provenance rather than a positive wild-type assay. Independent human CFTR measurements establish the retained activity; do not attribute normal transport to the defective variant. supported_by: - reference_id: Reactome:R-HSA-5678822 - reference_id: PMID:19019741 - term: id: GO:0015108 label: chloride transmembrane transporter activity evidence_type: TAS original_reference_id: Reactome:R-HSA-5678863 qualifier: enables review: summary: The Reactome chloride-conduction event matches the core activity. action: ACCEPT reason: The curated event models wild-type CFTR chloride movement. Independent electrophysiology supports its channel mechanism without interpreting CFTR as a primary-active transporter. supported_by: - reference_id: Reactome:R-HSA-5678863 - reference_id: PMID:19019741 - term: id: GO:0043225 label: obsolete ATPase-coupled inorganic anion transmembrane transporter activity evidence_type: TAS original_reference_id: Reactome:R-HSA-1454916 qualifier: enables review: summary: Replace the pump-like activity with the experimentally supported ATP-gated channel. action: MODIFY reason: The original Reactome parent describes broad MRP organic-anion transport and does not demonstrate a CFTR ATPase-driven anion pump. CFTR hydrolysis controls gating while anions flow passively. The official obsolete source ID is preserved; the replacement corrects the functional mechanism rather than simply reacting to obsolescence. supported_by: - reference_id: Reactome:R-HSA-1454916 - reference_id: PMID:8910473 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0005260 label: intracellularly ATP-gated chloride channel activity - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868658 qualifier: located_in review: summary: Retain the endocytic-vesicle membrane location. action: KEEP_AS_NON_CORE reason: The selected Reactome record places CFTR-containing membrane cargo in HSPA8-mediated uncoating. This is its own curated event/complex provenance, not a separate localization experiment for each row. The location is compatible with endocytosis; the enzyme or mechanical work named by the event is not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8868658 - reference_id: PMID:19398555 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868659 qualifier: located_in review: summary: Retain the endocytic-vesicle membrane location. action: KEEP_AS_NON_CORE reason: The selected Reactome record places CFTR-containing membrane cargo in auxilin recruitment. This is its own curated event/complex provenance, not a separate localization experiment for each row. The location is compatible with endocytosis; the enzyme or mechanical work named by the event is not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8868659 - reference_id: PMID:19398555 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868660 qualifier: located_in review: summary: Retain the endocytic-vesicle membrane location. action: KEEP_AS_NON_CORE reason: The selected Reactome record places CFTR-containing membrane cargo in ATP-dependent HSPA8 association. This is its own curated event/complex provenance, not a separate localization experiment for each row. The location is compatible with endocytosis; the enzyme or mechanical work named by the event is not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8868660 - reference_id: PMID:19398555 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868661 qualifier: located_in review: summary: Retain the endocytic-vesicle membrane location. action: KEEP_AS_NON_CORE reason: The selected Reactome record places CFTR-containing membrane cargo in dynamin-dependent vesicle scission. This is its own curated event/complex provenance, not a separate localization experiment for each row. The location is compatible with endocytosis; the enzyme or mechanical work named by the event is not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8868661 - reference_id: PMID:19398555 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8869438 qualifier: located_in review: summary: Retain the endocytic-vesicle membrane location. action: KEEP_AS_NON_CORE reason: The selected Reactome record places CFTR-containing membrane cargo in clathrin-coat dissociation. This is its own curated event/complex provenance, not a separate localization experiment for each row. The location is compatible with endocytosis; the enzyme or mechanical work named by the event is not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8869438 - reference_id: PMID:19398555 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8871193 qualifier: located_in review: summary: Retain the endocytic-vesicle membrane location. action: KEEP_AS_NON_CORE reason: The selected Reactome record places CFTR-containing membrane cargo in AAK1/AP2-associated uncoating. This is its own curated event/complex provenance, not a separate localization experiment for each row. The location is compatible with endocytosis; the enzyme or mechanical work named by the event is not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8871193 - reference_id: PMID:19398555 - term: id: GO:0030669 label: clathrin-coated endocytic vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8871194 qualifier: located_in review: summary: Retain the endocytic-vesicle membrane location. action: KEEP_AS_NON_CORE reason: The selected Reactome record places CFTR-containing membrane cargo in RAB5/GAPVD1-associated uncoating. This is its own curated event/complex provenance, not a separate localization experiment for each row. The location is compatible with endocytosis; the enzyme or mechanical work named by the event is not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8871194 - reference_id: PMID:19398555 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:28067262 qualifier: located_in review: summary: CFTR reaches the plasma membrane in the tested trafficking context. action: ACCEPT reason: The authentic source reports stress-linked surface trafficking; independent human CFTR surface function supports the same location. Preserve the original IDA without equating unconventional export with an intrinsic CFTR transport-machinery activity. supported_by: - reference_id: PMID:28067262 - reference_id: PMID:19621064 - term: id: GO:0034976 label: response to endoplasmic reticulum stress evidence_type: IDA original_reference_id: PMID:28067262 qualifier: involved_in review: summary: Retain the documented stress-responsive channel-trafficking context. action: KEEP_AS_NON_CORE reason: The source examines CFTR redistribution under ER-stress/unconventional secretion conditions. Retain this existing response annotation with cargo context; it does not establish CFTR as an ER stress sensor, transcription factor or export catalyst. supported_by: - reference_id: PMID:28067262 - reference_id: PMID:21884936 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:21884936 qualifier: located_in review: summary: The trafficking study supports surface localization of CFTR. action: ACCEPT reason: GRASP-dependent export places CFTR at the plasma membrane, where channel activity is independently established. The source is retained without attributing GRASP adaptor activity to the cargo. supported_by: - reference_id: PMID:21884936 - term: id: GO:0034976 label: response to endoplasmic reticulum stress evidence_type: IDA original_reference_id: PMID:21884936 qualifier: involved_in review: summary: Retain the ER-stress-linked trafficking response. action: KEEP_AS_NON_CORE reason: The source reports GRASP-associated unconventional export under ER-to-Golgi blockade/stress conditions. CFTR is a responding channel/cargo, not established as the upstream UPR sensor; no new general stress-pathway assertion is added. supported_by: - reference_id: PMID:21884936 - term: id: GO:0106138 label: Sec61 translocon complex binding evidence_type: IDA original_reference_id: PMID:9792704 qualifier: enables review: summary: Retain association with the Sec61 translocon complex. action: KEEP_AS_NON_CORE reason: The authentic source reports membrane CFTR in a complex with Sec61 during retrotranslocation/quality control. This is a specific client-complex association, not evidence that CFTR itself constitutes a protein-translocation pore. supported_by: - reference_id: PMID:9792704 - term: id: GO:0051087 label: protein-folding chaperone binding evidence_type: IPI original_reference_id: PMID:16207813 qualifier: enables review: summary: Retain directly supported chaperone binding. action: KEEP_AS_NON_CORE reason: Selected full source describes human CFTR NBD1 peptide recognition by purified Hsc70 and BAG-2 in a folding-quality-control context. CFTR is the client; the chaperone activity belongs to the binding proteins. supported_by: - reference_id: PMID:16207813 - term: id: GO:0005634 label: nucleus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Retain the rat-supported nuclear processed-product context. action: KEEP_AS_NON_CORE reason: Full rat primary Methods/Results show Sertoli nuclear immunofluorescence, peptide-blocking and independent-antibody controls, and an approximately 85-kDa nuclear fraction band. The authors propose a processed CFTR fragment; nuclear gene regulation is untested. Retain this unscoped source conservatively as non-core ortholog/product context, not evidence that intact human CFTR is a nuclear anion channel. