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FLASH GENE
Symbol CFTR contributors: mct/ - updated : 13-01-2016
HGNC name cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)
HGNC id 1884
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N terminus mediates its direct interaction with STX16
  • two tandemly repeated polytopic membrane-spanning domains (MSDs) typical of ABC transporters, and a third NH(2)-terminal MSD, with six transmembrane segments (TM6)
  • two NBDs (nucleotide-binding domains), NBD1 and NBD2 (Walker B motif of NBD2 plays a key role in ATPase activity by the NBD1-NBD2 heterodimer), and binding of potentiators (molecules increasing the activity of CFTR) involves salt bridge formation with AAs of NBD1
  • two cytoplasmic nucleotide-binding fold domains (NBF), with C terminus of the first NBF being an important molecular site for the trafficking of CFTR protein, for the control of CFTR channel gating, and for the pharmacological effect of a dual activity agent
  • a regulatory (R) domain from N terminal TMD1-NBF1-R-TMD2-NBF2-C terminal cytoplasmic domain
  • two CSNK2A1 phosphorylation sites
  • conjugated GlycoP
    mono polymer homomer , dimer
    HOMOLOGY
    Homologene
    FAMILY
  • ABC transporter superfamily
  • ABCC family
  • CFTR transporter subfamily
  • CATEGORY transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endosome
    text
  • localized CFTR protein and mRNA signals to the cytoplasm of neurons in all regions of the brain, but not to glial cells
  • CFTR anion channel is localized in the apical membrane of airway epithelia
  • basic FUNCTION
  • cystic fibrosis transmembrane conductance regulator, cAMP-regulated chloride channel, having an ATPase and an adenylate kinase activity
  • epithelial chloride channel, regulator of separate ion channels through NBF1
  • might be implicated in the pathogenesis of primary sclerosing cholangitis
  • having critical role for completion of enamel mineralization and conceivably functions as a regulator of pH during rapid crystal growth
  • plays a role in fluid absorption in the distal air spaces of adult lung (importance of Cl- movement in alveolar fluid clearance may be, in part, the result of Cl-transport across alveolar type I cells)
  • implicated in transporting halides into the phagosomal lumen of neutrophils
  • cytosolic pH affects CFTR activity in multiple ways
  • role of CFTR and CLCN5 in modulating vacuolar H+-ATPase activity in kidney proximal tubule
  • role of CFTR and soluble adenylyl cyclase in regulating the cAMP-CREB1 signaling pathway in Sertoli cells, defect of which may result in impaired spermatogenesis and azoospermia
  • CFTR predominately controls the rate of liquid secretion, whereas SLC26A4 regulates the composition of the secreted fluid and identifies a critical role for this anion exchanger in transcellular HCO3&
  • 8722; secretion in airway serous cells
  • both CFTR and ANO1 are separate molecular entities that show functional and molecular interaction
  • ATP-dependent gating of CFTR is potentially associated with the opening and closing of a gate within the permeation pathway at the level of these pore-lining amino acids
  • presence of CFTR on the plasma membrane influences the cytoskeletal organizational state and, consequently, cAMP distribution
  • lymphocyte CFTR promotes epithelial bicarbonate secretion for bacterial killing
  • can function as an adenylate kinase
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • significant role for the multiprotein complex CFTR-SLC9A3R1-EZR-actin in maintaining tight junctions organisation and barrier function, suggesting that the RHOA/ROCK pathway is involved
  • SLC26A8-CFTR complex impicated in the regulation of the chloride and bicarbonate fluxes required for sperm motility and capacitation
  • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP binding
  • interaction of nucleotide triphosphate with CFTR at ATP-binding site 2 is required for its adenylate kinase activity
  • protein
  • interacts with and regulates the activity of SLC4A7
  • endosomal SNARE proteins physically and functionally interact with CFTR
  • interacting with SLC9A3R1, SLC9A3R2, PDZK1 (SLC9A3R1, SLC9A3R2, and PDZK1, modulate CFTR membrane retention, conductivity, and interactions with other transporters)
  • SLC26A5 may interact physically with CFTR in the lateral membrane of OHCs (CFTR is capable of enhancing voltage-dependent charge displacement, a signature of OHC motility, whereas prestin does not affect the chloride conductance of CFTR)
  • interacting with Ig domains of FLNA
  • interacting with CELF2 (novel CFTR splice repressor protein that, depending on its level and type of intron 8 polymorphism, may impose a strong control of the amount of correctly spliced CFTR transcript in the region of exon 9
