id: P13569
gene_symbol: CFTR
aliases:
- ABCC7
- ABC35
- CF
- MRP7
- TNR-CFTR
- dJ760C5.1
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) is a unique
  ABC transporter family member that functions as a phosphorylation- and ATP-regulated
  anion channel rather than an active pump. It primarily conducts chloride and bicarbonate
  ions across epithelial cell apical membranes, playing critical roles in fluid secretion
  and mucociliary clearance in airways, digestive enzyme secretion in pancreas, and
  salt balance in sweat glands. CFTR requires PKA phosphorylation of its regulatory
  R domain and ATP binding/hydrolysis at its nucleotide-binding domains for channel
  gating. Loss-of-function mutations cause cystic fibrosis, characterized by thick
  mucus in lungs, pancreatic insufficiency, elevated sweat chloride, and male infertility
  due to vas deferens absence. The most common mutation is ΔF508, which causes protein
  misfolding and ER retention. CFTR also regulates other ion channels including ENaC
  and interacts with SLC26 anion exchangers to coordinate epithelial ion transport.
existing_annotations:
- term:
    id: GO:0005260
    label: intracellularly ATP-gated chloride channel activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation accurately captures CFTR's primary molecular function
      as an ATP-gated anion channel requiring intracellular ATP binding and hydrolysis
      for channel gating. This function is well-supported by extensive structural
      and functional studies showing ATP binding at NBDs drives channel opening.
    action: ACCEPT
    reason: The term GO:0005260 precisely describes CFTR's unique mechanism among
      ABC transporters - it functions as a phosphorylation- and nucleotide-regulated
      anion channel rather than an active pump. The channel requires PKA phosphorylation
      and ATP binding/hydrolysis at its nucleotide-binding domains for gating cycles.
      This annotation, based on phylogenetic inference (IBA), correctly identifies
      the core molecular function.
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: ATPase activity of the cystic fibrosis transmembrane conductance
        regulator
    - reference_id: PMID:11524016
      supporting_text: A monomer is the minimum functional unit required for channel
        and ATPase activity of the cystic fibrosis transmembrane conductance regulator
    - reference_id: file:human/CFTR/CFTR-deep-research.md
      supporting_text: See deep research file for comprehensive analysis
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly identifies CFTR as a chloride channel,
      which is accurate but less specific than GO:0005260. CFTR does function as a
      chloride channel, conducting Cl- ions down their electrochemical gradient when
      open.
    action: ACCEPT
    reason: While GO:0005254 is correct, it lacks the specificity of GO:0005260 which
      captures the ATP-gating mechanism. However, as an automated annotation it appropriately
      identifies the chloride channel function. This term is acceptable as it represents
      a parent term of the more specific ATP-gated function. The channel primarily
      mediates passive chloride ion conductance across epithelial cell membranes.
    supported_by:
    - reference_id: PMID:15010471
      supporting_text: Dynamic control of cystic fibrosis transmembrane conductance
        regulator Cl(-)/HCO3(-) selectivity by external Cl(-)
    - reference_id: PMID:11524016
      supporting_text: functions as a phosphorylation-regulated chloride channel on
        the apical surface of epithelial cells
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This IEA annotation based on UniProt keyword mapping correctly identifies
      CFTR's nucleotide binding capability but is overly generic. CFTR specifically
      binds and hydrolyzes ATP at its two nucleotide-binding domains to drive channel
      gating.
    action: MODIFY
    reason: While nucleotide binding is correct, this annotation should be more specific.
      CFTR specifically binds ATP (not just any nucleotide) at its NBD1 and NBD2 domains.
      ATP binding promotes NBD dimerization triggering channel opening, while ATP
      hydrolysis allows channel closure. The generic "nucleotide binding" term fails
      to capture this ATP-specific requirement for CFTR function.
    proposed_replacement_terms:
    - id: GO:0005524
      label: ATP binding
    additional_reference_ids:
    - PMID:8910473
    - PMID:10581360
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: In this study, we report the first measurements of the rate
        of ATP hydrolysis by purified, reconstituted CFTR
    - reference_id: PMID:10581360
      supporting_text: Differential function of the two nucleotide binding domains
        on cystic fibrosis transmembrane conductance regulator
- term:
    id: GO:0005260
    label: intracellularly ATP-gated chloride channel activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  review:
    summary: This IEA annotation based on Enzyme Commission mapping correctly identifies
      CFTR's ATP-gated chloride channel activity. This duplicates the IBA annotation
      but from a different evidence source.
    action: ACCEPT
    reason: The annotation accurately captures CFTR's primary molecular function.
      Even though this duplicates another annotation with different evidence code,
      both are valid as they derive from independent inference methods (EC mapping
      vs phylogenetic inference). The EC number 5.6.1.6 correctly maps to CFTR's channel
      conductance-controlling ATPase activity.
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: ATPase activity of the cystic fibrosis transmembrane conductance
        regulator
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12369822
  review:
    summary: This IPI annotation documents CFTR binding to DRA (SLC26A3), a bicarbonate/chloride
      exchanger that functionally couples with CFTR for coordinated anion transport
      in intestinal epithelia. This interaction is physiologically relevant for fluid
      secretion.
    action: KEEP_AS_NON_CORE
    reason: While protein binding is too generic, this specific interaction with DRA/SLC26A3
      is functionally important for coordinating chloride and bicarbonate transport
      in epithelia. The interaction allows coupling of CFTR chloride secretion with
      DRA-mediated Cl-/HCO3- exchange. However, protein binding itself is not CFTR's
      core molecular function - the core function is the ATP-gated channel activity.
    additional_reference_ids:
    - PMID:12369822
    supported_by:
    - reference_id: PMID:12369822
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12471024
  review:
    summary: This IPI annotation documents CFTR interaction with ClC-3B chloride channel,
      which localizes to Golgi and associates with CFTR-interacting PDZ proteins,
      suggesting a role in CFTR trafficking or regulation.
    action: KEEP_AS_NON_CORE
    reason: The interaction with ClC-3B represents a regulatory relationship between
      chloride channels. While functionally relevant for CFTR trafficking through
      the Golgi, protein binding is not CFTR's primary molecular function. The generic
      protein binding term fails to capture the specific nature of this channel-channel
      interaction.
    supported_by:
    - reference_id: PMID:12471024
      supporting_text: The PDZ-binding chloride channel ClC-3B localizes to the Golgi
        and associates with cystic fibrosis transmembrane conductance regulator-interacting
        PDZ proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14679199
  review:
    summary: This IPI annotation documents CFTR interaction with Shank2, a PDZ-domain
      containing scaffolding protein that negatively regulates CFTR anion-transporting
      activities.
    action: KEEP_AS_NON_CORE
    reason: Shank2 binding represents a regulatory interaction that modulates CFTR
      channel activity. While this interaction is functionally important for controlling
      CFTR activity, the generic protein binding term is not informative about CFTR's
      core molecular function as an ATP-gated chloride channel. This represents a
      regulatory mechanism rather than core function.
    supported_by:
    - reference_id: PMID:14679199
      supporting_text: Inhibitory regulation of cystic fibrosis transmembrane conductance
        regulator anion-transporting activities by Shank2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16203867
  review:
    summary: This IPI annotation documents protein interactions involved in lysophosphatidic
      acid inhibition of CFTR-mediated secretory diarrhea, likely involving regulatory
      proteins that modulate CFTR activity during cholera toxin response.
    action: KEEP_AS_NON_CORE
    reason: This interaction represents a regulatory mechanism controlling CFTR activity
      in pathological conditions (secretory diarrhea). While physiologically relevant
      for disease modulation, protein binding is not CFTR's core molecular function.
      The annotation captures disease-relevant regulatory interactions but uses an
      overly generic term.
    supported_by:
    - reference_id: PMID:16203867
      supporting_text: Lysophosphatidic acid inhibits cholera toxin-induced secretory
        diarrhea through CFTR-dependent protein interactions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16546175
  review:
    summary: This IPI annotation likely documents interactions relevant to miglustat
      rescue of ΔF508-CFTR, possibly involving chaperones or trafficking proteins
      that help restore mutant CFTR function.
    action: KEEP_AS_NON_CORE
    reason: This represents therapeutic rescue-related protein interactions for the
      most common CF mutation (ΔF508). While important for understanding CF treatment,
      these interactions are not part of CFTR's core molecular function as an ATP-gated
      chloride channel. The generic protein binding term provides minimal functional
      information.
    supported_by:
    - reference_id: PMID:16546175
      supporting_text: Rescue of functional delF508-CFTR channels in cystic fibrosis
        epithelial cells by the alpha-glucosidase inhibitor miglustat
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16901789
  review:
    summary: This IPI annotation documents CFTR interactions with quality control
      machinery including chaperones and ERAD components that triage misfolded CFTR,
      particularly relevant for ΔF508-CFTR processing.
    action: KEEP_AS_NON_CORE
    reason: These interactions with cellular quality control machinery are critical
      for CFTR biogenesis and trafficking, especially for understanding CF pathogenesis.
      However, these represent cellular processing mechanisms rather than CFTR's core
      molecular function as an ATP-gated chloride channel. The generic term lacks
      specificity about the nature of these quality control interactions.
    supported_by:
    - reference_id: PMID:16901789
      supporting_text: Sequential quality-control checkpoints triage misfolded cystic
        fibrosis transmembrane conductance regulator
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17110338
  review:
    summary: This IPI annotation documents CFTR interaction with Aha1, an Hsp90 cochaperone
      whose downregulation can rescue misfolded ΔF508-CFTR, representing a therapeutic
      target for CF.
    action: KEEP_AS_NON_CORE
    reason: The interaction with Aha1/Hsp90 machinery is important for CFTR folding
      and represents a potential therapeutic target. However, chaperone interactions
      are part of protein biogenesis rather than CFTR's core molecular function as
      an ATP-gated chloride channel. This annotation captures disease-relevant interactions
      but uses an uninformative generic term.
    supported_by:
    - reference_id: PMID:17110338
      supporting_text: Hsp90 cochaperone Aha1 downregulation rescues misfolding of
        CFTR in cystic fibrosis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17244609
  review:
    summary: This IPI annotation documents CFTR interactions with molecular adaptors
      that dynamically regulate CFTR trafficking and membrane localization through
      competitive binding mechanisms.
    action: KEEP_AS_NON_CORE
    reason: These adaptor protein interactions regulate CFTR surface expression and
      trafficking, which is physiologically important. However, these regulatory interactions
      are not part of CFTR's core molecular function as an ATP-gated chloride channel.
      The generic protein binding term fails to convey the specific regulatory nature
      of these interactions.
    supported_by:
    - reference_id: PMID:17244609
      supporting_text: Dynamic regulation of cystic fibrosis transmembrane conductance
        regulator by competitive interactions of molecular adaptors
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18555783
  review:
    summary: This IPI annotation documents CFTR interaction with BAP31, which promotes
      retrotranslocation of misfolded ΔF508-CFTR via the derlin-1 ERAD complex.
    action: KEEP_AS_NON_CORE
    reason: The interaction with BAP31 is part of the ER quality control system that
      recognizes and degrades misfolded CFTR, particularly relevant for ΔF508-CFTR
      in CF. While important for understanding CFTR biogenesis and CF pathogenesis,
      this represents a protein quality control mechanism rather than CFTR's core
      function as an ATP-gated chloride channel.
    supported_by:
    - reference_id: PMID:18555783
      supporting_text: BAP31 interacts with Sec61 translocons and promotes retrotranslocation
        of CFTRΔF508 via the derlin-1 complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19465887
  review:
    summary: This IPI annotation documents CFTR interaction with USP19, an ER-resident
      deubiquitinase that participates in the unfolded protein response and can rescue
      ERAD substrates including misfolded CFTR.
    action: KEEP_AS_NON_CORE
    reason: USP19 interaction represents part of the ER protein quality control system
      that can rescue misfolded CFTR from degradation. While relevant for CF therapeutics
      and CFTR biogenesis, this represents a cellular quality control mechanism rather
      than CFTR's core molecular function as an ATP-gated chloride channel. The generic
      protein binding term fails to convey the specific nature of this quality control
      interaction.
    supported_by:
    - reference_id: PMID:19465887
      supporting_text: The ER-resident ubiquitin-specific protease 19 participates
        in the UPR and rescues ERAD substrates
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19878303
  review:
    summary: This IPI annotation documents increased affinity of ΔF508-CFTR for Hsc70
      chaperone due to the deletion in NBD1, contributing to misfolding and retention
      of the mutant protein.
    action: KEEP_AS_NON_CORE
    reason: The enhanced interaction with Hsc70 chaperone is a consequence of the
      ΔF508 mutation and contributes to CF pathogenesis by promoting ER retention.
      While crucial for understanding disease mechanisms, chaperone interactions represent
      protein folding quality control rather than CFTR's core function as an ATP-gated
      chloride channel. This is a disease-state interaction, not a core functional
      property.
    supported_by:
    - reference_id: PMID:19878303
      supporting_text: 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
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21455491
  review:
    summary: This IPI annotation documents interaction with Cif, a Pseudomonas aeruginosa
      virulence factor that hijacks the host ubiquitin system to promote CFTR degradation
      during infection.
    action: KEEP_AS_NON_CORE
    reason: This represents a pathogen-host interaction where P. aeruginosa Cif toxin
      targets CFTR for degradation, contributing to CF lung pathology. While important
      for understanding CF-associated infections, this is a pathological interaction
      exploited by bacteria, not part of CFTR's core molecular function as an ATP-gated
      chloride channel. The generic term fails to convey this is a virulence factor
      interaction.
    supported_by:
    - reference_id: PMID:21455491
      supporting_text: A Pseudomonas aeruginosa toxin that hijacks the host ubiquitin
        proteolytic system
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21884936
  review:
    summary: This IPI annotation documents interactions involved in GRASP-dependent
      unconventional secretion that can rescue ΔF508-CFTR trafficking by bypassing
      the Golgi.
    action: KEEP_AS_NON_CORE
    reason: These interactions are part of an unconventional secretion pathway that
      can rescue misfolded CFTR. While therapeutically relevant for CF, this represents
      an alternative trafficking mechanism rather than CFTR's core function as an
      ATP-gated chloride channel. The generic protein binding term inadequately describes
      these specialized trafficking interactions.
    supported_by:
    - reference_id: PMID:21884936
      supporting_text: Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional
        secretion pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22038833
  review:
    summary: This IPI annotation documents CFTR interaction with cytokeratin-8, where
      disrupting this interaction can correct ΔF508-CFTR functional defects.
    action: KEEP_AS_NON_CORE
    reason: The cytokeratin-8 interaction affects CFTR stability and function, with
      disruption of this interaction offering therapeutic potential for ΔF508-CFTR.
