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FLASH GENE
Symbol PKD1 contributors: mct/shn/pgu - updated : 14-07-2015
HGNC name polycystic kidney disease 1 (autosomal dominant)
HGNC id 9008
Corresponding disease
PKD polycystic kidney disease 1
PKTS polycystic kidney disease, infantile, severe, with tuberous sclerosis
Location 16p13.3      Physical location : 2.138.710 - 2.185.899
Synonym name
  • polycystin 1
  • polycystin-1
  • protein kinase C mu type
  • protein kinase D
  • transient receptor potential cation channel, subfamily P, member 1
  • autosomal dominant polycystic kidney disease 1 protein
  • polycystic kidney disease-associated protein
  • Synonym symbol(s) PBP, PKD, PRKCM, nPKC-D1, nPKC-mu, PC1, Pc-1, TRPP1
    EC.number 2.7.11.13
    DNA
    TYPE functioning gene
    SPECIAL FEATURE
    text with a duplicated portion
    STRUCTURE 47.19 kb     46 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure transcription factor-binding sites, AP2, E2F, E-Box, EGRF, ETS, MINI, MZF1, SP1, and ZBP-89
    MAPPING cloned Y linked Y status confirmed
    Map pter - D16S3024 - D16S3395 - PKD1 - D16S3124 - D16S3070 - cen
    Physical map
    NME3 16q13 non-metastatic cells 3, protein expressed in MRPS34 16p13.3 mitochondrial ribosomal protein S34 LOC390668 16 similar to hypothetical protein 6820428D13 SSB3 16p13.3 SPRY domain-containing SOCS box protein SSB-3 NUBP2 16p13.3 nucleotide binding protein 2 (MinD homolog, E. coli) IGFALS 16p13.3 insulin-like growth factor binding protein, acid labile subunit HAGH 16p13.3 hydroxyacyl glutathione hydrolase DKFZP566J2046 16p13.3 hypothetical protein DKFZp566J2046 MGC35212 16p13.3 hypothetical protein MGC35212 LOC342460 16p13.3 similar to c439A6.1 (novel protein similar to heparan sulfate (glucosamine) 3-O-sulfotransferases) SEPX1 16p13.3 selenoprotein X, 1 RPL3L 16p13.3 ribosomal protein L3-like NDUFB10 16p13.3 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22kDa RPS2 16p13.3 ribosomal protein S2 RNF151 16p13.3 ring finger protein 151 TBL3 16p13.3 transducin (beta)-like 3 NOXO1 16p13.3 NADPH oxidase organizer 1 GFER 16p13.3-p13.12 growth factor, augmenter of liver regeneration (ERV1 homolog, S. cerevisiae) SYNGR3 16p13 synaptogyrin 3 LOC90850 16p13.3 hypothetical protein LOC90850 SLC9A3R2 16p13.3 solute carrier family 9 (sodium/hydrogen exchanger), isoform 3 regulatory factor 2 NTHL1 16p13.3p13.2 nth endonuclease III-like 1 (E. coli) TSC2 16p13.3 tuberous sclerosis 2 PKD1 16p13.3 polycystic kidney disease 1 (autosomal dominant) RFWD1 16p13.3 ring finger and WD repeat domain 1 RAB26 16p13.3 RAB26, member RAS oncogene family CASKIN1 16p13.11 CASK interacting protein 1 GBL 16p13.3 G protein beta subunit-like MGC21830 16p13.3 hypothetical protein MGC21830 LOC388203 16 LOC388203 LOC283871 16p13.3 hypothetical protein LOC283871 E4F1 16p13.3 E4F transcription factor 1 DNASE1L2 16p13.3 deoxyribonuclease I-like 2 DCI 16p13.3 dodecenoyl-Coenzyme A delta isomerase (3,2 trans-enoyl-Coenzyme A isomerase) RNPS1 16p13.3 RNA binding protein S1, serine-rich domain
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    46 - 14138 - 4303 - 2008 18422703
    46 - 14135 - 4302 - 2008 18422703
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately Homo sapiens
    Nervousbrain   moderately Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal lowly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Urinaryepithelial cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, pregnancy
    cell cycle     cell cycle, checkpoint
    Text brain, kidney
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal region with an extracellular portion of >3000 amino acids, which is predicted to be a site of protein-protein or receptor-ligand interactions , 11 transmembrane spanning this extracellular region containing a number of adhesive domains
  • a large extracellular segment, with (from NH2) two leucine rich repeats
  • a homer-binding motif (PPxxF), which lies within its purported cytoplasmic domain
  • a C-type lectin domain
  • a LDL-A domain, 16 copies of a repeat
  • the PKD domain with low homology to the Ig superfamily
  • four type III fibronectin
  • one REJ (receptor for egg jelly) domain
  • one GPS domain (cleavage essential for the normal function)
  • 11 transmembrane domains (TM11)
  • extracellular information across the plasma membrane
  • a probable coiled-coil domain interacting with PKD2 and TSC2