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:29453757 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:28130590 qualifier: located_in review: summary: Retain CFTR localization in human epithelial membranes. action: ACCEPT reason: The authentic primary abstract explicitly reports human epidermal/eccrine CFTR localization. This supports the preserved plasma/apical location without requiring every tissue to have identical polarity. supported_by: - reference_id: PMID:28130590 - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:28130590 qualifier: located_in review: summary: Retain CFTR localization in human epithelial membranes. action: ACCEPT reason: The authentic primary abstract explicitly reports human epidermal/eccrine CFTR localization. This supports the preserved plasma/apical location without requiring every tissue to have identical polarity. supported_by: - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:15010471 qualifier: located_in review: summary: The functional expression assay supports plasma-membrane CFTR. action: ACCEPT reason: Oocyte electrophysiology establishes functional membrane expression. This does not resolve an endogenous human tissue distribution, which is independently supported by human localization studies. supported_by: - reference_id: PMID:15010471 - reference_id: PMID:28130590 - term: id: GO:0015106 label: bicarbonate transmembrane transporter activity evidence_type: IDA original_reference_id: PMID:15010471 qualifier: enables review: summary: Specify a bicarbonate-conducting channel. action: MODIFY reason: The source measures CFTR chloride/bicarbonate permeation in oocytes and proposes dynamic selectivity. Independent human-CFTR BHK patches establish direct bicarbonate conduction while reporting invariant selectivity under their tested conditions. Preserve both source claims with their conditions; do not attribute the dynamic-selectivity claim to the latter paper. supported_by: - reference_id: PMID:15010471 - reference_id: PMID:19019741 proposed_replacement_terms: - id: GO:0160133 label: bicarbonate channel activity - term: id: GO:0015106 label: bicarbonate transmembrane transporter activity evidence_type: IDA original_reference_id: PMID:19019741 qualifier: enables review: summary: The human-protein patch assay supports bicarbonate channel activity. action: MODIFY reason: Inside-out patches from BHK cells expressing human CFTR directly measure bicarbonate permeation. This is channel-mediated transport, not an exchanger or ATP-driven bicarbonate pump; the tested selectivity is reported as stable. supported_by: - reference_id: PMID:19019741 supporting_text: share a common transport pathway in CFTR - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0160133 label: bicarbonate channel activity - term: id: GO:0015701 label: bicarbonate transport evidence_type: IDA original_reference_id: PMID:15010471 qualifier: involved_in review: summary: Retain bicarbonate transport in the source expression assay. action: ACCEPT reason: The oocyte study directly measures CFTR-dependent bicarbonate permeation. Its dynamic external-chloride selectivity interpretation remains source-specific rather than a universal pore property. supported_by: - reference_id: PMID:15010471 - term: id: GO:0015701 label: bicarbonate transport evidence_type: IDA original_reference_id: PMID:19019741 qualifier: involved_in review: summary: Retain directly measured bicarbonate transport. action: ACCEPT reason: Human CFTR inside-out patch assays establish bicarbonate flow through the anion pore, with condition-specific relative permeability and conductance. supported_by: - reference_id: PMID:19019741 - term: id: GO:0016324 label: apical plasma membrane evidence_type: IMP original_reference_id: PMID:19621064 qualifier: located_in review: summary: Apical epithelial CFTR is functionally restored by gene delivery. action: ACCEPT reason: The full human airway-culture study places CFTR at the luminal surface and measures rescue of chloride/fluid transport. This is direct epithelial context, not a purified channel stoichiometry assay. supported_by: - reference_id: PMID:19621064 - term: id: GO:0035377 label: transepithelial water transport evidence_type: IMP original_reference_id: PMID:19621064 qualifier: involved_in review: summary: Retain CFTR-dependent transepithelial fluid movement. action: KEEP_AS_NON_CORE reason: Human airway-culture rescue measures fluid/airway-surface consequences of restored CFTR. Ion transport supplies the osmotic contribution; the experiment does not establish direct water passage through the CFTR protein. supported_by: - reference_id: PMID:19621064 - term: id: GO:0050891 label: multicellular organismal-level water homeostasis evidence_type: IMP original_reference_id: PMID:19621064 qualifier: involved_in review: summary: Retain the broad epithelial contribution to water homeostasis. action: KEEP_AS_NON_CORE reason: The human airway rescue provides a physiological context for CFTR-dependent hydration, while the experiment is an epithelial culture rather than a whole-body water-balance assay. Preserve the existing broad IMP with that scope and avoid adding another process solely from mucus clearance. supported_by: - reference_id: PMID:19621064 - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: IDA original_reference_id: PMID:19019741 qualifier: involved_in review: summary: Human CFTR directly transports chloride across a membrane. action: ACCEPT reason: Inside-out patch currents support anion movement through the pore. ATP dependence of gating is distinguished from the electrochemical driving force for chloride flux. supported_by: - reference_id: PMID:19019741 - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: IMP original_reference_id: PMID:19621064 qualifier: involved_in review: summary: Human epithelial rescue supports chloride transport. action: ACCEPT reason: The source measures CFTR-dependent chloride secretion after gene delivery. Associated sodium and fluid responses are distinct endpoints and are not all assigned to a single direct CFTR inhibitory interface. supported_by: - reference_id: PMID:19621064 - term: id: GO:1904322 label: cellular response to forskolin evidence_type: IDA original_reference_id: PMID:15010471 qualifier: involved_in review: summary: Retain the pharmacological forskolin-response context. action: KEEP_AS_NON_CORE reason: Forskolin raises cAMP in the source assay and activates phosphorylation-dependent CFTR transport. This is a useful experimental response annotation but not a separate defining molecular activity of the channel. supported_by: - reference_id: PMID:15010471 - term: id: GO:1904322 label: cellular response to forskolin evidence_type: IDA original_reference_id: PMID:19621064 qualifier: involved_in review: summary: Retain the pharmacological forskolin-response context. action: KEEP_AS_NON_CORE reason: Forskolin raises cAMP in the source assay and activates phosphorylation-dependent CFTR transport. This is a useful experimental response annotation but not a separate defining molecular activity of the channel. supported_by: - reference_id: PMID:19621064 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:11524016 qualifier: located_in review: summary: Functional human CFTR occupies the plasma membrane. action: ACCEPT reason: The source combines CFTR functional analysis with its membrane expression; the location is independently consistent with epithelial and patch measurements. supported_by: - reference_id: PMID:11524016 - reference_id: PMID:19019741 - term: id: GO:0016020 label: membrane evidence_type: IDA original_reference_id: PMID:8910473 qualifier: located_in review: summary: The reconstituted channel is membrane associated. action: ACCEPT reason: Purified CFTR is reconstituted for functional/ATPase measurements, directly supporting membrane association. This does not identify a native tissue compartment by itself. supported_by: - reference_id: PMID:8910473 - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: IDA original_reference_id: PMID:11524016 qualifier: involved_in review: summary: Retain the source-supported chloride flux. action: ACCEPT reason: The human-CFTR channel/ATPase study supports chloride movement, corroborated independently by direct patch assays. supported_by: - reference_id: PMID:11524016 - reference_id: PMID:19019741 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: IDA original_reference_id: PMID:11707463 qualifier: located_in review: summary: Retain the ER membrane pool in CFTR trafficking. action: KEEP_AS_NON_CORE reason: The CAL-centered primary supports intracellular trafficking/retention context for the channel. ER localization is also independently consistent with CFTR biogenesis and quality control; it is not presented as the dominant mature epithelial location. supported_by: - reference_id: PMID:11707463 - reference_id: PMID:9792704 - term: id: GO:0005886 label: plasma membrane evidence_type: IMP original_reference_id: PMID:11707463 qualifier: located_in review: summary: Retain plasma-membrane localization in the trafficking perturbation. action: ACCEPT reason: The source measures changes in CFTR surface function/trafficking after perturbing its CAL interaction. The native channel surface location remains core despite regulated intracellular retention. supported_by: - reference_id: PMID:11707463 - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: IDA original_reference_id: PMID:11707463 qualifier: involved_in review: summary: Retain chloride transport in the CAL-regulated context. action: ACCEPT reason: Changes in trafficking alter channel availability, but CFTR itself carries chloride. The source partner mechanism does not transfer an adaptor function to CFTR. supported_by: - reference_id: PMID:11707463 - reference_id: PMID:19019741 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866542 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in VCP-associated retrotranslocation. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8866542 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866546 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in RNF5/RNF185 ubiquitination. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8866546 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866551 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in ERAD-complex binding. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8866551 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866553 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in proteasomal disposal. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8866553 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866851 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in biosynthetic export. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8866851 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866854 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in F508del retrotranslocation. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8866854 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866856 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in mutant ubiquitination. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8866856 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866857 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in mutant ERAD-complex association. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-8866857 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9641109 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in misfolded-protein polyubiquitination. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-9641109 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9641111 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in misfolded-client recognition. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-9641111 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9641127 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in polyubiquitinated-client handling. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-9641127 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9646348 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in HDAC6/dynein association. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-9646348 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9646679 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in aggresome organization. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-9646679 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9646685 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in aggresome release. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-9646685 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005789 label: endoplasmic reticulum membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-9700266 qualifier: located_in review: summary: Retain the source-modeled ER membrane/quality-control pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record supplies CFTR-containing complex/cargo provenance in corrector-associated F508del trafficking. Its broad pathway summary is not a new independent ER-localization experiment, and later transport/aggresome steps do not mean the client is ER-confined throughout. CFTR ER retention and biosynthesis are independently supported; the named quality-control machinery activities are not assigned to CFTR. supported_by: - reference_id: Reactome:R-HSA-9700266 - reference_id: PMID:9792704 - reference_id: PMID:11707463 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8866854 qualifier: located_in review: summary: Retain a cytosolic retrotranslocation/degradation context. action: KEEP_AS_NON_CORE reason: The selected Reactome event models F508del CFTR after ER extraction or during proteasomal disposal. This supports a contextual cytosolic species, consistent with the Sec61 study, rather than interpreting cytoplasmic domains of the intact membrane channel as free-cytosol localization. supported_by: - reference_id: Reactome:R-HSA-8866854 - reference_id: PMID:9792704 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8866858 qualifier: located_in review: summary: Retain a cytosolic retrotranslocation/degradation context. action: KEEP_AS_NON_CORE reason: The selected Reactome event models F508del CFTR after ER extraction or during proteasomal disposal. This supports a contextual cytosolic species, consistent with the Sec61 study, rather than interpreting cytoplasmic domains of the intact membrane channel as free-cytosol localization. supported_by: - reference_id: Reactome:R-HSA-8866858 - reference_id: PMID:9792704 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866277 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in AP2-dependent cargo capture. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8866277 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8867754 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in BAR-domain membrane curvature. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8867754 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8867756 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in CLASP recruitment. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8867756 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868071 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in PIK3C2A recruitment. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8868071 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868072 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in phosphoinositide phosphorylation. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8868072 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868230 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in actin-machinery recruitment. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8868230 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868236 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in dynamin recruitment. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8868236 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868648 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in synaptojanin lipid hydrolysis. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8868648 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868651 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in endophilin/synaptojanin assembly. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8868651 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8868661 qualifier: located_in review: summary: Retain the core plasma-membrane location. action: ACCEPT reason: The selected Reactome record places CFTR-containing membrane cargo in vesicle scission. This is source-modeled location provenance rather than evidence that CFTR performs the event machinery work. The same plasma-membrane location is independently supported by human channel function and localization. supported_by: - reference_id: Reactome:R-HSA-8868661 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-6782106 qualifier: located_in review: summary: Retain endosome-membrane localization during recycling. action: KEEP_AS_NON_CORE reason: The Reactome event describes USP10-mediated deubiquitination of CFTR in endosomes. CFTR is the membrane client; this does not assign its partner peptidase activity to the channel. supported_by: - reference_id: Reactome:R-HSA-6782106 - reference_id: PMID:19398555 - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:24885604 qualifier: located_in review: summary: Retain the source-reported intracellular imaging pool with resolution limits. action: KEEP_AS_NON_CORE reason: Full human/mouse beta-cell Methods and Figure 1 quantify CFTR immunofluorescence in plasma-membrane versus cytosolic image regions. This supports the original broad intracellular location but does not biochemically distinguish soluble intact CFTR from internal membranes or fragments. Independent retrotranslocation evidence establishes cytosolic species; do not infer localization merely from domain topology. supported_by: - reference_id: PMID:24885604 - reference_id: PMID:9792704 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:24885604 qualifier: located_in review: summary: Human beta-cell imaging supports plasma-membrane CFTR. action: ACCEPT reason: Full Methods and Results quantify membrane enrichment and colocalization with syntaxin 1A. The localization is direct cellular evidence; proposed effects on granule priming remain mechanistically distinct. supported_by: - reference_id: PMID:24885604 supporting_text: CFTR was co-localized with syntaxin 1A in the plasma membrane of human beta-cells - term: id: GO:1902476 label: chloride transmembrane transport evidence_type: IMP original_reference_id: PMID:24885604 qualifier: involved_in review: summary: Retain the beta-cell chloride-current contribution. action: ACCEPT reason: Full Results measure human/mouse cAMP-dependent current components and antagonist responses. This pharmacological cellular assay is distinguished from the separate purified/heterologous pore measurements that independently establish CFTR chloride transport. supported_by: - reference_id: PMID:24885604 - reference_id: PMID:19019741 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5678822 qualifier: located_in review: summary: Retain the plasma-membrane channel location. action: ACCEPT reason: The selected Reactome event concerns defective-channel chloride transport. The variant/drug context is retained; it is not a claim that untreated disease variants have normal activity. Independent human channel localization supports the compartment. supported_by: - reference_id: Reactome:R-HSA-5678822 - reference_id: PMID:19621064 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5678992 qualifier: located_in review: summary: Retain the plasma-membrane channel location. action: ACCEPT reason: The selected Reactome event concerns ivacaftor-rescued G551D conductance. The variant/drug context is retained; it is not a claim that untreated disease variants have normal activity. Independent human channel localization supports the compartment. supported_by: - reference_id: Reactome:R-HSA-5678992 - reference_id: PMID:19621064 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5679000 qualifier: located_in review: summary: Retain the plasma-membrane channel location. action: ACCEPT reason: The selected Reactome event concerns ivacaftor binding to mutant CFTR. The variant/drug context is retained; it is not a claim that untreated disease variants have normal activity. Independent human channel localization supports the compartment. supported_by: - reference_id: Reactome:R-HSA-5679000 - reference_id: PMID:19621064 - term: id: GO:0005765 label: lysosomal membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5627275 qualifier: located_in review: summary: Retain lysosomal-membrane targeting of CFTR cargo. action: KEEP_AS_NON_CORE reason: The Reactome event models GOPC-dependent sorting of CFTR toward lysosomes. This is a degradation/trafficking location, not an independently established lysosomal channel function. supported_by: - reference_id: Reactome:R-HSA-5627275 - reference_id: PMID:11707463 - reference_id: PMID:21455491 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:18570918 qualifier: located_in review: summary: Retain the broader intracellular trafficking pool. action: KEEP_AS_NON_CORE reason: The authentic endosomal SNARE source supports intracellular CFTR alongside the apical and recycling-endosome pools. Preserve its imaging-based cytoplasmic location without equating every signal with soluble protein. supported_by: - reference_id: PMID:18570918 - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:18570918 qualifier: located_in review: summary: Retain apical CFTR in the recycling study. action: ACCEPT reason: The source examines apical expression/function and its recycling regulation, consistent with the defining epithelial surface