      While relevant for CFTR regulation and CF therapeutics, cytoskeletal interactions
      are supportive rather than core to CFTR's primary function as an ATP-gated chloride
      channel. The generic term fails to specify this is a cytoskeletal interaction.
    supported_by:
    - reference_id: PMID:22038833
      supporting_text: Disruption of cytokeratin-8 interaction with F508del-CFTR corrects
        its functional defect
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22121115
  review:
    summary: This IPI annotation documents CFTR interaction with TAT1/SLC26A8, a testis
      anion transporter important for sperm capacitation, suggesting coordinated anion
      transport in male reproduction.
    action: KEEP_AS_NON_CORE
    reason: The interaction with TAT1/SLC26A8 represents functional coupling between
      anion transporters in the male reproductive tract. While physiologically important
      for fertility, this tissue-specific regulatory interaction is not part of CFTR's
      core molecular function as an ATP-gated chloride channel. The generic protein
      binding term fails to convey this is a specialized reproductive system interaction.
    supported_by:
    - reference_id: PMID:22121115
      supporting_text: 'The testis anion transporter TAT1 (SLC26A8) physically and
        functionally interacts with the cystic fibrosis transmembrane conductance
        regulator channel: a potential role during sperm capacitation'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22768251
  review:
    summary: This IPI annotation identifies calumenin as a G551D-CFTR associated protein,
      relevant for understanding this gating mutation that causes CF with preserved
      protein expression.
    action: KEEP_AS_NON_CORE
    reason: Calumenin interaction with G551D-CFTR may influence the processing or
      function of this gating mutant. While relevant for understanding genotype-specific
      CF mechanisms, this represents a mutation-specific interaction rather than CFTR's
      core function as an ATP-gated chloride channel. The generic term provides no
      information about the nature of this ER/calcium-binding protein interaction.
    supported_by:
    - reference_id: PMID:22768251
      supporting_text: Proteomic identification of calumenin as a G551D-CFTR associated
        protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25661196
  review:
    summary: This IPI annotation likely documents CFTR interactions related to calcium
      homeostasis, as the study shows SERCA and PMCA pumps contribute to deregulated
      Ca2+ in CF epithelia.
    action: KEEP_AS_NON_CORE
    reason: Interactions affecting calcium homeostasis in CF epithelia represent secondary
      consequences of CFTR dysfunction rather than direct protein binding. While important
      for understanding CF pathophysiology, these interactions are not part of CFTR's
      core molecular function as an ATP-gated chloride channel. The generic term fails
      to specify the nature of these calcium-regulatory interactions.
    supported_by:
    - reference_id: PMID:25661196
      supporting_text: SERCA and PMCA pumps contribute to the deregulation of Ca2+
        homeostasis in human CF epithelial cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25712891
  review:
    summary: This IPI annotation documents enhanced actin binding requirement for
      G551D-CFTR to maintain plasma membrane localization compared to wild-type CFTR.
    action: KEEP_AS_NON_CORE
    reason: The interaction with actin cytoskeleton is important for CFTR membrane
      stability, with G551D-CFTR showing increased dependence on actin binding. While
      relevant for understanding mutation-specific effects, cytoskeletal interactions
      support but are not core to CFTR's primary function as an ATP-gated chloride
      channel. The generic term fails to identify this as an actin interaction.
    supported_by:
    - reference_id: PMID:25712891
      supporting_text: G551D-CFTR needs more bound actin than wild-type CFTR to maintain
        its presence in plasma membranes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26618866
  review:
    summary: This IPI annotation documents ΔF508-CFTR interactome remodeling that
      promotes rescue of the mutant protein, identifying therapeutic targets for CF.
    action: KEEP_AS_NON_CORE
    reason: This represents the altered protein interaction network of ΔF508-CFTR
      and how remodeling these interactions can rescue mutant function. While crucial
      for CF therapeutic development, these are disease-state interactions rather
      than CFTR's core function as an ATP-gated chloride channel. The generic term
      provides no information about the complex interactome changes involved.
    supported_by:
    - reference_id: PMID:26618866
      supporting_text: ∆f508 cftr interactome remodelling promotes rescue of cystic
        fibrosis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27092946
  review:
    summary: This IPI annotation documents CFTR interaction with KCa3.1 calcium-activated
      potassium channel, suggesting coordinated ion transport mechanisms in epithelia.
    action: KEEP_AS_NON_CORE
    reason: The interaction with KCa3.1 represents functional coupling between chloride
      and potassium channels important for driving epithelial fluid secretion. While
      physiologically relevant for coordinated ion transport, this regulatory interaction
      is not part of CFTR's core molecular function as an ATP-gated chloride channel.
      The generic term fails to convey this is an ion channel partnership.
    supported_by:
    - reference_id: PMID:27092946
      supporting_text: Investigating CFTR and KCa3.1 Protein/Protein Interactions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28360110
  review:
    summary: This IPI annotation shows ΔF508-CFTR trafficking mutation inhibits the
      constitutive activity of SLC26A9, demonstrating functional consequences of CFTR
      misfolding on partner proteins.
    action: KEEP_AS_NON_CORE
    reason: This interaction shows how ΔF508-CFTR mutation affects SLC26A9 function,
      illustrating disease mechanisms where mutant CFTR disrupts partner anion channels.
      While important for CF pathophysiology, this represents a pathological interaction
      consequence rather than CFTR's core function as an ATP-gated chloride channel.
      The generic term fails to convey the functional inhibition aspect.
    supported_by:
    - reference_id: PMID:28360110
      supporting_text: The CFTR trafficking mutation F508del inhibits the constitutive
        activity of SLC26A9
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29924966
  review:
    summary: This IPI annotation from a proteomic variant approach study identifies
      protein interactions relevant for personalized medicine approaches in CF and
      other diseases.
    action: KEEP_AS_NON_CORE
    reason: This represents proteomic-scale interaction mapping for personalized medicine
      applications. While useful for understanding CFTR's interaction network, these
      broad proteomic interactions are not part of CFTR's core molecular function
      as an ATP-gated chloride channel. The generic term provides no specific functional
      information about individual interactions identified.
    supported_by:
    - reference_id: PMID:29924966
      supporting_text: A Proteomic Variant Approach (ProVarA) for Personalized Medicine
        of Inherited and Somatic Disease
- term:
    id: GO:0006695
    label: cholesterol biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation incorrectly assigns CFTR to cholesterol biosynthesis
      based on ortholog transfer. CFTR is a chloride channel with no enzymatic role
      in cholesterol synthesis pathways.
    action: REMOVE
    reason: This annotation is clearly erroneous. CFTR is an ATP-gated chloride channel
      with no biochemical role in cholesterol biosynthesis. This appears to be a false
      positive from automated ortholog annotation transfer. There is no evidence in
      the literature supporting CFTR involvement in cholesterol synthesis - its only
      connection to cholesterol is through membrane organization and lipid raft association,
      not biosynthesis.
    additional_reference_ids:
    - PMID:11524016
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: A monomer is the minimum functional unit required for channel
        and ATPase activity of the cystic fibrosis transmembrane conductance regulator
- term:
    id: GO:0030301
    label: cholesterol transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation incorrectly assigns CFTR to cholesterol transport
      based on ortholog transfer. CFTR transports chloride and bicarbonate ions, not
      cholesterol.
    action: REMOVE
    reason: This annotation is incorrect. CFTR is an anion channel that transports
      chloride and bicarbonate ions, not cholesterol. While CFTR may localize to cholesterol-rich
      membrane microdomains (lipid rafts), it does not transport cholesterol itself.
      This appears to be another false positive from automated annotation transfer,
      possibly confused with other ABC transporters that do transport lipids.
    additional_reference_ids:
    - PMID:15010471
    - PMID:19019741
    supported_by:
    - reference_id: PMID:15010471
      supporting_text: dynamic control of CFTR Cl(-)/HCO(3)(-) permeability ratio,
        which is regulated by external Cl(-)
    - reference_id: PMID:19019741
      supporting_text: Mechanism of direct bicarbonate transport by the CFTR anion
        channel
- term:
    id: GO:0051649
    label: establishment of localization in cell
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation is overly vague. While CFTR does establish ion gradients
      and regulate fluid localization through its channel activity, this generic term
      provides minimal functional information.
    action: REMOVE
    reason: This annotation is too generic to be informative. While technically CFTR
      does contribute to establishing ion localization across membranes, this vague
      term fails to capture CFTR's specific function as an ATP-gated chloride channel.
      More specific terms like "chloride transmembrane transport" (GO:1902476) better
      describe CFTR's actual function. Generic cellular localization terms add no
      value when specific transport functions are known.
    proposed_replacement_terms:
    - id: GO:1902476
      label: chloride transmembrane transport
    additional_reference_ids:
    - PMID:19019741
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
- term:
    id: GO:0160133
    label: bicarbonate channel activity
  evidence_type: IDA
  original_reference_id: PMID:19019741
  review:
    summary: CFTR directly transports bicarbonate ions through its anion-selective
      pore, with HCO3-/Cl- selectivity dynamically regulated by external chloride
      concentration. This function is critical for pancreatic secretion, airway surface
      liquid pH, and male fertility.
    action: NEW
    reason: This core function is missing from the existing annotations. CFTR transports
      both chloride and bicarbonate ions, with bicarbonate transport being essential
      for multiple physiological processes including pancreatic enzyme secretion,
      airway mucus properties, and sperm capacitation. The bicarbonate conductance
      is not secondary to chloride transport but occurs directly through the CFTR
      pore. This should be annotated with IDA evidence based on multiple publications.
    additional_reference_ids:
    - PMID:19019741
    - PMID:15010471
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
    - reference_id: PMID:15010471
      supporting_text: dynamic control of CFTR Cl(-)/HCO(3)(-) permeability ratio,
        which is regulated by external Cl(-)
- term:
    id: GO:2000649
    label: regulation of sodium ion transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:19621064
  review:
    summary: CFTR negatively regulates ENaC (epithelial sodium channel) activity,
      preventing excessive sodium absorption and maintaining proper airway surface
      liquid hydration. Loss of this regulation in CF leads to sodium hyperabsorption
      and mucus dehydration.
    action: NEW
    reason: This critical regulatory function is missing from existing annotations.
      CFTR inhibits ENaC through multiple mechanisms, and loss of this inhibition
      in CF patients leads to sodium hyperabsorption, dehydrated mucus, and impaired
      mucociliary clearance. This regulation is essential for maintaining airway surface
      liquid homeostasis and represents a core physiological function of CFTR beyond
      its channel activity.
    additional_reference_ids:
    - PMID:19621064
    supported_by:
    - reference_id: PMID:19621064
      supporting_text: CFTR delivery to 25% of surface epithelial cells restores normal
        rates of mucus transport to human cystic fibrosis airway epithelium
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29393851
  review:
    summary: This IPI annotation documents CFTR interaction with ADGRG2 (adhesion
      GPCR G2) required for male fertility, involving both Gq activity and β-arrestin-1
      scaffolding.
    action: KEEP_AS_NON_CORE
    reason: The ADGRG2/CFTR coupling is essential for male fertility, representing
      a specialized reproductive function. While physiologically important in the
      male reproductive tract, this tissue-specific regulatory interaction is not
      part of CFTR's core molecular function as an ATP-gated chloride channel. The
      generic term fails to convey this is a GPCR-channel interaction critical for
      reproduction.
    supported_by:
    - reference_id: PMID:29393851
      supporting_text: Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR
        coupling are required for male fertility
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23818989
  review:
    summary: This IPI annotation documents CFTR degradation by E3 ubiquitin ligase
      MARCH2 through association with adaptor proteins CAL and STX6, representing
      a protein degradation pathway.
    action: KEEP_AS_NON_CORE
    reason: The interaction with MARCH2 E3 ligase and adaptors represents a degradation
      pathway controlling CFTR levels. While important for CFTR homeostasis and regulation,
      protein degradation mechanisms are not part of CFTR's core molecular function
      as an ATP-gated chloride channel. The generic term fails to specify this is
      an E3 ligase-mediated degradation interaction.
    supported_by:
    - reference_id: PMID:23818989
      supporting_text: Ubiquitination and degradation of CFTR by the E3 ubiquitin
        ligase MARCH2 through its association with adaptor proteins CAL and STX6
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IDA
  original_reference_id: PMID:15010471
  review:
    summary: This IDA annotation with direct experimental evidence confirms CFTR's
      chloride channel activity, specifically demonstrating dynamic control of Cl-/HCO3-
      selectivity by external chloride concentration.
    action: ACCEPT
    reason: Strong experimental evidence directly demonstrates CFTR's chloride channel
      activity. The referenced study shows CFTR mediates both chloride and bicarbonate
      transport, with selectivity controlled by external chloride concentration. While
      GO:0005260 (ATP-gated) is more specific, this annotation correctly captures
      the fundamental chloride channel function with solid experimental support.
    supported_by:
    - reference_id: PMID:15010471
      supporting_text: Dynamic control of cystic fibrosis transmembrane conductance
        regulator Cl(-)/HCO3(-) selectivity by external Cl(-)
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IDA
  original_reference_id: PMID:19019741
  review:
    summary: This IDA annotation provides direct experimental evidence for CFTR's
      chloride channel activity, with the study specifically demonstrating the mechanism
      of direct bicarbonate transport through the CFTR pore.
    action: ACCEPT
    reason: Solid experimental evidence demonstrates CFTR functions as a chloride
      channel that also conducts bicarbonate ions. The study shows CFTR transports
      HCO3- directly through its pore rather than through a coupled mechanism, confirming
      its role as an anion-selective channel. This annotation accurately reflects
      CFTR's demonstrated chloride channel activity.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Mechanism of direct bicarbonate transport by the CFTR anion
        channel
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IMP
  original_reference_id: PMID:19621064
  review:
    summary: This IMP annotation uses mutant phenotype evidence showing that restoring
      CFTR to 25% of epithelial cells restores normal mucus transport rates, confirming
      CFTR's chloride channel function in airway physiology.
    action: ACCEPT
    reason: The mutant phenotype evidence clearly demonstrates CFTR's chloride channel
      activity is essential for normal mucus transport in airways. The study shows
      a direct relationship between CFTR channel function and physiological mucus
      clearance, with partial restoration being sufficient for normal function. This
      supports CFTR's role as a chloride channel critical for airway surface liquid
      homeostasis.
    supported_by:
    - reference_id: PMID:19621064
      supporting_text: CFTR delivery to 25% of surface epithelial cells restores normal
        rates of mucus transport to human cystic fibrosis airway epithelium
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IDA
  original_reference_id: PMID:11524016
  review:
    summary: This IDA annotation provides direct experimental evidence that a CFTR
      monomer is the minimum functional unit for chloride channel activity, definitively
      establishing CFTR's channel function.
    action: ACCEPT
    reason: Strong experimental evidence demonstrates that CFTR functions as a chloride
      channel, with a monomer being sufficient for both channel and ATPase activity.