  • normally inhibits SCNN1A function in the airways, but in CF, where CFTR is mutated and nonfunctional, SCNN1A activity is enhanced
  • SCNN1A and CFTR physically associate in mammalian cells (limiting proteolytic cleavage of SCNN1A is a mechanism by which CFTR down-regulates Na+ absorption)
  • biochemical and functional association between CFTR and syntaxin 16 (STX16) that mediates vesicle transport within the early/late endosomes and trans-Golgi network
  • interacts with STX3
  • CSE1L is a negative regulator of CFTR-dependent fluid secretion
  • COMMD1 is a new CFTR partner, and CFTR is protected from ubiquitination by COMMD1, which sustains CFTR expression at the plasma membrane
  • central role for the IL13/IL13RA1 pathway in the regulation of intestinal epithelial cell Cl(-) secretion via up-regulation of CFTR, suggesting an important role for this pathway in secretory diarrhea
  • activates ORCC (outwardly rectifying chloride channel)
  • produced by ANO6
  • dual role for FKBP8 in regulating CFTR synthesis and post-translational folding
  • SLC26A8 and CFTR physically interact, and SLC26A8 expression strongly stimulates CFTR activity
  • 14-3-3 binding to phosphorylated CFTR augments its biogenesis by reducing retrograde retrieval of CFTR to the endoplasmic reticulum
  • acts as a cAMP efflux pump to regulate intracellular cAMP levels and alter effector function, including activation of the cAMP-stimulated Cl(-) channel, CFTR
  • SERP1 appears to promote expression of CFTR and is a novel cochaperone and regulator of SCNN1A, SCNN1B, SCNN1G expression
  • MIR138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis
  • PRKAA1 binds to and phosphorylates CFTR, attenuating PKA-activated CFTR gating
  • exists in a functional cellular complex with PRKAA1 and CFTR in airway epithelia, and its catalytic function is required for the PRKAA1-dependent regulation of CFTR
  • SLC9A3R1 is involved in PKA-dependent activation of CFTR by interacting with CFTR via its PDZ domains and with ezrin via its C-terminal domain
  • CFTR function is required to suppress IL8 secretion
  • KRT18 controls the function of CFTR, and increases the cell surface expression of CFTR by interacting with the CFTR C-terminal hydrophobic patch
  • ubiquitination and degradation of CFTR by the E3 ubiquitin ligase MARCH2 through its association with adaptor proteins GOPC and STX6
  • RNF185 and RNF5 are a novel E3 ligase module central to the control of CFTR degradation
  • glucocorticoid-induced increase in CFTR abundance requires phosphorylation of SHANK2 at an SGK1 consensus site
  • CFTR binds to and colocalizes with TRADD
  • by reducing the levels of TRADD, CFTR suppresses downstream proinflammatory NFKB1 signaling
  • interdependence between SLC9A3 and CFTR is critical for maintaining a precise microenvironment in the epithelial cytoarchitecture of the male reproductive tract
  • cell & other
    REGULATION
    inhibited by CALR
    STX8 (strong inhibition of CFTR chloride current by syntaxin 8 overexpression)
    Other reulated by STX16 (regulates CFTR activity by increasing surface abundance via its membrane trafficking SNARE function rather than directly affecting CFTR channel)
    regulated by the pH (pHi has multiple effects on CFTR activity)
    regulation of CFTR by SYK, a recognized controller of inflammation
    ASSOCIATED DISORDERS
    corresponding disease(s) CBAVD , CF
    related resource Cysticfibrosis
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    dDecreased CFTR and CREB1 expression are also observed in human testes with azoospermia
    Susceptibility maybe a susceptibility gene for sarcoidosis and susceptibility for pancreatic chronic idiopathic
    Variant & Polymorphism overexpression of splicing factors (cellular and viral) can modulate the splicing pattern
    Candidate gene
    Marker
  • may function as a novel tumor marker, and a prospective prognostic indicator for cervical cancer
  • Therapy target
    SystemTypeDisorderPubmed
    respiratoryCF (mucoviscidosis) 
    ion channel modulating agents, such as lancovutide (Moli1901, duramycin) and denufosol, which activate alternate (non-CF transmembrane regulator [CFTR]) chloride channels, and GS 9411, a sodium channel antagonist, are now at the stages of clinical study a
    cancerreproductiveuterus
    may function as a potential therapeutic target for cervical cancer
    ANIMAL & CELL MODELS
  • mice lacking functional CFTR (Cftrdelta508) have no lung phenotype but show similar ileal problems to humans, but properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer
  • severe osteopenia and altered bone architecture were found in young and mature adult F508del Cftr(tm1Eur) mice