activity. supported_by: - reference_id: PMID:18570918 - term: id: GO:0055037 label: recycling endosome evidence_type: IDA original_reference_id: PMID:18570918 qualifier: located_in review: summary: Retain CFTR in recycling endosomes. action: KEEP_AS_NON_CORE reason: The authentic endosomal SNARE study supports the channel as recycling cargo. Endosome occupancy does not make CFTR the membrane-recycling motor or adaptor. supported_by: - reference_id: PMID:18570918 supporting_text: we found a colocalization of CFTR and endosomal SNARE proteins in Rab11-positive recycling endosomes - term: id: GO:0030660 label: Golgi-associated vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5627071 qualifier: located_in review: summary: Retain the Golgi-associated vesicle membrane pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record describes GOPC/RHOQ-dependent CFTR sorting or diversion toward lysosomes. This is specific trafficking-complex provenance, not a separate channel activity in every transport vesicle. supported_by: - reference_id: Reactome:R-HSA-5627071 - reference_id: PMID:11707463 - term: id: GO:0030660 label: Golgi-associated vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5627072 qualifier: located_in review: summary: Retain the Golgi-associated vesicle membrane pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record describes GOPC/RHOQ-dependent CFTR sorting or diversion toward lysosomes. This is specific trafficking-complex provenance, not a separate channel activity in every transport vesicle. supported_by: - reference_id: Reactome:R-HSA-5627072 - reference_id: PMID:11707463 - term: id: GO:0030660 label: Golgi-associated vesicle membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5627275 qualifier: located_in review: summary: Retain the Golgi-associated vesicle membrane pool. action: KEEP_AS_NON_CORE reason: The selected Reactome record describes GOPC/RHOQ-dependent CFTR sorting or diversion toward lysosomes. This is specific trafficking-complex provenance, not a separate channel activity in every transport vesicle. supported_by: - reference_id: Reactome:R-HSA-5627275 - reference_id: PMID:11707463 - term: id: GO:0009986 label: cell surface evidence_type: IDA original_reference_id: PMID:20658517 qualifier: located_in review: summary: Retain epithelial surface/apical CFTR localization. action: ACCEPT reason: The SLC26A9 source reports an apical functional association in bronchial epithelial cells. CFTR surface localization is independently supported by human airway rescue; no binary-binding inference is needed for this location. supported_by: - reference_id: PMID:20658517 - reference_id: PMID:19621064 - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:20658517 qualifier: located_in review: summary: Retain epithelial surface/apical CFTR localization. action: ACCEPT reason: The SLC26A9 source reports an apical functional association in bronchial epithelial cells. CFTR surface localization is independently supported by human airway rescue; no binary-binding inference is needed for this location. supported_by: - reference_id: PMID:20658517 - reference_id: PMID:19621064 - term: id: GO:0015106 label: bicarbonate transmembrane transporter activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: Specify the bicarbonate-channel mechanism of the conserved activity. action: MODIFY reason: The ISS source retains its ortholog provenance. Independent human-CFTR inside-out patches establish direct bicarbonate conduction, allowing a molecular specificity refinement without changing the original evidence code or inventing a human donor assay. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0160133 label: bicarbonate channel activity - term: id: GO:0015108 label: chloride transmembrane transporter activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: Retain conserved chloride-transporter activity. action: ACCEPT reason: Direct human chloride-channel measurements independently support the broad ISS activity. Its passive pore mechanism is stated without altering the original ortholog-source assertion. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0048240 label: sperm capacitation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Retain the reproductive context of CFTR-dependent sperm capacitation. action: KEEP_AS_NON_CORE reason: The source transfer is grounded in mouse CFTR-dependent chloride/pH/electrical responses during capacitation. The accessed primary material reports pharmacological perturbations and transporter cooperation, not a human purified assay or an additional autonomous sperm-development mechanism. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:21976599 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0051454 label: intracellular pH elevation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Retain the sperm-context intracellular alkalinization role. action: KEEP_AS_NON_CORE reason: The mouse source links CFTR-dependent anion handling to capacitation-associated pH change. Keep the physiological process as a contextual consequence of channel participation; this does not establish direct proton transport through CFTR or universal pH regulation in every compartment. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:21976599 - reference_id: PMID:19019741 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0060081 label: membrane hyperpolarization evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Retain context-dependent membrane hyperpolarization. action: KEEP_AS_NON_CORE reason: Selected mouse primary Discussion reports reduced capacitation-associated hyperpolarization after CFTR inhibition alongside chloride-pathway interactions. The channel can contribute to an electrical response without becoming the sole voltage-determining transporter. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:21976599 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0071320 label: cellular response to cAMP evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: cAMP-dependent channel regulation is a core cellular response. action: ACCEPT reason: PKA-dependent CFTR phosphorylation and gating connect elevated cAMP to anion conductance. This is a channel response to signaling, not intrinsic adenylate-cyclase or kinase activity. supported_by: - reference_id: GO_REF:0000024 - reference_id: PMID:15010471 - reference_id: PMID:19621064 - reference_id: file:human/CFTR/CFTR-source-evidence.json - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-1454916 qualifier: located_in review: summary: Retain the established plasma-membrane location. action: ACCEPT reason: The selected Reactome record supplies curated CFTR membership in the broad ABC/MRP pathway. Generic pathway mechanisms are not transferred to CFTR; the location itself agrees with direct human epithelial function and localization. supported_by: - reference_id: Reactome:R-HSA-1454916 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-383190 qualifier: located_in review: summary: Retain the established plasma-membrane location. action: ACCEPT reason: The selected Reactome record supplies curated CFTR membership in the bicarbonate-transport event. Generic pathway mechanisms are not transferred to CFTR; the location itself agrees with direct human epithelial function and localization. supported_by: - reference_id: Reactome:R-HSA-383190 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5627071 qualifier: located_in review: summary: Retain the established plasma-membrane location. action: ACCEPT reason: The selected Reactome record supplies curated CFTR membership in GOPC/RHOQ-associated surface delivery. Generic pathway mechanisms are not transferred to CFTR; the location itself agrees with direct human epithelial function and localization. supported_by: - reference_id: Reactome:R-HSA-5627071 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-5678863 qualifier: located_in review: summary: Retain the established plasma-membrane location. action: ACCEPT reason: The selected Reactome record supplies curated CFTR membership in wild-type chloride transport. Generic pathway mechanisms are not transferred to CFTR; the location itself agrees with direct human epithelial function and localization. supported_by: - reference_id: Reactome:R-HSA-5678863 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-8866851 qualifier: located_in review: summary: Retain the established plasma-membrane location. action: ACCEPT reason: The selected Reactome record supplies curated CFTR membership in biosynthetic surface delivery. Generic pathway mechanisms are not transferred to CFTR; the location itself agrees with direct human epithelial function and localization. supported_by: - reference_id: Reactome:R-HSA-8866851 - reference_id: PMID:19621064 - reference_id: PMID:28130590 - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:22178883 qualifier: located_in review: summary: Retain surface localization in the TMEM16A coupling context. action: ACCEPT reason: The authentic primary abstract reports membrane-associated CFTR/TMEM16A functional coupling and co-IP. Independent CFTR surface experiments support the retained location without equating the two channel mechanisms. supported_by: - reference_id: PMID:22178883 supporting_text: CFTR and TMEM16A were both membrane localized and could be coimmunoprecipitated - reference_id: PMID:19621064 - term: id: GO:0019869 label: chloride channel inhibitor activity evidence_type: IDA original_reference_id: PMID:22178883 qualifier: enables review: summary: Retain contextual inhibition of a chloride conductance. action: KEEP_AS_NON_CORE reason: The source reports suppression of TMEM16A calcium-activated chloride currents by CFTR in the tested system. This is a specific regulatory observation, distinct from CFTR pore conduction, and does not establish a general ENaC or chloride-channel inhibitory mechanism. supported_by: - reference_id: PMID:22178883 supporting_text: TMEM16A-currents were attenuated by additional expression of CFTR - term: id: GO:0032991 label: protein-containing complex evidence_type: IDA original_reference_id: PMID:17462998 qualifier: part_of review: summary: Retain participation in a trafficking protein complex. action: KEEP_AS_NON_CORE reason: The authentic source describes CFTR with myosin Vb/Rab11a-associated machinery in polarized human airway cells. The broad complex term is supported without assigning the