      This landmark study established that unlike other ABC transporters that function
      as dimers, CFTR operates as a monomeric channel. The annotation accurately captures
      CFTR's demonstrated chloride channel activity.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: A monomer is the minimum functional unit required for channel
        and ATPase activity of the cystic fibrosis transmembrane conductance regulator
- term:
    id: GO:0005260
    label: intracellularly ATP-gated chloride channel activity
  evidence_type: IMP
  original_reference_id: PMID:8910473
  review:
    summary: This IMP annotation with mutant phenotype evidence demonstrates CFTR's
      ATP-gated chloride channel activity, showing that ATPase activity is directly
      coupled to channel gating.
    action: ACCEPT
    reason: This seminal study established that CFTR's ATPase activity is essential
      for its function as an ATP-gated chloride channel. The evidence shows ATP binding
      and hydrolysis at the nucleotide-binding domains drives channel opening and
      closing cycles. This annotation precisely captures CFTR's unique mechanism as
      an ATP-regulated ion channel, distinguishing it from other chloride channels.
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: ATPase activity of the cystic fibrosis transmembrane conductance
        regulator
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IDA
  original_reference_id: PMID:11707463
  review:
    summary: This IDA annotation documents CFTR chloride channel activity in the context
      of studying how CAL/GOPC modulates CFTR plasma membrane expression and function.
    action: ACCEPT
    reason: The study provides direct evidence of CFTR chloride channel activity while
      investigating PDZ protein interactions. The research shows functional chloride
      currents mediated by CFTR and how these are modulated by CAL overexpression.
      This annotation correctly identifies CFTR's chloride channel function with experimental
      validation.
    supported_by:
    - reference_id: PMID:11707463
      supporting_text: Overexpression of CAL reduces CFTR chloride currents in mammalian
        cells and decreases expression, rate of insertion and half-life of CFTR in
        the plasma membrane
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IMP
  original_reference_id: PMID:24885604
  review:
    summary: This IMP annotation demonstrates CFTR chloride channel activity in pancreatic
      beta cells, showing CFTR contributes to cAMP-amplified exocytosis and insulin
      secretion alongside ANO1.
    action: ACCEPT
    reason: Mutant phenotype evidence confirms CFTR functions as a chloride channel
      in pancreatic beta cells, where it works with ANO1 to regulate insulin secretion.
      This expands understanding of CFTR's physiological roles beyond epithelial tissues.
      The annotation accurately reflects CFTR's chloride channel activity in endocrine
      function.
    supported_by:
    - reference_id: PMID:24885604
      supporting_text: CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis
        and insulin secretion in human and murine pancreatic beta-cells
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IDA
  original_reference_id: PMID:18570918
  review:
    summary: This IDA annotation provides direct evidence that endosomal SNARE proteins
      regulate CFTR chloride channel activity and trafficking in epithelial cells.
    action: ACCEPT
    reason: Direct experimental evidence demonstrates CFTR chloride channel activity
      and shows how SNARE proteins regulate both CFTR trafficking and function. The
      study establishes that proper CFTR channel activity depends on appropriate membrane
      trafficking mediated by SNARE proteins. This annotation correctly identifies
      CFTR's chloride channel function.
    supported_by:
    - reference_id: PMID:18570918
      supporting_text: Endosomal SNARE proteins regulate CFTR activity and trafficking
        in epithelial cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19289574
  review:
    summary: This IPI annotation documents CFTR interaction with SLC26A9, a constitutively
      active CFTR-regulated anion conductance that functionally couples with CFTR
      in bronchial epithelia.
    action: KEEP_AS_NON_CORE
    reason: The interaction with SLC26A9 is functionally important as SLC26A9 provides
      a CFTR-regulated alternative chloride conductance in airways. This represents
      a physiologically relevant regulatory relationship where CFTR modulates another
      anion channel. However, this regulatory interaction is not CFTR's core molecular
      function as an ATP-gated chloride channel.
    supported_by:
    - reference_id: PMID:19289574
      supporting_text: SLC26A9 is a constitutively active, CFTR-regulated anion conductance
        in human bronchial epithelia
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20658517
  review:
    summary: This IPI annotation documents interaction between CFTR and SLC26A9, where
      SLC26A9 stimulates CFTR expression and function in human bronchial cells, suggesting
      reciprocal regulation.
    action: KEEP_AS_NON_CORE
    reason: This interaction shows bidirectional regulation between CFTR and SLC26A9
      anion transporters. While functionally important for coordinated anion transport
      in airways, this regulatory relationship is not part of CFTR's core molecular
      function as an ATP-gated chloride channel. The generic protein binding term
      inadequately describes this specific functional coupling.
    supported_by:
    - reference_id: PMID:20658517
      supporting_text: SLC26A9 stimulates CFTR expression and function in human bronchial
        cell lines
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: IDA
  original_reference_id: PMID:22178883
  review:
    summary: This IDA annotation demonstrates CFTR chloride channel activity is distinct
      from but functionally related to TMEM16A/ANO1 calcium-activated chloride channels
      in epithelia.
    action: ACCEPT
    reason: Direct experimental evidence confirms CFTR functions as a chloride channel
      separate from TMEM16A, though they are functionally related in epithelial chloride
      secretion. This study clarifies the distinct roles of cAMP-activated (CFTR)
      versus calcium-activated (TMEM16A) chloride channels. The annotation accurately
      captures CFTR's chloride channel activity.
    supported_by:
    - reference_id: PMID:22178883
      supporting_text: CFTR and TMEM16A are separate but functionally related Cl-
        channels
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22178883
  review:
    summary: This IPI annotation documents functional interaction between CFTR and
      TMEM16A chloride channels, showing they work together in epithelial chloride
      secretion despite being separate channels.
    action: KEEP_AS_NON_CORE
    reason: The interaction between CFTR and TMEM16A represents functional coupling
      between two chloride channel systems in epithelia. While physiologically relevant
      for coordinated chloride secretion, this interaction is not part of CFTR's core
      molecular function as an ATP-gated channel. The generic protein binding term
      fails to capture the specific nature of this channel-channel functional relationship.
    supported_by:
    - reference_id: PMID:22178883
      supporting_text: CFTR and TMEM16A are separate but functionally related Cl-
        channels
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11707463
  review:
    summary: This IPI annotation documents CFTR interaction with CAL/GOPC, a Golgi-associated
      PDZ protein that retains CFTR intracellularly and reduces its plasma membrane
      expression, competing with NHERF for CFTR binding.
    action: KEEP_AS_NON_CORE
    reason: The CAL/GOPC interaction is functionally important for regulating CFTR
      trafficking and surface expression. CAL competes with NHERF for CFTR's C-terminal
      PDZ-binding motif, determining whether CFTR is retained intracellularly or reaches
      the plasma membrane. While physiologically relevant, this represents a trafficking
      regulatory mechanism rather than CFTR's core channel function.
    supported_by:
    - reference_id: PMID:11707463
      supporting_text: CAL modulates the surface expression of CFTR. CAL favors retention
        of CFTR within the cell, whereas NHE-RF favors surface expression by competing
        with CAL for the binding of CFTR
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15247260
  review:
    summary: This IPI annotation documents CFTR interaction with myosin VI, which
      regulates CFTR endocytosis from the plasma membrane, controlling surface expression
      levels.
    action: KEEP_AS_NON_CORE
    reason: The myosin VI interaction regulates CFTR endocytosis and membrane turnover.
      While important for controlling CFTR surface levels and activity, this represents
      a trafficking mechanism rather than CFTR's core molecular function as an ATP-gated
      chloride channel. The generic term fails to identify this as a motor protein
      interaction controlling endocytosis.
    supported_by:
    - reference_id: PMID:15247260
      supporting_text: Myosin VI regulates endocytosis of the cystic fibrosis transmembrane
        conductance regulator
- term:
    id: GO:0005260
    label: intracellularly ATP-gated chloride channel activity
  evidence_type: NAS
  original_reference_id: PMID:11707463
  review:
    summary: This NAS (Non-traceable Author Statement) annotation correctly identifies
      CFTR's ATP-gated chloride channel activity based on established knowledge referenced
      in this trafficking study.
    action: ACCEPT
    reason: While based on author statement rather than direct experimental evidence
      in this paper, the annotation accurately reflects well-established knowledge
      about CFTR's ATP-gated chloride channel activity. The paper focuses on trafficking
      regulation but correctly references CFTR's known molecular function. This annotation
      captures CFTR's primary functional mechanism.
    supported_by:
    - reference_id: PMID:11707463
      supporting_text: CFTR chloride currents in mammalian cells
- term:
    id: GO:0005254
    label: chloride channel activity
  evidence_type: TAS
  original_reference_id: PMID:9931011
  review:
    summary: This TAS annotation based on author statement confirms CFTR chloride
      channel activity, with the study showing Walker mutations reveal the relationship
      between catalytic and channel-gating activities.
    action: ACCEPT
    reason: The study provides strong evidence for CFTR's chloride channel activity
      by analyzing Walker motif mutations that affect ATP binding/hydrolysis. It demonstrates
      the coupling between ATPase activity and channel gating, confirming CFTR functions
      as a chloride channel whose gating is controlled by ATP. This annotation accurately
      reflects CFTR's established channel function.
    supported_by:
    - reference_id: PMID:9931011
      supporting_text: Walker mutations reveal loose relationship between catalytic
        and channel-gating activities of purified CFTR
- term:
    id: GO:0005260
    label: intracellularly ATP-gated chloride channel activity
  evidence_type: TAS
  original_reference_id: PMID:10581360
  review:
    summary: This TAS annotation demonstrates differential functions of CFTR's two
      nucleotide binding domains, confirming the ATP-gated nature of the chloride
      channel.
    action: ACCEPT
    reason: The study provides detailed evidence for CFTR's ATP-gated chloride channel
      activity by analyzing the distinct roles of NBD1 and NBD2 in channel gating.
      It shows how ATP binding and hydrolysis at these domains controls channel opening
      and closing. This annotation precisely captures CFTR's unique mechanism as an
      ATP-regulated chloride channel.
    supported_by:
    - reference_id: PMID:10581360
      supporting_text: Differential function of the two nucleotide binding domains
        on cystic fibrosis transmembrane conductance regulator
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31324722
  review:
    summary: This IPI annotation documents CFTR protein interactions. The publication
      could not be accessed for detailed review.
    action: UNDECIDED
    reason: Unable to access the referenced publication PMID:31324722 to evaluate
      the specific protein interactions documented. The annotation uses the generic
      protein binding term which provides minimal functional insight, but a proper
      review requires access to the primary literature.
    supported_by:
    - reference_id: PMID:31324722
      supporting_text: Epub 2019 Jul 19. Inhibition of calpain 1 restores plasma membrane
        stability to pharmacologically rescued Phe508del-CFTR variant.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35156780
  review:
    summary: This IPI annotation documents CFTR protein interactions. The publication
      could not be accessed for detailed review.
    action: UNDECIDED
    reason: Unable to access the referenced publication PMID:35156780 to evaluate
      the specific protein interactions documented. The annotation uses the generic
      protein binding term which provides minimal functional insight, but a proper
      review requires access to the primary literature.
    supported_by:
    - reference_id: PMID:35156780
      supporting_text: CFTR interactome mapping using the mammalian membrane two-hybrid
        high-throughput screening system.
- term:
    id: GO:0140359
    label: ABC-type transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation classifies CFTR as an ABC-type transporter, which
      is technically correct as CFTR is a member of the ABC transporter superfamily
      (ABCC7). However, CFTR is unique among ABC transporters in that it functions
      as an ion channel rather than an active transporter.
    action: ACCEPT
    reason: CFTR is a bona fide ABC transporter family member containing two transmembrane
      domains and two nucleotide-binding domains characteristic of ABC proteins. While
      CFTR is unique in functioning as an ion channel rather than a transporter, it
      retains the ABC transporter structural architecture and uses ATP binding/hydrolysis
      for channel gating [PMID:11524016]. The term is appropriate as it describes
      CFTR's protein family membership.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: CFTR is a transmembrane protein that spans the plasma membrane and functions
      as an ion channel. Its membrane topology is essential for its role in anion
      transport across epithelial cell membranes.
    action: ACCEPT
    reason: As a transmembrane chloride channel, CFTR must be embedded in the plasma
      membrane to function properly, with extracellular and intracellular domains
      positioned on opposite sides of the membrane to enable ion transport.
- term:
    id: GO:0016323
    label: basolateral plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation suggests CFTR localization to the basolateral plasma
      membrane. However, CFTR is predominantly localized to the apical plasma membrane
      of epithelial cells where it mediates chloride secretion into luminal spaces.
    action: REMOVE
    reason: CFTR is primarily an apical membrane protein in polarized epithelial cells,
      not basolateral. The apical localization is essential for CFTR's physiological
      function in secreting chloride and bicarbonate into lumens of airways, intestines,
      and ducts [PMID:11524016]. Basolateral localization would be inconsistent with
      CFTR's established role in vectorial ion transport across epithelia. This may
      represent an erroneous phylogenetic inference.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0006833
    label: water transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation suggests CFTR involvement in water transport. While
      CFTR indirectly regulates water movement through its control of ion gradients
      that drive osmotic water flow, CFTR itself does not transport water directly.
    action: KEEP_AS_NON_CORE
    reason: CFTR regulates transepithelial water transport indirectly by controlling
      chloride and bicarbonate secretion, which creates osmotic gradients that drive
      water movement. This is a downstream physiological consequence of CFTR's chloride
      channel activity rather than direct water transport. CFTR is an anion channel,
      not a water channel like aquaporins. The annotation captures a physiologically
      relevant outcome but may overstate CFTR's direct role.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: CFTR contributes to HCO(3)(-) transport in epithelial cells
        both directly (by HCO(3)(-) permeation through the channel) and indirectly
        (by regulating Cl(-)/HCO(3)(-) exchange proteins)
- term:
    id: GO:0015701
    label: bicarbonate transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation correctly identifies CFTR's role in bicarbonate transport.
      CFTR directly conducts bicarbonate ions through its channel pore, in addition
      to chloride ions, which is essential for pancreatic secretion, airway surface
      liquid pH, and sperm capacitation.
    action: ACCEPT
    reason: CFTR directly transports bicarbonate ions through its anion-selective
      pore. Patch clamp studies demonstrate that HCO3- permeability is approximately
      25% that of Cl- and that both ions share a common transport pathway [PMID:19019741].
      Bicarbonate transport by CFTR is critical for pancreatic ductal secretion, airway
      surface liquid pH regulation, and male fertility. This is a core transport function
      of CFTR.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation correctly identifies CFTR's primary biological process
      - chloride transmembrane transport. CFTR is the main chloride channel responsible
      for regulated chloride secretion across epithelial cell membranes.
    action: ACCEPT
    reason: Chloride transmembrane transport is CFTR's defining biological function.
      CFTR mediates regulated chloride ion movement across epithelial cell membranes,
      which is essential for fluid secretion in airways, pancreas, intestine, and
      other epithelia [PMID:11524016]. This is a core biological process annotation.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation suggests cytosolic localization. While CFTR has cytosolic
      domains (NBDs and R domain), CFTR is primarily a membrane protein and cytosol
      is not its primary localization.
    action: KEEP_AS_NON_CORE
    reason: CFTR is an integral membrane protein, not a cytosolic protein. However,
      portions of CFTR (the nucleotide-binding domains NBD1/NBD2 and the regulatory
      R domain) do extend into the cytosol. Nascent CFTR also transiently exists in
      the cytosol during biosynthesis before membrane insertion. This annotation is
      technically not incorrect but may be misleading about CFTR's primary localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation correctly identifies CFTR's localization to the apical
      plasma membrane of polarized epithelial cells. This is the correct functional
      localization for CFTR's role in chloride secretion.
    action: ACCEPT
    reason: CFTR is specifically targeted to the apical plasma membrane of polarized
      epithelial cells, where it mediates chloride and bicarbonate secretion into
      luminal spaces [PMID:11524016]. This apical localization is essential for CFTR's
      physiological function in fluid secretion and is a core cellular component annotation.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly identifies CFTR's ATP binding capability.
      CFTR contains two nucleotide-binding domains (NBD1 and NBD2) that bind ATP to
      regulate channel gating.
    action: ACCEPT
    reason: ATP binding is essential for CFTR function. The two NBDs bind ATP, promoting
      NBD dimerization that opens the channel pore. ATP hydrolysis at NBD2 then allows
      channel closure [PMID:8910473]. This is a core molecular function of CFTR.
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: Following reconstitution the mutant protein exhibited both
        defective ATP hydrolysis and channel gating, providing direct evidence that
        CFTR utilizes ATP to gate its channel activity
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: This IEA annotation suggests nuclear localization for CFTR. There is
      no established evidence that CFTR localizes to or functions in the nucleus.
      CFTR is a plasma membrane chloride channel.
    action: REMOVE
    reason: CFTR is an integral plasma membrane protein that functions as a chloride
      channel at the cell surface [PMID:11524016]. There is no credible evidence for
      nuclear localization of full-length CFTR. This appears to be an erroneous computational
      annotation, possibly from misinterpretation of proteomics data or spurious sequence-based
      predictions.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This IEA annotation indicates cytoplasmic localization. While CFTR has
      cytoplasmic domains and nascent protein is synthesized in the cytoplasm, CFTR's
      functional localization is at the plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: CFTR is primarily a plasma membrane protein. However, newly synthesized
      CFTR exists in the cytoplasm/ER during biosynthesis, and the large cytoplasmic
      domains (NBD1, R domain, NBD2) technically extend into the cytoplasm. This annotation
      is not incorrect but does not represent CFTR's primary functional localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: This IEA annotation identifies ER membrane localization for CFTR. This
      is correct as CFTR is synthesized and initially folded in the ER membrane before
      trafficking to the plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: CFTR is synthesized as an integral membrane protein in the ER, where it
      undergoes folding and quality control. Immature CFTR transiently resides in
      the ER membrane during biosynthesis. ER retention of misfolded CFTR (especially
      deltaF508-CFTR) is a hallmark of cystic fibrosis pathogenesis. While not CFTR's
      functional destination, ER membrane localization is part of its normal biogenesis
      pathway.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly identifies CFTR's localization to the plasma
      membrane, which is its primary functional location.
    action: ACCEPT
    reason: CFTR's functional localization is at the plasma membrane, specifically
      the apical plasma membrane of epithelial cells, where it mediates chloride and
      bicarbonate secretion [PMID:11524016]. This is a core cellular component annotation.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0006811
    label: monoatomic ion transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly identifies CFTR's role in ion transport.
      CFTR transports chloride and bicarbonate ions, which are monoatomic/simple inorganic
      anions.
    action: ACCEPT
    reason: CFTR mediates the transport of chloride and bicarbonate ions across epithelial
      cell membranes [PMID:19019741]. While this term is more general than specific
      chloride or bicarbonate transport terms, it correctly captures CFTR's core function
      as an ion channel.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
- term:
    id: GO:0006821
    label: chloride transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly identifies CFTR's primary biological process
      - chloride transport. CFTR is the main chloride channel in epithelial cells.
    action: ACCEPT
    reason: Chloride transport is CFTR's defining biological function. CFTR mediates
      regulated chloride ion movement across epithelial cell membranes [PMID:11524016].
      This is a core biological process annotation.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0015701
    label: bicarbonate transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This IEA annotation correctly identifies CFTR's role in bicarbonate transport.
      CFTR directly conducts bicarbonate ions in addition to chloride ions.
    action: ACCEPT
    reason: CFTR directly transports bicarbonate through its anion-selective channel
      pore [PMID:19019741]. Bicarbonate transport by CFTR is essential for pancreatic
      secretion, airway surface liquid pH, and male fertility. This is a core biological
      process annotation.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: This IEA annotation identifies CFTR as a membrane protein, which is correct
      but very general. CFTR is an integral membrane protein.
    action: ACCEPT
    reason: CFTR is an integral membrane protein with multiple membrane-spanning domains
      [PMID:11524016]. While this term is less specific than plasma membrane or apical
      plasma membrane, it correctly captures CFTR's membrane association.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly identifies CFTR localization to the apical
      plasma membrane of epithelial cells.
    action: ACCEPT
    reason: CFTR is specifically targeted to the apical plasma membrane of polarized
      epithelial cells [PMID:11524016]. This is a core cellular component annotation
      essential for CFTR's physiological function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0016853
    label: isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This IEA annotation suggests isomerase activity for CFTR. This annotation
      appears erroneous as CFTR is a chloride channel with ATPase activity, not an
      isomerase.
    action: REMOVE
    reason: CFTR is a chloride channel that uses ATP binding and hydrolysis for channel
      gating [PMID:8910473]. It has no known isomerase activity. This annotation appears
      to be an incorrect automated transfer, possibly due to misinterpretation of
      CFTR's EC number 5.6.1.6 (channel-conductance-controlling ATPase), which is
      in the isomerase class but refers to the conformational changes coupled to ATP
      hydrolysis, not true isomerase activity.
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: Following reconstitution the mutant protein exhibited both
        defective ATP hydrolysis and channel gating, providing direct evidence that
        CFTR utilizes ATP to gate its channel activity
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly identifies CFTR's ATP hydrolysis activity.
      CFTR hydrolyzes ATP at its nucleotide-binding domains to regulate channel gating.
    action: ACCEPT
    reason: ATP hydrolysis is essential for CFTR channel gating. Purified reconstituted
      CFTR has intrinsic ATPase activity required for opening and closing the channel
      gate [PMID:8910473]. This is a core molecular function of CFTR.
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: In this study, we report the first measurements of the rate
        of ATP hydrolysis by purified, reconstituted CFTR
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: This IEA annotation identifies early endosome membrane localization.
      CFTR does traffic through the endosomal system as part of its recycling pathway
      between the plasma membrane and intracellular compartments.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes constitutive endocytosis and recycling. After internalization
      from the plasma membrane, CFTR is found in early endosomes before being sorted
      for recycling back to the surface or degradation. This represents a trafficking
      intermediate rather than CFTR's primary functional localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0034220
    label: monoatomic ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation correctly identifies CFTR's role in ion transmembrane
      transport. CFTR transports chloride and bicarbonate ions across membranes.
    action: ACCEPT
    reason: CFTR mediates transmembrane transport of chloride and bicarbonate ions
      [PMID:19019741]. While this term is more general than specific anion transport
      terms, it correctly captures CFTR's fundamental function.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
- term:
    id: GO:0034707
    label: chloride channel complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This IEA annotation identifies CFTR as part of a chloride channel complex.
      While CFTR is a chloride channel, the monomeric form is sufficient for function.
    action: ACCEPT
    reason: CFTR functions as a chloride channel, and while a monomer is sufficient
      for channel activity [PMID:11524016], CFTR does interact with other proteins
      (NHERF, SLC26 transporters) to form functional complexes at the cell surface.
      The term appropriately captures CFTR's role as a chloride channel component.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: CFTR function does not require a multimeric complex for function
        as we determined that purified, reconstituted CFTR monomers are sufficient
        to mediate regulated chloride conduction and ATPase activity
- term:
    id: GO:0055038
    label: recycling endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: This IEA annotation identifies recycling endosome membrane localization.
      CFTR does transit through recycling endosomes as part of its constitutive endocytic
      recycling pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes constitutive endocytosis and recycling between the plasma
      membrane and intracellular compartments. Recycling endosomes are key intermediates
      in this trafficking pathway that maintains CFTR surface expression. However,
      this represents a trafficking compartment rather than CFTR's primary functional
      localization at the apical plasma membrane.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: This IEA annotation correctly identifies CFTR's involvement in transmembrane
      transport. CFTR mediates chloride and bicarbonate transport across epithelial
      cell membranes.
    action: ACCEPT
    reason: CFTR mediates transmembrane transport of anions (chloride and bicarbonate)
      [PMID:19019741]. While this is a general term, it correctly captures CFTR's
      fundamental transport function.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
- term:
    id: GO:0098660
    label: obsolete inorganic ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This annotation uses an obsolete GO term and should be replaced with
      current terminology.
    action: REMOVE
    reason: This GO term is marked as obsolete. The annotation should use current
      GO terminology such as GO:0034220 (monoatomic ion transmembrane transport) or
      more specific terms like GO:1902476 (chloride transmembrane transport). Obsolete
      terms should not be retained.
    supported_by: []
- term:
    id: GO:0140359
    label: ABC-type transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: This IEA annotation classifies CFTR as an ABC-type transporter. CFTR
      is a member of the ABC transporter superfamily (ABCC7) though it uniquely functions
      as a channel rather than a pump.
    action: ACCEPT
    reason: CFTR belongs to the ABC transporter superfamily and has the characteristic
      ABC domain architecture [PMID:11524016]. While CFTR functions as an ion channel
      rather than an active transporter, the ABC-type transporter activity term appropriately
      describes its protein family classification.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36012204
  review:
    summary: This IPI annotation documents CFTR protein interactions. The publication
      could not be accessed for detailed review.
    action: UNDECIDED
    reason: Unable to access the referenced publication PMID:36012204 to evaluate
      the specific protein interactions documented. A proper review requires access
      to the primary literature.
    supported_by:
    - reference_id: PMID:36012204
      supporting_text: Differential CFTR-Interactome Proximity Labeling Procedures
        Identify Enrichment in Multiple SLC Transporters.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39009827
  review:
    summary: This IPI annotation documents CFTR protein interactions. The publication
      could not be accessed for detailed review.
    action: UNDECIDED
    reason: Unable to access the referenced publication PMID:39009827 to evaluate
      the specific protein interactions documented. A proper review requires access
      to the primary literature.
    supported_by:
    - reference_id: PMID:39009827
      supporting_text: 2024 Jul 15. Proteome-scale characterisation of motif-based
        interactome rewiring by disease mutations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9671706
  review:
    summary: This IPI annotation documents CFTR protein interactions. The publication
      could not be accessed for detailed review.
    action: UNDECIDED
    reason: Unable to access the referenced publication PMID:9671706 to evaluate the
      specific protein interactions documented. A proper review requires access to
      the primary literature.
    supported_by:
    - reference_id: PMID:9671706
      supporting_text: 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.
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-382556
  review:
    summary: This TAS annotation from Reactome correctly identifies CFTR's role in
      transmembrane transport.
    action: ACCEPT
    reason: CFTR mediates transmembrane transport of chloride and bicarbonate ions
      [PMID:19019741]. This Reactome annotation correctly captures CFTR's fundamental
      transport function.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation suggests cytosolic localization. CFTR is primarily
      a membrane protein with cytosolic domains.
    action: KEEP_AS_NON_CORE
    reason: CFTR is an integral membrane protein, but its NBDs and R domain extend
      into the cytosol. This annotation is not incorrect but does not represent CFTR's
      primary functional localization at the plasma membrane.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0015106
    label: bicarbonate transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation correctly identifies CFTR's bicarbonate transport
      function.
    action: ACCEPT
    reason: CFTR directly transports bicarbonate ions through its anion-selective
      pore [PMID:19019741]. This is a core molecular function of CFTR essential for
      pancreatic secretion and airway surface liquid pH.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
- term:
    id: GO:0015108
    label: chloride transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation correctly identifies CFTR's chloride transport function.
    action: ACCEPT
    reason: CFTR is a chloride transmembrane transporter that mediates chloride ion
      movement across epithelial cell membranes [PMID:11524016]. This is CFTR's primary
      molecular function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0048240
    label: sperm capacitation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation identifies CFTR's role in sperm capacitation. CFTR
      is expressed in sperm and required for normal capacitation through bicarbonate
      transport and pH regulation.
    action: KEEP_AS_NON_CORE
    reason: CFTR is expressed in sperm and contributes to capacitation through its
      bicarbonate transport function, which helps regulate intracellular pH and membrane
      hyperpolarization. Male infertility due to congenital bilateral absence of vas
      deferens (CBAVD) is a common CF manifestation. While physiologically important,
      sperm capacitation is a tissue-specific downstream process rather than CFTR's
      core molecular function.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: CFTR contributes to HCO(3)(-) transport in epithelial cells
        both directly (by HCO(3)(-) permeation through the channel) and indirectly
- term:
    id: GO:0051454
    label: intracellular pH elevation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation suggests CFTR involvement in intracellular pH elevation.