motor or small-GTPase activity to CFTR. supported_by: - reference_id: PMID:17462998 supporting_text: Endogenous CFTR formed a complex with endogenous myosin Vb and Rab11a - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:12801959 qualifier: located_in review: summary: Retain apical localization in human pancreatic ducts. action: ACCEPT reason: The authentic source explicitly describes CFTR localization in human pancreatic epithelial context. This supports the core compartment without treating every tissue-specific trafficking observation as a separate molecular function. supported_by: - reference_id: PMID:12801959 supporting_text: Both AQP1 and AQP5 were colocalised with cystic fibrosis transmembrane conductance regulator (CFTR) at the apical membrane of intercalated duct cells - term: id: GO:0005769 label: early endosome evidence_type: IDA original_reference_id: PMID:19398555 qualifier: located_in review: summary: Retain early-endosome localization during USP10 regulation. action: KEEP_AS_NON_CORE reason: The authentic primary describes CFTR recycling and deubiquitination in early endosomes. CFTR is the membrane substrate/cargo, not an intrinsic deubiquitinase. supported_by: - reference_id: PMID:19398555 - term: id: GO:0019899 label: enzyme binding evidence_type: IPI original_reference_id: PMID:19398555 qualifier: enables review: summary: Retain the substrate association with USP10. action: KEEP_AS_NON_CORE reason: The source supports CFTR association with the deubiquitinating enzyme in the recycling pathway, corroborated by direct endosomal co-IP in PMID:21455491. Enzyme binding does not mean CFTR performs the partner enzyme reaction. supported_by: - reference_id: PMID:19398555 - reference_id: PMID:21455491 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9792704 qualifier: enables review: summary: Specify the directly implicated Sec61 translocon complex. action: MODIFY reason: The authentic primary describes CFTR association with Sec61 during retrotranslocation, and the same source already supports a specific Sec61-complex-binding annotation. A source-preserving specificity refinement is appropriate; it does not assign translocon activity to the CFTR client. supported_by: - reference_id: PMID:9792704 supporting_text: CFTR associates with the Sec61 trimeric complex - reference_id: file:human/CFTR/CFTR-source-evidence.json proposed_replacement_terms: - id: GO:0106138 label: Sec61 translocon complex binding - term: id: GO:0016324 label: apical plasma membrane evidence_type: IDA original_reference_id: PMID:15247260 qualifier: located_in review: summary: Retain apical CFTR in the human endocytosis study. action: ACCEPT reason: The authentic source reports CFTR in polarized human Calu-3 cells with Dab2/myosin VI-associated endocytosis. Its surface location is core even though the machinery interactions are ancillary. supported_by: - reference_id: PMID:15247260 - term: id: GO:0030165 label: PDZ domain binding evidence_type: IDA original_reference_id: PMID:11707463 qualifier: enables review: summary: Retain direct terminal PDZ-domain binding. action: KEEP_AS_NON_CORE reason: The CAL/GOPC study directly supports CFTR terminal-domain engagement. This is an ancillary anchoring/trafficking interaction, consistent with independent NHERF experiments, rather than a separate defining activity-centered core. supported_by: - reference_id: PMID:11707463 supporting_text: The PDZ domain of CAL binds to the C terminus of CFTR - reference_id: PMID:9671706 - term: id: GO:0005524 label: ATP binding evidence_type: TAS original_reference_id: PMID:2475911 qualifier: enables review: summary: Retain ATP binding with independent biochemical support. action: ACCEPT reason: The original human CFTR cDNA study supplies sequence-based nucleotide-domain context, not a newly inspected purified ATP-binding assay. Direct ATP-dependent gating and hydrolysis independently support the correct TAS molecular activity. supported_by: - reference_id: PMID:2475911 - reference_id: PMID:8910473 references: - id: GO_REF:0000003 title: Gene Ontology annotation based on Enzyme Commission mapping findings: - statement: Automated annotation transfer based on enzyme classification finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: - statement: PAINT transfers curated ancestral-node functional inferences to descendant genes using the family phylogeny and experimental evidence. finding_review: finding_status: CURRENT review_notes: The older ortholog-conservation shorthand is replaced by the actual ancestral-node inference model; donor count and target self-reference are not negative evidence. reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: GO_REF:0000043 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping findings: - statement: Automated annotation from Swiss-Prot keywords finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara. findings: - statement: Ortholog-based annotation transfer using Ensembl Compara finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods. findings: - statement: Combined computational evidence from multiple IEA sources finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: PMID:10581360 title: Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Authentic abstract read: synthesis of differential NBD function and passive flux versus ATP-dependent gating. This is not presented as a new purified experiment or exact one-ATP-per-opening stoichiometry.' full_text_unavailable: true - id: PMID:11524016 title: A monomer is the minimum functional unit required for channel and ATPase activity of the cystic fibrosis transmembrane conductance regulator. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Authentic abstract read: CFTR self-association in CHO/Sf9 membranes but purified reconstituted monomers suffice for conduction and ATPase activity. No obligatory dimer pore is inferred; full original Methods were not recovered.' full_text_unavailable: true - id: PMID:11707463 title: A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract directly reports CAL/GOPC PDZ interaction, intracellular localization and CFTR surface/channel regulation. Relevant source assertions are retained with independent corroboration; no full original Methods claim. full_text_unavailable: true - id: PMID:12369822 title: The down regulated in adenoma (dra) gene product binds to the second PDZ domain of the NHE3 kinase A regulatory protein (E3KARP), potentially linking intestinal Cl-/HCO3- exchange to Na+/H+ exchange. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and original GOA partner inspected. Despite the DRA-centered title, CFTR is the direct affinity comparator for E3KARP PDZ2; preserved partner Q15599 is NHERF2, not DRA. Full original Methods not recovered. full_text_unavailable: true - id: PMID:12471024 title: The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins. findings: - statement: ClC-3B and CFTR share several PDZ partners; PDZK1 can support their association, while their predominant cellular distributions differ. finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract plus exact positive IntAct pull-down/co-IP records inspected. Preserve mixed NHERF1/ClC-3B/PDZK1/GOPC partners and fragment/host context; do not infer every co-complex contact is binary or that ClC-3B controls CFTR trafficking. full_text_unavailable: true - id: PMID:14679199 title: Inhibitory regulation of cystic fibrosis transmembrane conductance regulator anion-transporting activities by Shank2. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract reports Y2H/co-IP, PDZ-site dependence, NIH3T3 function and human T84 perturbation. Exact source partner is rat Shank; no unverified species assignment to every construct or full-Methods access claim. full_text_unavailable: true - id: PMID:15010471 title: Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-). findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Authentic abstract read, with independent primary-source assessment: Xenopus expression, external-chloride-dependent delayed bicarbonate/OH permeability and proteolysis patterns. This is the dynamic-selectivity source, distinct from 19019741; full original Methods not independently recovered in this assessment.' full_text_unavailable: true - id: PMID:15247260 title: Myosin VI regulates endocytosis of the cystic fibrosis transmembrane conductance regulator. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Authentic abstract read: polarized human Calu-3 CFTR/Dab2/myosin-VI complex and endocytosis. The channel is cargo, not the motor; no purified direct affinity is asserted.' full_text_unavailable: true - id: PMID:16203867 title: Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact IntAct fragment/complex records read. NHERF2 contact and LPAR2-containing complexes have different assay resolution; receptor-driven physiology does not establish CFTR receptor/scaffold activity. - id: PMID:16546175 title: Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat. findings: - statement: Miglustat disrupted the F508del-CFTR/calnexin interaction and rescued mutant channel function in the tested epithelial and mouse preparations. finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract reports miglustat-dependent loss of F508del-CFTR/calnexin association and functional rescue. Variant scope is explicit; no full Methods or wild-type universal interaction claimed. full_text_unavailable: true - id: PMID:16901789 title: Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact positive human expression-system records inspected. RNF5/DERL1 interactions concern CFTR quality-control substrates; no intrinsic CFTR E3 activity. full_text_unavailable: true - id: PMID:17110338 title: Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. findings: - statement: Hsp90 cochaperones influence CFTR folding stability, and partial Aha1 depletion rescues cell-surface delivery of F508del CFTR. finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. supporting_text: partial siRNA silencing of the Hsp90 cochaperone ATPase regulator Aha1 - statement: The CFTR interactome implicates cargo-associated chaperone networks in ER folding and exit; these are partner activities acting on CFTR. finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact source partner records inspected. Six preserved partners are distinguished from the Aha1-centered narrative; endogenous epithelial co-IP records are retained as complex association, not purified affinities. full_text_unavailable: true - id: PMID:17244609 title: Dynamic regulation of cystic fibrosis transmembrane conductance regulator by competitive interactions of molecular adaptors. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Authentic abstract and exact SPR records inspected: terminal CFTR GST fragments versus PDZ constructs, including rat Shank. Domain binding is supported; full-length endogenous stoichiometry is not claimed.' full_text_unavailable: true - id: PMID:18555783 title: BAP31 interacts with Sec61 translocons and promotes retrotranslocation of CFTRDeltaF508 via the derlin-1 complex. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact positive records inspected. BAP31 association uses F508del and N-terminal CFTR constructs in human cells; the ERAD machinery activity is not transferred to its client. full_text_unavailable: true - id: PMID:18570918 title: Endosomal SNARE proteins regulate CFTR activity and trafficking in epithelial cells. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract directly describes endosomal SNARE proteins syntaxin7/8, Vti1b and VAMP8; LLC-PK1-CFTR and endogenous Caco-2 assays, cell-surface biotinylation and Rab11-positive recycling colocalization. This is not an RME-1/EHD study. full_text_unavailable: true - id: PMID:19019741 title: Mechanism of direct bicarbonate transport by the CFTR anion channel. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: Canonical cache remains abstract-only. Independently inspected original publisher Methods, Results and Discussion describe human CFTR in BHK cells and inside-out patch recordings. Bicarbonate permeation and tested selectivity are positive; high bicarbonate conditions limit physiological extrapolation. This differs from the external-chloride-dependent model in PMID:15010471. Exact publisher URL and indexed receipt hash are in the evidence artifact. - id: PMID:19289574 title: SLC26A9 is a constitutively active, CFTR-regulated anion conductance in human bronchial epithelia. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Selected full source and independent source assessment: SLC26A9/CFTR co-IP and functional conductance coupling, with possible ER retention offered as a model. This is not an ENaC study or purified binary interface.' full_text_unavailable: false - id: PMID:19465887 title: The ER-resident ubiquitin-specific protease 19 participates in the UPR and rescues ERAD substrates. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Normal cache is incomplete despite its full flag. Indexed original Results independently recovered: Figure 5 reports USP19 co-IP with GFP-CFTR F508del, distinct from rescue/stability experiments. Selected text was inspected, not new panel pixels; target query returned no records and was not treated as a biological negative.' full_text_unavailable: false - id: PMID:19621064 title: CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Selected full source and independent source assessment: human CF airway cultures, CFTR gene delivery, chloride and benzamil-sensitive sodium transport, airway-surface-liquid and mucus-transport readouts. Sodium transport was actually measured; it is not a mucus-only study. No defined direct CFTR-to-ENaC molecular step or regulated mucus-release experiment is asserted.' full_text_unavailable: false - id: PMID:19878303 title: Deletion of Phe508 in the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator increases its affinity for the heat shock cognate 70 chaperone. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract explicitly studies murine NBD1 wild-type/F508del and Hsc70 by SPR. The preserved partner is bovine Hsc70. This is not described as a full-length human CFTR assay; independent human chaperone evidence supports the broad association. full_text_unavailable: true - id: PMID:20658517 title: SLC26A9 stimulates CFTR expression and function in human bronchial cell lines. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract reports bronchial epithelial SLC26A9/CFTR co-IP, apical expression and functional effects. No purified binary affinity or general transporter mechanism is inferred. full_text_unavailable: true - id: PMID:21455491 title: A Pseudomonas aeruginosa toxin that hijacks the host ubiquitin proteolytic system. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Selected full Results Figure 4A and endosomal assays read: USP10 co-IP/CFTR immunoblot from human airway-cell early endosomes, altered by Cif. The preserved binding pair is CFTR/USP10, not CFTR/Cif; BiFC elsewhere tests USP10/G3BP1.' full_text_unavailable: false - id: PMID:21884936 title: Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact IntAct PDZ-fragment pull-down/HEK293 co-IP records read. GRASP55 interaction and unconventional export are distinguished from CFTR acting as the export machinery. No unsupported full Methods scope claimed. full_text_unavailable: true - id: PMID:22038833 title: Disruption of cytokeratin-8 interaction with F508del-CFTR corrects its functional defect. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact records inspected. Keratin8 and actin co-IP in wild-type/F508del expression contexts; direct SPR is keratin8/NBD1. Neither all contacts nor all variants are treated as equivalent. - id: PMID:22121115 title: 'The testis anion transporter TAT1 (SLC26A8) physically and functionally interacts with the cystic fibrosis transmembrane conductance regulator channel: a potential role during sperm capacitation.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract explicitly reports SLC26A8 physical/functional interaction, oocyte/CHO assays and mouse reproductive context. Construct species is not inferred solely from the expression host. full_text_unavailable: true - id: PMID:22178883 title: CFTR and TMEM16A are separate but functionally related Cl- channels. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Authentic abstract and independent source assessment: distinct CFTR/TMEM16A channels, co-IP and conditional suppression of calcium-activated chloride current. No ENaC inference or isolated binary interface.' full_text_unavailable: true - id: PMID:22768251 title: Proteomic identification of calumenin as a G551D-CFTR associated protein. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Authentic abstract and exact records read: G551D CFTR/calumenin-1 association, co-IP/pull-down and reported SPR. Calumenin folding support is a hypothesis, not an established catalytic mechanism.' - id: PMID:23818989 title: Ubiquitination and degradation of CFTR by the E3 ubiquitin ligase MARCH2 through its association with adaptor proteins CAL and STX6. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Selected full Methods/Results and Figure 7 read: HA-MARCH2/GFP-CFTR co-IP in HEK293, terminal-deletion dependence and CFBE colocalization. CFTR is ubiquitination/trafficking cargo; complex recovery is not a binary ligase-substrate structure.' full_text_unavailable: false - id: PMID:24885604 title: CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Selected full Methods, Results and Figure 1/5 legends read: human/mouse beta-cell imaging, cAMP-dependent currents, pharmacological perturbation and exocytosis. Membrane/cytosolic image-region ratios do not distinguish soluble intact CFTR from internal membranes; direct priming mechanism remains proposed.' full_text_unavailable: false - id: PMID:25661196 title: SERCA and PMCA pumps contribute to the deregulation of Ca2+ homeostasis in human CF epithelial cells. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact SERCA2 co-IP/proximity-ligation records read in human epithelial contexts. Positive association is acknowledged; no CFTR calcium-pump activity or purified binary interface is inferred. full_text_unavailable: true - id: PMID:25712891 title: G551D-CFTR needs more bound actin than wild-type CFTR to maintain its presence in plasma membranes. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact HeLa co-IP records read, including WT/G551D contexts and actin. No assignment of actin-assembly activity to CFTR. full_text_unavailable: true - id: PMID:26618866 title: ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Complete primary and genuine publisher tables independently peer-read; all 31 old partners resolved:24 exact pooled-core accessions, 6 treatment-network edges with official identity joins, plus HACD3/PTPLAD1 reciprocal co-IP text. WT/F508del/treatment scope and indirect complex associations are retained; no claim all 31 are untreated WT binary contacts. full_text_unavailable: false - id: PMID:27092946 title: Investigating CFTR and KCa3.1 Protein/Protein Interactions. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Authentic abstract, indexed source Results and exact records read: human CFTR/KCa3.1 fragments in bacterial two-hybrid assays and reciprocal co-IP in CFBE WT/F508del cells. No potassium-channel activity is attributed to CFTR.' - id: PMID:28360110 title: The CFTR trafficking mutation F508del inhibits the constitutive activity of SLC26A9. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Authentic abstract and exact records inspected: CFTR terminal PDZ interactions plus SLC26A9-containing complexes, with F508del-related functional effects. The heterogeneous original group is not forced into one binary-domain mechanism.' - id: PMID:29393851 title: Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Selected full Results Figure 5/9 and HEK293 Figure 9 supplement3 read: mouse efferent-duct complexes and tagged cellular co-IP. Beta-arrestin1 provides the scaffolding interpretation; no direct purified CFTR/ADGRG2 interface or human endogenous tissue assay is claimed.' full_text_unavailable: false - id: PMID:29924966 title: A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact ProVarA records inspected for all 17 original partners. Variant/pooling features remain explicit; positive recovery is not automatically wild-type confirmation or native binary binding. - id: PMID:8910473 title: ATPase activity of the cystic fibrosis transmembrane conductance regulator. findings: - statement: Purified reconstituted CFTR directly hydrolyzes ATP. finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. - statement: Reconstituted G551D CFTR exhibited defects in both ATP hydrolysis and gating, supporting nucleotide-dependent channel control without establishing a fixed turnover-to-gating ratio. finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Authentic primary abstract directly reports ATP hydrolysis by purified reconstituted CFTR and G551D effects on hydrolysis/gating. This supports catalysis without requiring a fixed hydrolysis-to-gating stoichiometry or primary active transport. full_text_unavailable: true - id: PMID:9931011 title: Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator). findings: - statement: Walker A mutations in the two nucleotide-binding folds have unequal effects on ATPase and gating, demonstrating functional asymmetry and a nonidentical relationship between these readouts. finding_review: finding_status: CURRENT review_notes: Reassessed against the cited source at the access scope recorded above. The complete original statement and quotation remain in historical_findings_provenance; long repeated quotations are not republished as current evidence. supporting_text: ATP hydrolysis by the purified, intact protein reference_review: relevance: HIGH correctness: VERIFIED review_notes: Authentic abstract reports purified intact WalkerA mutants K464A/K1250A, ATPase inhibition and nonidentical gating effects. This cautions against strict turnover/gating stoichiometry while supporting both activities. full_text_unavailable: true - id: PMID:31324722 title: Inhibition of calpain 1 restores plasma membrane stability to pharmacologically rescued Phe508del-CFTR variant. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and exact19-partner crosslinked co-IP/proteomic records read in CFBE41o expression/rescue contexts. CAPN1 mutant-selective recovery and tagged WT/F508del contexts are distinguished; not all partners are universal WT binary contacts. - id: PMID:35156780 title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Complete primary Methods/Results and genuine publisher EV2/EV4/EV5/TableEV2 independently peer-read. All94 source targets are actual MaMTH positives, not IID-only imports;32 WT-only, 44 F508del-only, 18 shared. Retest and co-IP outcomes are mixed and preserved separately. Reporter tags and human ORFeome constructs are explicit. full_text_unavailable: false - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Original annotation-method identity retained. Target biology and literal donor/domain/keyword records are evaluated separately; the full historical PAINT node/IBD or electronic-rule state is not claimed reconstructed. - id: PMID:12801959 title: Distribution of aquaporin water channels AQP1 and AQP5 in the ductal system of the human pancreas. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract directly reports human pancreatic AQP1/AQP5 colocalization with CFTR at apical intercalated ducts. The aquaporin-focused title does not make the CFTR localization a wrong-target claim. - id: PMID:16207813 title: BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Selected full source read: purified Hsc70/BAG2 recognition of CFTR NBD1 peptide regions and CFTR maturation context. CFTR is a chaperone client, not the CHIP inhibitor or a chaperone enzyme.' full_text_unavailable: false - id: PMID:17462998 title: Myosin Vb is required for trafficking of the cystic fibrosis transmembrane conductance regulator in Rab11a-specific apical recycling endosomes in polarized human airway epithelial cells. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract directly concerns polarized human airway CFTR trafficking with myosinVb/Rab11a complexes. Complex participation does not confer motor/GTPase activity on CFTR. full_text_unavailable: true - id: PMID:19398555 title: The deubiquitinating enzyme USP10 regulates the post-endocytic sorting of cystic fibrosis transmembrane conductance regulator in airway epithelial cells. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract reports USP10-dependent early-endosomal CFTR sorting/deubiquitination; independently inspected 21455491 endosomal co-IP corroborates the enzyme-substrate association. No intrinsic CFTR deubiquitinase activity. - id: PMID:22006324 title: Anoctamin 6 is an essential component of the outwardly rectifying chloride channel. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract foregrounds ANO6/ORCC but includes CFTR functional context. The CFTR chloride-transport assertion is independently supported; no rejection from title and no claim full target Methods independently inspected. full_text_unavailable: true - id: PMID:2475911 title: 'Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic original human cDNA abstract read. Nucleotide-domain prediction is distinguished from subsequent direct ATPase/channel experiments; the TAS ATP-binding source is preserved. full_text_unavailable: true - id: PMID:26888287 title: Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Selected full Results and assay/construct descriptions read: phosphorylated CFTR R-domain binding, tandem sites, FP/ITC and crystal structures with 14-3-3. Beta binding versus zeta/gamma structures and engineered linkers are distinguished; not every structure is a native full-length channel complex.' full_text_unavailable: false - id: PMID:28067262 title: Sec16A is critical for both conventional and unconventional secretion of CFTR. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract describes Sec16A conventional/unconventional CFTR export under ER-stress contexts. CFTR is trafficking cargo; source-specific stress response is not elevated to a sensor or export-catalyst claim. - id: PMID:28130590 title: Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract explicitly concerns human epidermis/eccrine appendages, CFTR/ENaC expression and localization. It is used for location, not direct ENaC regulation. full_text_unavailable: true - id: PMID:32487539 title: 'TMEM16A deficiency: a potentially fatal neonatal disease resulting from impaired chloride currents.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract reports ANO1-variant patients, respiratory epithelial/HEK293 studies and secondary CFTR functional effects. Exact apical panel was not independently accessed; CFTR apical location is independently established. full_text_unavailable: true - id: PMID:36012204 title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Complete original Methods/Discussion independently peer-read. N-terminal APEX2/TurboID-CFTR WT/G551D/W1282X in HEK293;148 exact records for66/70 partners are proximity-method/proximity-type. Four unmatched accessions remain unresolved. Physical binding is not established by proximity enrichment; source-specific U is assay-resolution uncertainty, not failure to access the main text. full_text_unavailable: false - id: PMID:39009827 title: Proteome-scale characterisation of motif-based interactome rewiring by disease mutations. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Authentic abstract and exact feature-rich records read: engineered CASK kinase-domain/CFTR peptide and PTBP1 RRM/CFTR peptide contacts. Mutation and fragment scopes are preserved; no whole-protein native interaction or transferred kinase/RNA-binding function.' - id: PMID:9671706 title: A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Selected full Results Figure 4 read: CFTR terminal overlays, full-length in-vitro translated binding to NHERF, terminal-truncation/negative controls and native-airway extract overlays. Supports PDZ-domain binding with assay-resolution limits.' full_text_unavailable: false - id: PMID:9792704 title: The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes Sec61beta and a cytosolic, deglycosylated intermediary. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract directly reports CFTR/Sec61 complex, cytosolic deglycosylated intermediary, retrotranslocation and degradation. It supports client-complex binding and a cytosolic processed species, not intrinsic translocon activity. full_text_unavailable: true - id: Reactome:R-HSA-1454916 title: The ABCC family mediates organic anion transport findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-382556 title: ABC-family proteins mediated transport findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-383190 title: HCO3- transport through ion channel findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-5627071 title: RHOQ positively regulates trafficking of GOPC:CFTR to the plasma membrane findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-5627072 title: RHOQ binds GOPC:CFTR findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-5627275 title: GOPC promotes translocation of CFTR to lysosomes findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-5678822 title: Defective CFTR does not transport Cl- from cytosol to extracellular region findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-5678863 title: CFTR transports Cl- from cytosol to extracellular region findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-5678992 title: Ivacaftor:CFTR G551D transports Cl- from cytosol to extracellular region findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-5679000 title: Ivacaftor binds CFTR G551D findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-6782106 title: USP10 deubiquitinates SNX3, CFTR findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866277 title: AP-2 directly binds some endocytic cargo findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866542 title: VCP-catalyzed ATP hydrolysis promotes the translocation of misfolded CFTR into the cytosol findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866546 title: RNF5 and RNF185 ubiquitinate misfolded CFTR findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866551 title: CFTR binds components of the ERAD machinery for ubiquitination and degradation findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866553 title: misfolded CFTR is degraded by the 26S proteasome findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866851 title: CFTR transits to the plasma membrane findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866854 title: VCP-catalyzed ATP hydrolysis promotes the translocation of CFTR F508del into the cytosol findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866856 title: RNF5 and RNF185 ubiquitinate CFTR F508del findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866857 title: CFTR F508del binds components of the ERAD machinery for ubiquitination and degradation findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8866858 title: CFTR F508del is