      CFTR's bicarbonate transport can contribute to pH regulation.
    action: KEEP_AS_NON_CORE
    reason: CFTR transports bicarbonate ions, which can affect intracellular pH. In
      sperm, CFTR-mediated bicarbonate transport contributes to intracellular alkalinization
      during capacitation. However, this is a downstream physiological consequence
      of CFTR's bicarbonate transport rather than its primary molecular function.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: CFTR contributes to HCO(3)(-) transport in epithelial cells
        both directly (by HCO(3)(-) permeation through the channel) and indirectly
- term:
    id: GO:0060081
    label: membrane hyperpolarization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation suggests CFTR involvement in membrane hyperpolarization.
      Chloride efflux through CFTR can contribute to membrane potential changes.
    action: KEEP_AS_NON_CORE
    reason: CFTR-mediated chloride transport can affect membrane potential. In sperm,
      CFTR activity contributes to membrane hyperpolarization during capacitation.
      However, this is an indirect consequence of CFTR's anion channel activity rather
      than a direct function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0070175
    label: positive regulation of enamel mineralization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation suggests CFTR involvement in enamel mineralization.
      CFTR is expressed in ameloblasts and contributes to pH regulation during enamel
      formation.
    action: KEEP_AS_NON_CORE
    reason: CFTR is expressed in dental ameloblasts and contributes to the ion transport
      required for proper enamel mineralization. CF patients can have dental enamel
      defects. However, enamel mineralization is a tissue-specific downstream process
      rather than CFTR's core molecular function as an anion channel.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: CFTR contributes to HCO(3)(-) transport in epithelial cells
        both directly (by HCO(3)(-) permeation through the channel) and indirectly
- term:
    id: GO:0071320
    label: cellular response to cAMP
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation identifies CFTR's involvement in cellular response
      to cAMP. CFTR is activated by PKA-mediated phosphorylation in response to elevated
      cAMP.
    action: ACCEPT
    reason: CFTR channel activity is directly regulated by cAMP through PKA-mediated
      phosphorylation of its R domain [PMID:11524016]. This makes CFTR a key effector
      of cAMP signaling in epithelial cells, where cAMP elevation leads to CFTR-dependent
      chloride secretion. This annotation correctly captures CFTR's role in the cellular
      response to cAMP.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0097186
    label: amelogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation suggests CFTR involvement in amelogenesis (enamel
      formation). CFTR is expressed in ameloblasts and contributes to ion transport
      during tooth development.
    action: KEEP_AS_NON_CORE
    reason: CFTR contributes to amelogenesis through its role in ion transport in
      developing teeth. Dental enamel defects have been reported in CF patients. However,
      amelogenesis is a tissue-specific developmental process rather than CFTR's core
      molecular function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This IEA annotation correctly identifies CFTR's primary biological process
      - chloride transmembrane transport.
    action: ACCEPT
    reason: Chloride transmembrane transport is CFTR's defining biological function
      [PMID:11524016]. This is a core biological process annotation.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:22006324
  review:
    summary: This IDA annotation provides direct experimental evidence for CFTR's
      chloride transport function.
    action: ACCEPT
    reason: Direct assay evidence for CFTR-mediated chloride transmembrane transport.
      This is CFTR's core biological function [PMID:11524016].
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:22006324
      supporting_text: Anoctamin 6 is an essential component of the outwardly rectifying
        chloride channel.
- term:
    id: GO:0071889
    label: 14-3-3 protein binding
  evidence_type: EXP
  original_reference_id: PMID:26888287
  review:
    summary: This EXP annotation documents CFTR binding to 14-3-3 proteins via its
      phosphorylated R domain.
    action: ACCEPT
    reason: The CFTR R domain binds 14-3-3 proteins in a phosphorylation-dependent
      manner. This interaction enhances CFTR trafficking to the plasma membrane and
      is therapeutically relevant for correcting deltaF508-CFTR trafficking defects
      [PMID:26888287].
    supported_by:
    - reference_id: PMID:26888287
      supporting_text: The binding of the 14-3-3 protein to the CFTR regulatory (R)
        domain has been found to enhance CFTR trafficking to the plasma membrane
- term:
    id: GO:0071889
    label: 14-3-3 protein binding
  evidence_type: IMP
  original_reference_id: PMID:26888287
  review:
    summary: This IMP annotation provides mutational phenotype evidence for CFTR-14-3-3
      binding.
    action: ACCEPT
    reason: Mutational analysis demonstrates that specific phosphorylation sites in
      CFTR R domain (especially pS768) are required for 14-3-3 binding, and mutations
      affecting these sites reduce CFTR trafficking [PMID:26888287].
    supported_by:
    - reference_id: PMID:26888287
      supporting_text: The key binding site of CFTR (pS768) occupies one groove of
        the 14-3-3 dimer, and a weaker, secondary binding site occupies the other
        binding groove
- term:
    id: GO:0071889
    label: 14-3-3 protein binding
  evidence_type: IPI
  original_reference_id: PMID:26888287
  review:
    summary: This IPI annotation documents physical interaction between CFTR and 14-3-3
      proteins.
    action: ACCEPT
    reason: Crystal structures and biochemical assays demonstrate direct physical
      interaction between CFTR R domain peptides and 14-3-3 proteins [PMID:26888287].
    supported_by:
    - reference_id: PMID:26888287
      supporting_text: Using multiple biochemical assays and crystal structures, we
        show that the interaction between them is governed by two binding sites
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:32487539
  review:
    summary: CFTR functions as an ATP-gated chloride channel specifically localized
      to the apical plasma membrane of epithelial cells, where it regulates anion
      secretion and fluid transport across epithelial barriers.
    action: ACCEPT
    reason: Apical plasma membrane localization is critical for CFTR function as it
      enables proper directional chloride secretion from epithelial cells into luminal
      spaces, which is essential for maintaining proper fluid balance in airways,
      intestines, and other epithelia.
    supported_by:
    - reference_id: PMID:32487539
      supporting_text: '2020 Jun 2. TMEM16A deficiency: a potentially fatal neonatal
        disease resulting from impaired chloride currents.'
- term:
    id: GO:0070175
    label: positive regulation of enamel mineralization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This ISS annotation suggests CFTR involvement in enamel mineralization
      based on sequence similarity.
    action: KEEP_AS_NON_CORE
    reason: CFTR is expressed in ameloblasts and contributes to ion transport during
      tooth development. However, enamel mineralization is a tissue-specific developmental
      process rather than CFTR's core molecular function as an anion channel.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0097186
    label: amelogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This ISS annotation suggests CFTR involvement in amelogenesis based on
      sequence similarity.
    action: KEEP_AS_NON_CORE
    reason: CFTR contributes to amelogenesis through its ion transport function in
      developing teeth. However, amelogenesis is a tissue-specific developmental process
      rather than CFTR's core molecular function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This ISS annotation identifies CFTR's chloride transport function based
      on sequence similarity.
    action: ACCEPT
    reason: Chloride transmembrane transport is CFTR's primary biological function
      [PMID:11524016]. This is a core annotation.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0017081
    label: chloride channel regulator activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-383190
  review:
    summary: This TAS annotation from Reactome suggests CFTR has chloride channel
      regulator activity, which is accurate as CFTR regulates other chloride channels
      like ORCC and ClC channels.
    action: ACCEPT
    reason: CFTR regulates other chloride channels in addition to functioning as a
      chloride channel itself. CFTR activation influences the activity of outwardly
      rectifying chloride channels (ORCC) and other anion transport pathways. This
      regulatory function is well-established in the CF literature.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:11524016
  review:
    summary: This IDA annotation provides direct experimental evidence for CFTR's
      ATP hydrolysis activity.
    action: ACCEPT
    reason: Direct assay evidence demonstrates that purified, reconstituted CFTR has
      intrinsic ATPase activity required for channel gating [PMID:11524016, PMID:8910473].
      This is a core molecular function of CFTR.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: purified, reconstituted CFTR monomers are sufficient to mediate
        regulated chloride conduction and ATPase activity
- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:8910473
  review:
    summary: This IDA annotation provides the first direct measurements of CFTR ATPase
      activity.
    action: ACCEPT
    reason: This landmark study [PMID:8910473] provided the first biochemical evidence
      that CFTR possesses intrinsic ATPase activity. The G551D mutation that resides
      in a conserved nucleotidase motif caused both defective ATP hydrolysis and channel
      gating, demonstrating that ATP hydrolysis is essential for CFTR channel function.
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: In this study, we report the first measurements of the rate
        of 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
  review:
    summary: This TAS annotation from Reactome correctly identifies CFTR's chloride
      transport function.
    action: ACCEPT
    reason: CFTR is a chloride transmembrane transporter that mediates chloride ion
      movement across epithelial membranes [PMID:11524016]. This is CFTR's core molecular
      function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0015108
    label: chloride transmembrane transporter activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5678863
  review:
    summary: This TAS annotation from Reactome correctly identifies CFTR's chloride
      transport function.
    action: ACCEPT
    reason: CFTR is a chloride transmembrane transporter [PMID:11524016]. This is
      CFTR's core molecular function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0043225
    label: obsolete ATPase-coupled inorganic anion transmembrane transporter activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1454916
  review:
    summary: This annotation uses an obsolete GO term and should be replaced with
      current terminology.
    action: REMOVE
    reason: This GO term is marked as obsolete. The annotation should use current
      GO terminology. Additionally, while CFTR uses ATP for channel gating, it functions
      as a channel (facilitated diffusion) rather than an ATPase-coupled transporter
      (active transport).
    supported_by: []
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868658
  review:
    summary: This TAS annotation from Reactome identifies CFTR in clathrin-coated
      endocytic vesicle membranes during trafficking.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes clathrin-mediated endocytosis as part of its constitutive
      recycling pathway. This represents a trafficking intermediate rather than CFTR's
      primary functional localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868659
  review:
    summary: This TAS annotation from Reactome identifies CFTR in clathrin-coated
      endocytic vesicle membranes.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling
      pathway. This is a trafficking intermediate rather than CFTR's primary functional
      localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868660
  review:
    summary: This TAS annotation from Reactome identifies CFTR in clathrin-coated
      endocytic vesicle membranes.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling
      pathway. This is a trafficking intermediate.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868661
  review:
    summary: CFTR in clathrin-coated endocytic vesicle membranes during trafficking.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling
      pathway.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869438
  review:
    summary: CFTR in clathrin-coated endocytic vesicle membranes during trafficking.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling
      pathway.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871193
  review:
    summary: CFTR in clathrin-coated endocytic vesicle membranes during trafficking.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling
      pathway.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871194
  review:
    summary: CFTR in clathrin-coated endocytic vesicle membranes during trafficking.
    action: KEEP_AS_NON_CORE
    reason: CFTR undergoes clathrin-mediated endocytosis as part of its recycling
      pathway.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:28067262
  review:
    summary: Direct experimental evidence for CFTR plasma membrane localization.
    action: ACCEPT
    reason: CFTR localizes to the plasma membrane where it functions as a chloride
      channel [PMID:11524016]. Core localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:28067262
      supporting_text: Sec16A is critical for both conventional and unconventional
        secretion of CFTR.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:28067262
  review:
    summary: This annotation suggests CFTR involvement in ER stress response. Misfolded
      CFTR (especially deltaF508) triggers ER stress.
    action: KEEP_AS_NON_CORE
    reason: Misfolded CFTR variants trigger ER stress and activate the unfolded protein
      response. This is particularly relevant for deltaF508-CFTR. However, this reflects
      CFTR's role as a substrate of ER quality control rather than its primary function
      as a chloride channel.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:28067262
      supporting_text: Sec16A is critical for both conventional and unconventional
        secretion of CFTR.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:21884936
  review:
    summary: Direct experimental evidence for CFTR plasma membrane localization.
    action: ACCEPT
    reason: CFTR localizes to the plasma membrane where it functions as a chloride
      channel [PMID:11524016].
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:21884936
      supporting_text: Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional
        secretion pathway.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IDA
  original_reference_id: PMID:21884936
  review:
    summary: CFTR involvement in ER stress response related to protein folding.
    action: KEEP_AS_NON_CORE
    reason: Misfolded CFTR triggers ER stress. This reflects CFTR's role as a substrate
      of ER quality control rather than its primary function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:21884936
      supporting_text: Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional
        secretion pathway.
- term:
    id: GO:0106138
    label: Sec61 translocon complex binding
  evidence_type: IDA
  original_reference_id: PMID:9792704
  review:
    summary: CFTR binds to Sec61 translocon during its cotranslational insertion into
      the ER membrane.
    action: KEEP_AS_NON_CORE
    reason: CFTR interacts with the Sec61 translocon during membrane insertion in
      the ER. This is part of CFTR's biogenesis pathway rather than its primary function
      as a chloride channel.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:9792704
      supporting_text: The mechanism underlying cystic fibrosis transmembrane conductance
        regulator transport from the endoplasmic reticulum to the proteasome includes
        Sec61beta and a cytosolic, deglycosylated intermediary.
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:16207813
  review:
    summary: CFTR binds chaperone proteins during its folding in the ER.
    action: KEEP_AS_NON_CORE
    reason: CFTR interacts with multiple chaperones (Hsp70, Hsp90, calnexin) during
      its complex folding process. Chaperone interactions are important for CFTR maturation
      but represent biogenesis rather than its primary chloride channel function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:16207813
      supporting_text: 2005 Oct 5. BAG-2 acts as an inhibitor of the chaperone-associated
        ubiquitin ligase CHIP.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This annotation suggests nuclear localization for CFTR. There is no evidence
      CFTR localizes to or functions in the nucleus.
    action: REMOVE
    reason: CFTR is a plasma membrane chloride channel with no known nuclear localization
      or function [PMID:11524016]. This appears to be an erroneous computational annotation.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:28130590
  review:
    summary: Direct experimental evidence for CFTR plasma membrane localization.
    action: ACCEPT
    reason: CFTR localizes to the plasma membrane where it functions as a chloride
      channel [PMID:11524016].
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:28130590
      supporting_text: Epub 2017 Jan 27. Expression of epithelial sodium channel (ENaC)
        and CFTR in the human epidermis and epidermal appendages.
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:28130590
  review:
    summary: Direct experimental evidence for CFTR apical plasma membrane localization.
    action: ACCEPT
    reason: CFTR localizes specifically to the apical plasma membrane of polarized
      epithelial cells [PMID:11524016]. This is a core localization annotation.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:28130590
      supporting_text: Epub 2017 Jan 27. Expression of epithelial sodium channel (ENaC)
        and CFTR in the human epidermis and epidermal appendages.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15010471
  review:
    summary: Direct experimental evidence for CFTR plasma membrane localization from
      bicarbonate transport study.
    action: ACCEPT
    reason: CFTR localizes to the plasma membrane [PMID:11524016, PMID:15010471].
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:15010471
      supporting_text: 2004 Mar 9. Dynamic control of cystic fibrosis transmembrane
        conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-).
- term:
    id: GO:0015106
    label: bicarbonate transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:15010471
  review:
    summary: Direct experimental evidence for CFTR bicarbonate transport activity.
    action: ACCEPT
    reason: CFTR directly conducts bicarbonate ions through its channel pore [PMID:19019741,
      PMID:15010471]. This is a core molecular function.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR,
        and selectivity between Cl(-) and HCO(3)(-) is independent of ionic conditions
    - reference_id: PMID:15010471
      supporting_text: 2004 Mar 9. Dynamic control of cystic fibrosis transmembrane
        conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-).
- term:
    id: GO:0015106
    label: bicarbonate transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:19019741
  review:
    summary: Direct experimental evidence for CFTR bicarbonate transport using patch
      clamp.
    action: ACCEPT
    reason: This study provided direct patch clamp evidence that CFTR conducts bicarbonate
      with approximately 25% the permeability of chloride [PMID:19019741]. Core molecular
      function.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: The permeability of HCO(3)(-) was approximately 25% that of
        Cl(-) and was invariable under all ionic conditions studied
- term:
    id: GO:0015701
    label: bicarbonate transport
  evidence_type: IDA
  original_reference_id: PMID:15010471
  review:
    summary: Direct evidence for CFTR-mediated bicarbonate transport.
    action: ACCEPT
    reason: CFTR transports bicarbonate ions [PMID:19019741]. Core biological process.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR
    - reference_id: PMID:15010471
      supporting_text: 2004 Mar 9. Dynamic control of cystic fibrosis transmembrane
        conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-).
- term:
    id: GO:0015701
    label: bicarbonate transport
  evidence_type: IDA
  original_reference_id: PMID:19019741
  review:
    summary: Direct patch clamp evidence for CFTR-mediated bicarbonate transport.
    action: ACCEPT
    reason: CFTR transports bicarbonate ions [PMID:19019741]. Core biological process.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IMP
  original_reference_id: PMID:19621064
  review:
    summary: Mutant phenotype evidence for CFTR apical plasma membrane localization.
    action: ACCEPT
    reason: CFTR localizes to the apical plasma membrane [PMID:11524016]. Core localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:19621064
      supporting_text: 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells
        restores normal rates of mucus transport to human cystic fibrosis airway epithelium.
- term:
    id: GO:0035377
    label: transepithelial water transport
  evidence_type: IMP
  original_reference_id: PMID:19621064
  review:
    summary: CFTR indirectly regulates transepithelial water transport through ion
      transport.
    action: KEEP_AS_NON_CORE
    reason: CFTR controls water movement indirectly by regulating ion gradients that
      drive osmotic water flow. This is a downstream physiological consequence of
      CFTR's chloride channel activity.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:19621064
      supporting_text: 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells
        restores normal rates of mucus transport to human cystic fibrosis airway epithelium.
- term:
    id: GO:0050891
    label: multicellular organismal-level water homeostasis
  evidence_type: IMP
  original_reference_id: PMID:19621064
  review:
    summary: CFTR contributes to organismal water homeostasis through epithelial fluid
      secretion.
    action: KEEP_AS_NON_CORE
    reason: CFTR regulates fluid secretion across multiple epithelia, contributing
      to organismal water balance. This is an indirect, downstream consequence of
      CFTR's ion channel activity rather than its core function.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:19621064
      supporting_text: 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells
        restores normal rates of mucus transport to human cystic fibrosis airway epithelium.
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:19019741
  review:
    summary: Direct evidence for CFTR chloride transport from patch clamp studies.
    action: ACCEPT
    reason: CFTR mediates chloride transmembrane transport [PMID:19019741]. Core biological
      process.
    supported_by:
    - reference_id: PMID:19019741
      supporting_text: Cl(-) and HCO(3)(-) share a common transport pathway in CFTR
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: IMP
  original_reference_id: PMID:19621064
  review:
    summary: Mutant phenotype evidence for CFTR chloride transport.
    action: ACCEPT
    reason: CFTR mediates chloride transmembrane transport [PMID:11524016]. Core biological
      process.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:19621064
      supporting_text: 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells
        restores normal rates of mucus transport to human cystic fibrosis airway epithelium.
- term:
    id: GO:1904322
    label: cellular response to forskolin
  evidence_type: IDA
  original_reference_id: PMID:15010471
  review:
    summary: CFTR responds to forskolin via cAMP-PKA signaling pathway.
    action: KEEP_AS_NON_CORE
    reason: Forskolin elevates cAMP, which activates PKA-mediated CFTR phosphorylation
      and channel opening. This reflects CFTR's role as a cAMP-regulated channel rather
      than a direct response to forskolin.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:15010471
      supporting_text: 2004 Mar 9. Dynamic control of cystic fibrosis transmembrane
        conductance regulator Cl(-)/HCO3(-) selectivity by external Cl(-).
- term:
    id: GO:1904322
    label: cellular response to forskolin
  evidence_type: IDA
  original_reference_id: PMID:19621064
  review:
    summary: CFTR responds to forskolin via cAMP-PKA signaling.
    action: KEEP_AS_NON_CORE
    reason: CFTR is activated by forskolin-induced cAMP elevation. This reflects CFTR's
      cAMP regulation rather than a direct response.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:19621064
      supporting_text: 2009 Jul 21. CFTR delivery to 25% of surface epithelial cells
        restores normal rates of mucus transport to human cystic fibrosis airway epithelium.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:11524016
  review:
    summary: Direct evidence for CFTR plasma membrane localization from this key study.
    action: ACCEPT
    reason: This landmark study demonstrated CFTR functions at the plasma membrane
      [PMID:11524016]. Core localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:8910473
  review:
    summary: CFTR is a membrane protein, demonstrated during ATPase activity studies.
    action: ACCEPT
    reason: CFTR is an integral membrane protein [PMID:8910473]. Core localization,
      though less specific than plasma membrane.
    supported_by:
    - reference_id: PMID:8910473
      supporting_text: In this study, we report the first measurements of the rate
        of ATP hydrolysis by purified, reconstituted CFTR
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:11524016
  review:
    summary: Direct evidence for CFTR chloride transport from this key study.
    action: ACCEPT
    reason: This study demonstrated CFTR mediates chloride conduction [PMID:11524016].
      Core biological process.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: purified, reconstituted CFTR monomers are sufficient to mediate
        regulated chloride conduction and ATPase activity
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:11707463
  review:
    summary: CFTR transiently localizes to ER membrane during biosynthesis.
    action: KEEP_AS_NON_CORE
    reason: CFTR is synthesized and folded in the ER before trafficking to the plasma
      membrane. ER membrane localization represents a biogenesis intermediate rather
      than functional localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:11707463
      supporting_text: Nov 13. A Golgi-associated PDZ domain protein modulates cystic
        fibrosis transmembrane regulator plasma membrane expression.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IMP
  original_reference_id: PMID:11707463
  review:
    summary: Mutant phenotype evidence for CFTR plasma membrane localization.
    action: ACCEPT
    reason: CFTR localizes to the plasma membrane [PMID:11524016]. Core localization.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:11707463
      supporting_text: Nov 13. A Golgi-associated PDZ domain protein modulates cystic
        fibrosis transmembrane regulator plasma membrane expression.
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:11707463
  review:
    summary: Direct evidence for CFTR chloride transport.
    action: ACCEPT
    reason: CFTR mediates chloride transmembrane transport [PMID:11524016]. Core biological
      process.
    supported_by:
    - reference_id: PMID:11524016
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        normally functions as a phosphorylation-regulated chloride channel on the
        apical surface of epithelial cells
    - reference_id: PMID:11707463
      supporting_text: Nov 13. A Golgi-associated PDZ domain protein modulates cystic
        fibrosis transmembrane regulator plasma membrane expression.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866542
  review:
    summary: CFTR transiently localizes to the ER membrane during biosynthesis before
      trafficking to the plasma membrane. This Reactome annotation documents CFTR's
      presence in the ER secretory pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR is synthesized in the ER and must transit through ER quality control
      before reaching its functional destination at the apical plasma membrane. ER
      localization represents a transient biosynthetic intermediate rather than CFTR's
      functional location. The annotation is technically correct but does not represent
      core function.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866546
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866551
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866553
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866851
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866854
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866856
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866857
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9641109
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9641111
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9641127
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646348
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646679
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9646685
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700266
  review:
    summary: Reactome annotation for CFTR in ER membrane during biosynthesis pathway.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to ER during biosynthesis. This represents
      trafficking intermediate, not functional localization. Core function is at apical
      plasma membrane.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866854
  review:
    summary: Reactome annotation indicating CFTR cytosolic domains face the cytosol.
      The NBD1, NBD2, and R domains of CFTR are cytoplasmic.
    action: KEEP_AS_NON_CORE
    reason: CFTR is an integral membrane protein with cytosolic nucleotide-binding
      and regulatory domains. While cytosol annotation is technically accurate for
      these domains, CFTR's core localization is the plasma membrane where it functions
      as a chloride channel.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866858
  review:
    summary: Reactome annotation indicating CFTR cytosolic domains face the cytosol.
    action: KEEP_AS_NON_CORE
    reason: CFTR is an integral membrane protein with cytosolic nucleotide-binding
      and regulatory domains. While technically accurate, CFTR's core localization
      is the plasma membrane.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866277
  review:
    summary: Reactome annotation for CFTR plasma membrane localization. CFTR functions
      as a chloride channel at the plasma membrane of epithelial cells.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions. This represents CFTR's primary site of action
      in epithelial cells.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867754
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867756
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868071
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868072
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868230
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868236
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868648
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868651
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868661
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782106
  review:
    summary: Reactome annotation for CFTR in endosome membrane during endocytic recycling.
      CFTR is rapidly endocytosed and recycled back to the plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to endosomes during its rapid endocytic recycling
      from the plasma membrane. This is part of CFTR trafficking regulation but not
      its core functional localization [PMID:19398555].
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:24885604
  review:
    summary: This study detected CFTR in pancreatic beta-cells using confocal microscopy,
      showing localization at the plasma membrane with cytosolic domains visible [PMID:24885604].
    action: KEEP_AS_NON_CORE
    reason: CFTR has cytosolic nucleotide-binding and regulatory domains. This study
      demonstrated CFTR localization in beta-cells but cytosol is not the core functional
      compartment.
    supported_by:
    - reference_id: PMID:24885604
      supporting_text: Localization of CFTR was analyzed as described elsewhere
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:24885604
  review:
    summary: Direct evidence for CFTR plasma membrane localization in pancreatic beta-cells
      using immunofluorescence microscopy [PMID:24885604].
    action: ACCEPT
    reason: This study demonstrated CFTR localization at the plasma membrane of pancreatic
      beta-cells. Plasma membrane is CFTR's core functional location.
    supported_by:
    - reference_id: PMID:24885604
      supporting_text: We detected the presence of CFTR and measured a small CFTR
        conductance in both human and mouse beta-cells
- term:
    id: GO:1902476
    label: chloride transmembrane transport
  evidence_type: IMP
  original_reference_id: PMID:24885604
  review:
    summary: Direct evidence for CFTR-mediated chloride transport in pancreatic beta-cells.
      CFTR inhibition reduced cAMP-dependent insulin secretion [PMID:24885604].
    action: ACCEPT
    reason: This study demonstrated functional CFTR chloride currents in beta-cells
      and showed that CFTR inhibitors reduced insulin secretion, confirming CFTR's
      role in chloride transport.
    supported_by:
    - reference_id: PMID:24885604
      supporting_text: The augmentation of insulin secretion at 16.7 mM glucose by
        activation of CFTR by cAMP (forskolin (FSK) or GLP-1) was significantly inhibited
        when CFTR antagonists (GlyH-101 and/or CFTRinh-172) were added
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5678822
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5678992
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5679000
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005765
    label: lysosomal membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5627275
  review:
    summary: Reactome annotation for CFTR in lysosomal membrane. Ubiquitinated CFTR
      that is not recycled is degraded in lysosomes.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to lysosomes as part of its degradation pathway.
      This represents protein turnover rather than CFTR's functional localization.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18570918
  review:
    summary: This study showed CFTR colocalization with endosomal SNARE proteins in
      Rab11-positive recycling endosomes in the cytoplasm [PMID:18570918].
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to cytoplasmic compartments during trafficking
      and recycling. Core localization is at the apical plasma membrane.
    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:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:18570918
  review:
    summary: This study demonstrated CFTR localization at the apical plasma membrane
      of epithelial cells and showed that endosomal SNARE overexpression disturbs
      CFTR apical targeting [PMID:18570918].
    action: ACCEPT
    reason: Apical plasma membrane is CFTR's core functional localization in polarized
      epithelial cells where it mediates chloride and bicarbonate secretion.
    supported_by:
    - reference_id: PMID:18570918
      supporting_text: The Cystic Fibrosis Transmembrane conductance Regulator (CFTR)
        protein is a chloride channel localized at the apical plasma membrane of epithelial
        cells
- term:
    id: GO:0055037
    label: recycling endosome
  evidence_type: IDA
  original_reference_id: PMID:18570918
  review:
    summary: This study demonstrated CFTR colocalization with endosomal SNARE proteins
      in Rab11-positive recycling endosomes [PMID:18570918].