degraded by the 26S proteasome findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8867754 title: F- and N- BAR domain proteins bind the clathrin-coated pit findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8867756 title: CLASP proteins and cargo are recruited to the nascent clathrin-coated pit findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868071 title: Clathrin recruits PIK3C2A findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868072 title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2 findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868230 title: SNX9 recruits components of the actin polymerizing machinery findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868236 title: BAR domain proteins recruit dynamin findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868648 title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868651 title: Endophilins recruit synaptojanins to the clathrin-coated pit findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868658 title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868659 title: Clathrin recruits auxilins to the clathrin-coated vesicle findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868660 title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8868661 title: Dynamin-mediated GTP hydrolysis promotes vesicle scission findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8869438 title: Dissociation of clathrin-associated proteins findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8871193 title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2 findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-8871194 title: RAB5 and GAPVD1 bind AP-2 findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-9641109 title: PolyUb:misfolded proteins dissociate from PRKN:UBE2N:UBE2V1 findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-9641111 title: Parkin transfers Ub to misfolded proteins findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-9641127 title: Ub:misfolded proteins polymerize to PolyUb:misfolded proteins findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-9646348 title: PolyUb-Misfolded Proteins:HDAC6 bind dynein motor findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-9646679 title: PolyUb-Misfolded proteins bind vimentin to form aggresome findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-9646685 title: Aggresome dissociates from dynein and microtubule findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: Reactome:R-HSA-9700266 title: CFTR F508del binds CFTR correctors findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Exact selected historical cache title and event summary inspected. This is the source annotation pathway/entity provenance, not an independent localization experiment for every row. Generic ABC/MRP mechanisms, mutant failure events and trafficking-machinery work are separated from CFTR channel function. - id: file:human/CFTR/CFTR-deep-research.md title: Deep research on CFTR function findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Genuine inherited provider report retained byte-for-byte as historical research context. It is not primary experimental evidence; the current source-based audit supersedes unsupported mechanisms without editing the provider file. - id: PMID:17085523 title: Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Canonical cache remains abstract-only. The author-uploaded original journal text was independently inspected for Methods, Results and Discussion; source-qualified upstream effects are distinguished from an unresolved sterol mechanism. Exact TSV/donor qualifiers and access receipts are in the evidence artifact. - id: PMID:21976599 title: Participation of the Cl-/HCO(3)- exchangers SLC26A3 and SLC26A6, the Cl- channel CFTR, and the regulatory factor SLC9A3R1 in mouse sperm capacitation. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic abstract and indexed original Discussion accessed; pharmacological CFTR/SLC26-dependent mouse sperm chloride and hyperpolarization changes support a contextual process. Full method/construct resolution remained incomplete; no direct proton channel or human purified assay is claimed. full_text_unavailable: true - id: PMID:26403673 title: Ameloblast Modulation and Transport of Cl⁻, Na⁺, and K⁺ during Amelogenesis. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Canonical cache remains abstract-only. Independently accessed original PMC Methods and Results describe mouse Cftr/Ae2/Amelx knockouts, fluoride exposure and enamel elemental analysis. This is contextual donor evidence; the inspected apical Nckx4/NaPi-2b immunostaining is not a direct CFTR localization assay. Exact source URL, indexed receipt hash and locators are in the evidence artifact. - id: PMID:29453757 title: Localization of epithelial sodium channel (ENaC) and CFTR in the germinal epithelium of the testis, Sertoli cells, and spermatozoa. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Canonical cache remains abstract-only. Authentic publisher full text was independently read: rat testis/Sertoli immunostaining, peptide-blocking and an independent antiserum, and Figure 11 nuclear fraction immunoblot with an approximately 85-kDa band. These observations do not identify a functional intact human nuclear channel. URL, response hash, section locators and a short external excerpt are in the evidence artifact.' - id: PMID:1720311 title: 'CFTR: development of high- affinity antibodies and localization in sweat gland.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Authentic normal PubMed abstract describes human sweat-duct CFTR staining with two peptide antibodies, predominantly apical and also near basolateral membrane. Full original Methods unavailable; supports a limited contextual location rather than universal polarity. full_text_unavailable: true - id: file:human/CFTR/CFTR-source-evidence.json title: CFTR source projection, literal interaction evidence, ontology and primary-access audit findings: - statement: This review adjudicates the 203 historical machine assertions from the preserved 448-row GOA snapshot. A separate genuine normal fetch produced 539 deduplicated source objects from 540 raw rows; that expanded projection is archived for a later source-migration review and is not silently substituted here. No claim of reviewing all current GOA assertions is made. reference_review: relevance: HIGH review_notes: Literal GOA, interaction and worksheet fields, official ontology/domain records and source-access locators support inspection of the underlying sources. The artifact also contains explicitly authored interpretations and historical snapshots; those are not independent experimental evidence or primary quotations. core_functions: - description: Conducts chloride through an ATP-gated membrane pore, principally at epithelial apical surfaces. Phosphorylation and ATP-dependent gating control permeability while chloride follows its electrochemical gradient; this is not primary active anion pumping. molecular_function: id: GO:0005260 label: intracellularly ATP-gated chloride channel activity directly_involved_in: - id: GO:1902476 label: chloride transmembrane transport locations: - id: GO:0016324 label: apical plasma membrane supported_by: - reference_id: PMID:8910473 supporting_text: CFTR utilizes ATP to gate its channel activity - reference_id: PMID:19621064 supporting_text: restored ASL volume regulation and mucus transport - description: Conducts bicarbonate through the same anion pore, contributing to epithelial bicarbonate secretion. Human-protein inside-out patch assays establish direct permeation; dynamic external-chloride selectivity proposed in oocytes is distinguished from invariant selectivity under the later tested conditions. molecular_function: id: GO:0160133 label: bicarbonate channel activity directly_involved_in: - id: GO:0015701 label: bicarbonate transport locations: - id: GO:0016324 label: apical plasma membrane supported_by: - reference_id: PMID:19019741 supporting_text: invariable under all ionic conditions studied - reference_id: PMID:15010471 - description: Hydrolyzes ATP to support channel conformational cycling. Purified reconstituted CFTR ATPase measurements establish catalytic activity separate from passive pore permeation; the nucleotide-binding domains are functionally asymmetric. It is listed separately because nucleotide hydrolysis is a measured chemical reaction, whereas the channel terms describe ion permeation; ATP dependence alone would not establish this catalytic activity. molecular_function: id: GO:0016887 label: ATP hydrolysis activity locations: - id: GO:0005886 label: plasma membrane supported_by: - reference_id: PMID:8910473 supporting_text: ATP hydrolysis by purified, reconstituted CFTR - reference_id: PMID:11524016 - reference_id: PMID:10581360 suggested_questions: - question: Which defined CFTR molecular species underlies the rat Sertoli nuclear signal, and is an equivalent processed product present in human Sertoli nuclei? - question: Do CFTR-dependent cholesterol changes reflect direct molecular participation in lipid handling or secondary homeostatic responses to altered anion transport and trafficking? - question: Which proximity-labeled or variant-specific interactome partners form reproducible physical contacts with sequence-defined CFTR in the corresponding physiological compartment? - question: What performed CFTR molecular step accounts for sodium-transport normalization in rescued human airway epithelia, and how does it depend on extracellular fluid conditions and ENaC processing? suggested_experiments: - description: Map nuclear CFTR species with independent epitopes, peptide-resolved mass spectrometry, fraction-purity controls and matched rat/human Sertoli systems before assigning a nuclear biochemical role. - description: Separate anion-conduction, gating, localization and cholesterol phenotypes using matched-expression variants, acute rescue and compartment-resolved lipid-flux measurements. - description: Validate selected screen/proximity partners with reciprocal endogenous co-IP, compartment-compatible constructs and orthogonal binary or reconstituted assays where direct contact is claimed. status: DRAFT alternative_products: - name: '1' id: P13569-1 - name: '2' id: P13569-2 sequence_note: VSP_022123 - name: '3' id: P13569-3 sequence_note: VSP_022124, VSP_022125