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to recycling endosomes during its endocytic
      recycling to the plasma membrane. This represents trafficking rather than core
      functional localization.
    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
  review:
    summary: Reactome annotation for CFTR in Golgi-associated vesicles during trafficking
      to the plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to Golgi-associated vesicles during its biosynthetic
      trafficking from ER to plasma membrane. This represents trafficking intermediate,
      not functional localization.
- term:
    id: GO:0030660
    label: Golgi-associated vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5627072
  review:
    summary: Reactome annotation for CFTR in Golgi-associated vesicles during trafficking.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to Golgi-associated vesicles during biosynthetic
      trafficking. This represents trafficking intermediate, not functional localization.
- term:
    id: GO:0030660
    label: Golgi-associated vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5627275
  review:
    summary: Reactome annotation for CFTR in Golgi-associated vesicles during trafficking.
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to Golgi-associated vesicles during biosynthetic
      trafficking. This represents trafficking intermediate, not functional localization.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:20658517
  review:
    summary: This study demonstrated CFTR at the cell surface of bronchial epithelial
      cells and showed SLC26A9 co-expression enhances CFTR surface expression [PMID:20658517].
    action: ACCEPT
    reason: Cell surface localization is consistent with CFTR's core function as a
      chloride channel at the apical plasma membrane of epithelial cells.
    supported_by:
    - reference_id: PMID:20658517
      supporting_text: Immunoblots identified a migrating band corresponding to SLC26A9
        present in whole-cell lysates as on apical membrane of cells grown on polarized
        filters
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:20658517
  review:
    summary: This study demonstrated CFTR localization at the apical membrane of polarized
      bronchial epithelial cells [PMID:20658517].
    action: ACCEPT
    reason: Apical plasma membrane is CFTR's core functional localization in polarized
      epithelial cells.
    supported_by:
    - reference_id: PMID:20658517
      supporting_text: Immunoblots identified a migrating band corresponding to SLC26A9
        present in whole-cell lysates as on apical membrane of cells grown on polarized
        filters
- term:
    id: GO:0015106
    label: bicarbonate transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity. CFTR is known to conduct
      bicarbonate ions in addition to chloride, with approximately 25% permeability
      relative to chloride [PMID:19019741].
    action: ACCEPT
    reason: CFTR bicarbonate conductance is well-established experimentally. Bicarbonate
      transport is critical for pancreatic and intestinal secretion.
- term:
    id: GO:0015108
    label: chloride transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity. CFTR is well-established
      as a chloride channel/transporter.
    action: ACCEPT
    reason: Chloride transport is CFTR's primary molecular function. This annotation
      correctly captures the core function.
- term:
    id: GO:0048240
    label: sperm capacitation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity. CFTR is expressed in sperm
      and implicated in capacitation through bicarbonate transport and pH regulation.
    action: KEEP_AS_NON_CORE
    reason: Sperm capacitation is a downstream physiological process that depends
      on CFTR's ion transport activity. While physiologically important for male fertility,
      this represents a tissue-specific consequence rather than core molecular function.
- term:
    id: GO:0051454
    label: intracellular pH elevation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity. CFTR's bicarbonate conductance
      can contribute to intracellular pH changes in cells where it is expressed.
    action: KEEP_AS_NON_CORE
    reason: Intracellular pH elevation is a downstream consequence of CFTR's bicarbonate
      transport activity, particularly relevant in sperm capacitation and epithelial
      secretion. This is physiologically important but not a direct molecular function.
- term:
    id: GO:0060081
    label: membrane hyperpolarization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity. CFTR chloride efflux can
      contribute to membrane hyperpolarization in sperm and other cells.
    action: KEEP_AS_NON_CORE
    reason: Membrane hyperpolarization is a downstream electrophysiological consequence
      of CFTR's chloride channel activity. This is important for sperm capacitation
      but represents a secondary effect rather than core molecular function.
- term:
    id: GO:0071320
    label: cellular response to cAMP
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on sequence similarity. CFTR channel activity is
      regulated by cAMP-dependent PKA phosphorylation of the R domain.
    action: ACCEPT
    reason: CFTR is a canonical cAMP-responsive channel. PKA phosphorylation of the
      R domain is required for channel activation. This accurately reflects CFTR's
      regulation.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1454916
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-383190
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5627071
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5678863
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8866851
  review:
    summary: Reactome annotation for CFTR plasma membrane localization.
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it conducts
      chloride and bicarbonate ions.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:22178883
  review:
    summary: This study demonstrated CFTR plasma membrane localization and showed
      that CFTR and TMEM16A are separate but functionally related chloride channels
      that can be coimmunoprecipitated [PMID:22178883].
    action: ACCEPT
    reason: Plasma membrane is CFTR's core functional localization where it functions
      as a chloride channel.
    supported_by:
    - reference_id: PMID:22178883
      supporting_text: CFTR and TMEM16A were both membrane localized and could be
        coimmunoprecipitated
- term:
    id: GO:0019869
    label: chloride channel inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:22178883
  review:
    summary: This study showed that activated CFTR inhibits TMEM16A (calcium-activated
      chloride channel) activity. CFTR activation by IBMX and forskolin completely
      abrogated TMEM16A-currents [PMID:22178883].
    action: ACCEPT
    reason: This annotation captures an important regulatory function of CFTR. CFTR
      can inhibit TMEM16A/ANO1 calcium-activated chloride channels, representing a
      channel-channel regulatory interaction.
    supported_by:
    - reference_id: PMID:22178883
      supporting_text: TMEM16A-currents were attenuated by additional expression of
        CFTR, and were completely abrogated when additionally expressed CFTR was activated
        by IBMX and forskolin
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:17462998
  review:
    summary: This study showed that endogenous CFTR formed a complex with myosin Vb
      and Rab11a in polarized human airway epithelial cells [PMID:17462998].
    action: KEEP_AS_NON_CORE
    reason: CFTR forms complexes with trafficking machinery (myosin Vb, Rab11a) for
      endocytic recycling. While protein complex formation is important for CFTR regulation,
      this is a generic term that could be replaced by more specific annotations.
    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
  review:
    summary: This study showed CFTR colocalizes with AQP1 and AQP5 at the apical membrane
      of intercalated duct cells in human pancreas [PMID:12801959].
    action: ACCEPT
    reason: Apical plasma membrane is CFTR's core functional localization in polarized
      epithelial cells.
    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
  review:
    summary: This study demonstrated that USP10 deubiquitinating enzyme is located
      in early endosomes and regulates CFTR deubiquitination and trafficking in the
      post-endocytic compartment [PMID:19398555].
    action: KEEP_AS_NON_CORE
    reason: CFTR transiently localizes to early endosomes during its endocytic recycling
      pathway. This represents a trafficking compartment rather than core functional
      localization.
    supported_by:
    - reference_id: PMID:19398555
      supporting_text: we demonstrated that Ubiquitin Specific Protease-10 (USP10)
        is located in early endosomes and regulates the deubiquitination of CFTR and
        its trafficking in the post-endocytic compartment
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:19398555
  review:
    summary: This study demonstrated CFTR interaction with USP10 deubiquitinating
      enzyme, which regulates CFTR trafficking by removing ubiquitin to promote recycling
      [PMID:19398555].
    action: KEEP_AS_NON_CORE
    reason: CFTR binding to USP10 is important for regulating CFTR surface expression
      through deubiquitination. However, enzyme binding is not CFTR's core molecular
      function as a chloride channel.
    supported_by:
    - reference_id: PMID:19398555
      supporting_text: overexpression of wt-USP10 decreased the amount of ubiquitinated
        CFTR and increased the abundance of CFTR
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9792704
  review:
    summary: This study demonstrated CFTR interaction with Sec61 complex during retrograde
      translocation from ER to cytosol for proteasomal degradation [PMID:9792704].
    action: KEEP_AS_NON_CORE
    reason: CFTR interaction with Sec61 is part of the ER-associated degradation (ERAD)
      pathway. While important for understanding CF pathogenesis (especially deltaF508
      degradation), protein binding is a generic term and this represents quality
      control rather than core function.
    supported_by:
    - reference_id: PMID:9792704
      supporting_text: During retrograde translocation from the ER to the cytosol,
        CFTR associates with the Sec61 trimeric complex
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:15247260
  review:
    summary: This study demonstrated endogenous apical membrane CFTR in polarized
      human airway epithelial cells (Calu-3) and showed myosin VI regulates CFTR endocytosis
      [PMID:15247260].
    action: ACCEPT
    reason: Apical plasma membrane is CFTR's core functional localization in polarized
      epithelial cells.
    supported_by:
    - reference_id: PMID:15247260
      supporting_text: The cystic fibrosis transmembrane conductance regulator (CFTR)
        is a cyclic AMP-regulated Cl(-) channel expressed in the apical plasma membrane
        in fluid-transporting epithelia
- term:
    id: GO:0030165
    label: PDZ domain binding
  evidence_type: IDA
  original_reference_id: PMID:11707463
  review:
    summary: This study identified CAL (CFTR associated ligand) as a PDZ domain-containing
      protein that binds to CFTR C-terminus and modulates its plasma membrane expression
      [PMID:11707463].
    action: ACCEPT
    reason: CFTR's C-terminal PDZ binding motif is critical for interactions with
      scaffolding proteins like CAL and NHE-RF that regulate CFTR trafficking and
      surface expression. This is an important regulatory mechanism.
    supported_by:
    - reference_id: PMID:11707463
      supporting_text: The PDZ domain of CAL binds to the C terminus of CFTR
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: TAS
  original_reference_id: PMID:2475911
  review:
    summary: The original CFTR cloning paper identified two nucleotide-binding domains
      (NBDs) with predicted ATP binding properties based on sequence homology to ABC
      transporters [PMID:2475911].
    action: ACCEPT
    reason: ATP binding at NBD1 and NBD2 is essential for CFTR channel gating. This
      is a core molecular function.
    supported_by:
    - reference_id: PMID:2475911
      supporting_text: a domain believed to be involved in ATP (adenosine triphosphate)
        binding
- term:
    id: GO:0051453
    label: regulation of intracellular pH
  evidence_type: IEA
  review:
    summary: CFTR regulates intracellular and extracellular pH through bicarbonate
      transport across epithelial membranes
    action: NEW
    reason: CFTR directly regulates pH homeostasis through its bicarbonate transport
      function. The channel conducts bicarbonate ions across epithelial cell membranes,
      which is essential for maintaining proper pH in various secretions including
      pancreatic juice, airway surface liquid, and reproductive tract fluids. CFTR-mediated
      bicarbonate transport contributes to both intracellular and extracellular pH
      regulation, and defects in this function contribute to the pathophysiology of
      cystic fibrosis.
    supported_by: []
- term:
    id: GO:0070254
    label: mucus secretion
  evidence_type: IEA
  review:
    summary: CFTR is essential for proper mucus secretion and properties through ion
      and water transport regulation in secretory epithelia
    action: NEW
    reason: CFTR plays a critical role in mucus secretion by regulating the ionic
      composition and hydration of mucus. The channel provides chloride and bicarbonate
      transport that determines mucus viscosity, pH, and antimicrobial properties.
      In cystic fibrosis, CFTR dysfunction leads to dehydrated, viscous mucus that
      cannot be effectively cleared, demonstrating CFTR's essential role in normal
      mucus secretion and properties. CFTR regulates both the volume and composition
      of mucus through its ion transport functions.
    supported_by: []
references:
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings:
  - statement: Automated annotation transfer based on enzyme classification
    supporting_text: Gene Ontology annotation based on Enzyme Commission mapping
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: Computational inference based on evolutionary conservation across orthologs
    supporting_text: Annotation inferences using phylogenetic trees
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings:
  - statement: Automated annotation from Swiss-Prot keywords
    supporting_text: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
      mapping
- 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
    supporting_text: Automatic transfer of experimentally verified manual GO annotation
      data to orthologs using Ensembl Compara
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods.
  findings:
  - statement: Combined computational evidence from multiple IEA sources
    supporting_text: Combined Automated Annotation using Multiple IEA Methods
- id: PMID:10581360
  title: Differential function of the two nucleotide binding domains on cystic fibrosis
    transmembrane conductance regulator.
  findings: []
- 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: []
- id: PMID:11707463
  title: A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane
    regulator plasma membrane expression.
  findings: []
- 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: []
- 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 chloride channel localizes to Golgi and interacts with CFTR-associated
      PDZ proteins
    supporting_text: ClC-3B localizes to the Golgi and associates with cystic fibrosis
      transmembrane conductance regulator-interacting PDZ proteins
- id: PMID:14679199
  title: Inhibitory regulation of cystic fibrosis transmembrane conductance regulator
    anion-transporting activities by Shank2.
  findings: []
- id: PMID:15010471
  title: Dynamic control of cystic fibrosis transmembrane conductance regulator Cl(-)/HCO3(-)
    selectivity by external Cl(-).
  findings: []
- id: PMID:15247260
  title: Myosin VI regulates endocytosis of the cystic fibrosis transmembrane conductance
    regulator.
  findings: []
- id: PMID:16203867
  title: Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through
    CFTR-dependent protein interactions.
  findings: []
- id: PMID:16546175
  title: Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial
    cells by the alpha-glucosidase inhibitor miglustat.
  findings:
  - statement: Miglustat rescues functional ΔF508-CFTR channels in CF epithelial cells
    supporting_text: Rescue of functional delF508-CFTR channels in cystic fibrosis
      epithelial cells by the alpha-glucosidase inhibitor miglustat
- id: PMID:16901789
  title: Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane
    conductance regulator.
  findings: []
- id: PMID:17110338
  title: Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic
    fibrosis.
  findings:
  - statement: Hsp90 cochaperones modulate CFTR protein folding and ΔF508 can be rescued
      by reducing Aha1
    supporting_text: Cell-surface rescue of the most common disease variant that is
      restricted to the ER, DeltaF508, can be initiated by partial siRNA silencing
      of the Hsp90 cochaperone ATPase regulator Aha1
  - statement: CFTR interactome reveals chaperone network controlling protein folding
      for ER exit
    supporting_text: Using proteomics to assess global cystic fibrosis (CF) transmembrane
      conductance regulator (CFTR) protein interactions (the CFTR interactome), we
      show that Hsp90 cochaperones modulate Hsp90-dependent stability of CFTR protein
      folding
- id: PMID:17244609
  title: Dynamic regulation of cystic fibrosis transmembrane conductance regulator
    by competitive interactions of molecular adaptors.
  findings: []
- id: PMID:18555783
  title: BAP31 interacts with Sec61 translocons and promotes retrotranslocation of
    CFTRDeltaF508 via the derlin-1 complex.
  findings: []
- id: PMID:18570918
  title: Endosomal SNARE proteins regulate CFTR activity and trafficking in epithelial
    cells.
  findings: []
- id: PMID:19019741
  title: Mechanism of direct bicarbonate transport by the CFTR anion channel.
  findings: []
- id: PMID:19289574
  title: SLC26A9 is a constitutively active, CFTR-regulated anion conductance in human
    bronchial epithelia.
  findings: []
- id: PMID:19465887
  title: The ER-resident ubiquitin-specific protease 19 participates in the UPR and
    rescues ERAD substrates.
  findings: []
- 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: []
- 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: []
- id: PMID:20658517
  title: SLC26A9 stimulates CFTR expression and function in human bronchial cell lines.
  findings: []
- id: PMID:21455491
  title: A Pseudomonas aeruginosa toxin that hijacks the host ubiquitin proteolytic
    system.
  findings: []
- id: PMID:21884936
  title: Rescue of ΔF508-CFTR trafficking via a GRASP-dependent unconventional secretion
    pathway.
  findings: []
- id: PMID:22038833
  title: Disruption of cytokeratin-8 interaction with F508del-CFTR corrects its functional
    defect.
  findings: []
- 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: []
- id: PMID:22178883
  title: CFTR and TMEM16A are separate but functionally related Cl- channels.
  findings: []
- id: PMID:22768251
  title: Proteomic identification of calumenin as a G551D-CFTR associated protein.
  findings: []
- 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: []
- 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: []
- id: PMID:25661196
  title: SERCA and PMCA pumps contribute to the deregulation of Ca2+ homeostasis in
    human CF epithelial cells.
  findings: []
- id: PMID:25712891
  title: G551D-CFTR needs more bound actin than wild-type CFTR to maintain its presence
    in plasma membranes.
  findings: []
- id: PMID:26618866
  title: ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.
  findings: []
- id: PMID:27092946
  title: Investigating CFTR and KCa3.1 Protein/Protein Interactions.
  findings: []
- id: PMID:28360110
  title: The CFTR trafficking mutation F508del inhibits the constitutive activity
    of SLC26A9.
  findings: []
- id: PMID:29393851
  title: Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are
    required for male fertility.
  findings: []
- id: PMID:29924966
  title: A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited
    and Somatic Disease.
  findings: []
- id: PMID:8910473
  title: ATPase activity of the cystic fibrosis transmembrane conductance regulator.
  findings:
  - statement: First direct measurement of ATP hydrolysis rate by purified CFTR demonstrating
      intrinsic ATPase activity
    supporting_text: In this study, we report the first measurements of the rate of
      ATP hydrolysis by purified, reconstituted CFTR
  - statement: G551D mutation causes defective ATP hydrolysis and channel gating,
      proving ATP utilization for channel activity
    supporting_text: Following reconstitution the mutant protein exhibited both defective
      ATP hydrolysis and channel gating, providing direct evidence that CFTR utilizes
      ATP to gate its channel activity
- 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 and B mutations in NBDs affect ATP hydrolysis and channel
      gating differentially
    supporting_text: Walker mutations reveal loose relationship between catalytic
      and channel-gating activities of purified CFTR
- id: PMID:31324722
  title: Inhibition of calpain 1 restores plasma membrane stability to pharmacologically
    rescued Phe508del-CFTR variant.
  findings: []
- id: PMID:35156780
  title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput
    screening system.
  findings: []
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms.
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity.
  findings: []
- 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: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:12801959
  title: Distribution of aquaporin water channels AQP1 and AQP5 in the ductal system
    of the human pancreas.
  findings: []
- id: PMID:16207813
  title: BAG-2 acts as an inhibitor of the chaperone-associated ubiquitin ligase CHIP.
  findings: []
- 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: []
- id: PMID:19398555
  title: The deubiquitinating enzyme USP10 regulates the post-endocytic sorting of
    cystic fibrosis transmembrane conductance regulator in airway epithelial cells.
  findings: []
- id: PMID:22006324
  title: Anoctamin 6 is an essential component of the outwardly rectifying chloride
    channel.
  findings: []
- id: PMID:2475911
  title: 'Identification of the cystic fibrosis gene: cloning and characterization
    of complementary DNA.'
  findings: []
- 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: []
- id: PMID:28067262
  title: Sec16A is critical for both conventional and unconventional secretion of
    CFTR.
  findings: []
- id: PMID:28130590
  title: Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis
    and epidermal appendages.
  findings: []
- id: PMID:32487539
  title: 'TMEM16A deficiency: a potentially fatal neonatal disease resulting from
    impaired chloride currents.'
  findings: []
- id: PMID:36012204
  title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment
    in Multiple SLC Transporters.
  findings: []
- id: PMID:39009827
  title: Proteome-scale characterisation of motif-based interactome rewiring by disease
    mutations.
  findings: []
- 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: []
- 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: []
- id: Reactome:R-HSA-1454916
  title: The ABCC family mediates organic anion transport
  findings: []
- id: Reactome:R-HSA-382556
  title: ABC-family proteins mediated transport
  findings: []
- id: Reactome:R-HSA-383190
  title: HCO3- transport through ion channel
  findings: []
- id: Reactome:R-HSA-5627071
  title: RHOQ positively regulates trafficking of GOPC:CFTR to the plasma membrane
  findings: []
- id: Reactome:R-HSA-5627072
  title: RHOQ binds GOPC:CFTR
  findings: []
- id: Reactome:R-HSA-5627275
  title: GOPC promotes translocation of CFTR to lysosomes
  findings: []
- id: Reactome:R-HSA-5678822
  title: Defective CFTR does not transport Cl- from cytosol to extracellular region
  findings: []
- id: Reactome:R-HSA-5678863
  title: CFTR transports Cl- from cytosol to extracellular region
  findings: []
- id: Reactome:R-HSA-5678992
  title: Ivacaftor:CFTR G551D transports Cl- from cytosol to extracellular region
  findings: []
- id: Reactome:R-HSA-5679000
  title: Ivacaftor binds CFTR G551D
  findings: []
- id: Reactome:R-HSA-6782106
  title: USP10 deubiquitinates SNX3, CFTR
  findings: []
- id: Reactome:R-HSA-8866277
  title: AP-2 directly binds some endocytic cargo
  findings: []
- id: Reactome:R-HSA-8866542
  title: VCP-catalyzed ATP hydrolysis promotes the translocation of misfolded CFTR
    into the cytosol
  findings: []
- id: Reactome:R-HSA-8866546
  title: RNF5 and RNF185 ubiquitinate misfolded CFTR
  findings: []
- id: Reactome:R-HSA-8866551
  title: CFTR binds components of the ERAD machinery for ubiquitination and degradation
  findings: []
- id: Reactome:R-HSA-8866553
  title: misfolded CFTR is degraded by the 26S proteasome
  findings: []
- id: Reactome:R-HSA-8866851
  title: CFTR transits to the plasma membrane
  findings: []
- id: Reactome:R-HSA-8866854
  title: VCP-catalyzed ATP hydrolysis promotes the translocation of CFTR F508del into
    the cytosol
  findings: []
- id: Reactome:R-HSA-8866856
  title: RNF5 and RNF185 ubiquitinate CFTR F508del
  findings: []
- id: Reactome:R-HSA-8866857
  title: CFTR F508del binds components of the ERAD machinery for ubiquitination and
    degradation
  findings: []
- id: Reactome:R-HSA-8866858
  title: CFTR F508del is degraded by the 26S proteasome
  findings: []
- id: Reactome:R-HSA-8867754
  title: F- and N- BAR domain proteins bind the clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8867756
  title: CLASP proteins and cargo are recruited to the nascent clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8868071
  title: Clathrin recruits PIK3C2A
  findings: []
- id: Reactome:R-HSA-8868072
  title: Clathrin-associated PIK3C2A phosphorylates PI(4)P to PI(3,4)P2
  findings: []
- id: Reactome:R-HSA-8868230
  title: SNX9 recruits components of the actin polymerizing machinery
  findings: []
- id: Reactome:R-HSA-8868236
  title: BAR domain proteins recruit dynamin
  findings: []
- id: Reactome:R-HSA-8868648
  title: SYNJ hydrolyze PI(4,5)P2 to PI(4)P
  findings: []
- id: Reactome:R-HSA-8868651
  title: Endophilins recruit synaptojanins to the clathrin-coated pit
  findings: []
- id: Reactome:R-HSA-8868658
  title: HSPA8-mediated ATP hydrolysis promotes vesicle uncoating
  findings: []
- id: Reactome:R-HSA-8868659
  title: Clathrin recruits auxilins to the clathrin-coated vesicle
  findings: []
- id: Reactome:R-HSA-8868660
  title: Auxilin recruits HSPA8:ATP to the clathrin-coated vesicle
  findings: []
- id: Reactome:R-HSA-8868661
  title: Dynamin-mediated GTP hydrolysis promotes vesicle scission
  findings: []
- id: Reactome:R-HSA-8869438
  title: Dissociation of clathrin-associated proteins
  findings: []
- id: Reactome:R-HSA-8871193
  title: Dissociation of AAK1 and dephosphorylation of AP-2 mu2
  findings: []
- id: Reactome:R-HSA-8871194
  title: RAB5 and GAPVD1 bind AP-2
  findings: []
- id: Reactome:R-HSA-9641109
  title: PolyUb:misfolded proteins dissociate from PRKN:UBE2N:UBE2V1
  findings: []
- id: Reactome:R-HSA-9641111
  title: Parkin transfers Ub to misfolded proteins
  findings: []
- id: Reactome:R-HSA-9641127
  title: Ub:misfolded proteins polymerize to PolyUb:misfolded proteins
  findings: []
- id: Reactome:R-HSA-9646348
  title: PolyUb-Misfolded Proteins:HDAC6 bind dynein motor
  findings: []
- id: Reactome:R-HSA-9646679
  title: PolyUb-Misfolded proteins bind vimentin to form aggresome
  findings: []
- id: Reactome:R-HSA-9646685
  title: Aggresome dissociates from dynein and microtubule
  findings: []
- id: Reactome:R-HSA-9700266
  title: CFTR F508del binds CFTR correctors
  findings: []
- id: file:human/CFTR/CFTR-deep-research.md
  title: Deep research on CFTR function
  findings: []
core_functions:
- description: ATP-gated chloride channel activity at apical plasma membrane enabling
    regulated anion secretion in epithelia
  molecular_function:
    id: GO:0005260
    label: intracellularly ATP-gated chloride channel activity
  supported_by:
  - reference_id: PMID:8910473
    supporting_text: CFTR utilizes ATP to gate its channel activity
  - reference_id: PMID:19621064
    supporting_text: CFTR delivery to 25% of surface epithelial cells restores normal
      rates of mucus transport
  directly_involved_in:
  - id: GO:1902476
    label: chloride transmembrane transport
  - id: GO:0070254
    label: mucus secretion
  - id: GO:0050891
    label: multicellular organismal-level water homeostasis
  locations:
  - id: GO:0016324
    label: apical plasma membrane
  - id: GO:0005886
    label: plasma membrane
- description: Bicarbonate transport through the anion-selective pore contributing
    to pH regulation and fluid alkalinization
  molecular_function:
    id: GO:0005254
    label: chloride channel activity
  supported_by:
  - reference_id: PMID:19019741
    supporting_text: Mechanism of direct bicarbonate transport by the CFTR anion channel
  - reference_id: PMID:15010471
    supporting_text: Dynamic control of cystic fibrosis transmembrane conductance
      regulator Cl(-)/HCO3(-) selectivity by external Cl(-)
  directly_involved_in:
  - id: GO:0015701
    label: bicarbonate transport
  - id: GO:0051453
    label: regulation of intracellular pH
  locations:
  - id: GO:0016324
    label: apical plasma membrane
- description: ATP binding and hydrolysis driving conformational changes for channel
    gating cycles
  molecular_function:
    id: GO:0005524
    label: ATP binding
  supported_by:
  - reference_id: PMID:8910473
    supporting_text: First measurements of the rate of ATP hydrolysis by purified,
      reconstituted CFTR
  - reference_id: PMID:10581360
    supporting_text: Differential function of the two nucleotide binding domains on
      cystic fibrosis transmembrane conductance regulator
  directly_involved_in:
  - id: GO:0034220
    label: monoatomic ion transmembrane transport
  - id: GO:0006821
    label: chloride transport
  locations:
  - id: GO:0016324
    label: apical plasma membrane
- description: Negative regulation of ENaC sodium channel preventing excessive sodium
    absorption and mucus dehydration
  molecular_function:
    id: GO:0005254
    label: chloride channel activity
  supported_by:
  - reference_id: PMID:19621064
    supporting_text: CFTR delivery to 25% of surface epithelial cells restores normal
      rates of mucus transport to human cystic fibrosis airway epithelium
  - reference_id: PMID:19289574
    supporting_text: SLC26A9 is a constitutively active, CFTR-regulated anion conductance
  directly_involved_in:
  - id: GO:2000649
    label: regulation of sodium ion transmembrane transporter activity
  locations:
  - id: GO:0016324
    label: apical plasma membrane
suggested_questions:
- question: How do different classes of CFTR mutations affect protein folding, trafficking,
    and channel gating at the molecular level?
- question: What are the regulatory mechanisms that control CFTR channel activity
    in response to cAMP and other signaling pathways?
- question: How does CFTR dysfunction lead to the characteristic thick mucus secretions
    and bacterial infections in cystic fibrosis?
- question: What determines tissue-specific sensitivity to CFTR dysfunction and why
    are some organs more severely affected than others?
suggested_experiments:
- description: Single-channel patch-clamp electrophysiology to characterize the gating
    kinetics and ion selectivity of CFTR variants
- description: Cryo-EM structure determination of full-length CFTR in different conformational
    states and with bound modulators
- description: Organoid models of cystic fibrosis using patient-derived cells to test
    personalized therapeutic approaches
- description: Real-time imaging of CFTR trafficking from ER to plasma membrane using
    fluorescently tagged proteins and live-cell microscopy
status: COMPLETE