  • a cytoplasmic C-terminal tail (CTT), transmiting extracellular information across the plasma membrane, associating with beta-catenin and acting as an inhibitor of Wnt-dependent intracellular signaling (cleavage and release of CTT may be necessary components of a biological switch that acts to modulate Wnt-dependent signal transduction in renal epithelia), and can undergo proteolytic cleavage and nuclear translocation
  • a conserved amino acid sequence, KVHPSST, in the C-terminus that serves as a ciliary-targeting signal , and
  • interacts with numerous signaling molecules, including GNA12
    conjugated GlycoP
    HOMOLOGY
    interspecies ortholog to Pkd1, Mus musculus
    ortholog to Pkd1, Rattus norvegicus
    ortholog to PKD1, Pan troglodytes
    Homologene
    FAMILY
  • polycystin family
  • CATEGORY signaling , receptor membrane G , transport
    SUBCELLULAR LOCALIZATION     plasma membrane,junction,desmosome
        intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,cytoplasm,cytoskeleton,microfilament
    text
  • localizes in cilia and has been observed in the centrosome of endothelial cells
  • predicted to traverse the membrane 11 times and includes a massive extracellular amino terminal domain and a short intracellular carboxy terminal tail
  • with PKD2, colocalize to cilia, where they may enable a mechano/chemosensory response triggering a rise in intracellular Ca2+
  • basic FUNCTION
  • may be functioning through a signaling pathway necessary for normal tubulogenesis and involved in adhesive protein-protein and protein-carbohydrate interactions
  • involved in regulating ion transport required for the structural integrity of blood vessels
  • maintaining cell adhesion, protein sorting and cell polarity (features disrupted in cystic epithelium)
  • involved in chondrocyte development and in renal epithelium development
  • mediating mechanosensation in the primary cilium of kidney cells
  • acting as a regulator of G1 checkpoint, which controls entry into the S phase and prevents the replication of damaged DNA
  • playing a role in preventing immortalized proliferation of renal tubular epithelial cells through the induction of TP53 and activation of MAPK8
  • modulating renal tubular fluid and electrolyte transport
  • having a central role in regulating morphogenic protein signaling at cell-matrix interfaces in non-confluent cells
  • role in modulating cell proliferation through calcium oscillations in kidney cells
  • regulates induction of cell death by wild-type PTRH2 following loss of cell attachment to the extracellular matrix
  • one of the signaling molecules through which integrin-mediated cell attachment controls PTRH2 activity and anoikis
  • acting as an upstream activating kinase that regulates the function of PTRH2 in anoikis by phosphorylating the Ser5 and Ser87 residues
  • may play a role in regulating the stability of a pool of the beta-catenin protein
  • tumor suppressive function that may be at least partially dependent upon the ability of the free CTT to inhibit beta-catenin-dependent Wnt signaling
  • critical in both epithelium and chondrocyte development (
  • regulates tubular morphology in both developing and adult kidney (
  • can inhibit the mTOR pathway and regulate cell size
  • phosphorylates SSH1 in response to RhoA activation and blocks it in the cytoplasm, consequently blocking the formation of free actin-filament barbed ends
  • inhibits Ca2+ release, perhaps opposing the effect of PKD2, which facilitates Ca2+ release through the IP3R
  • plays a novel role in the regulation of ITPR1 to modulate intracellular Ca2+ signaling
  • may mediate the function of PRKX in kidney development
  • involved in cell/cell/matrix interaction and the regulation of several signalling pathways linked to cell proliferation
  • can both activate and coactivate multiple STATs, and STAT activation requires the membrane-anchored PC1 tail, whereas STAT coactivation requires the cleaved, soluble PKD1 tail
  • plays an essential role in stereocilia structure and maintenance but not directly in mechanoelectrical transduction channel function or planar cell polarity (
  • acts as a negative regulator of STAT3
  • MTOR-mediated inhibition of PKD1 expression drives renal cyst formation in tuberous sclerosis complex
  • CELLULAR PROCESS cell communication
    PHYSIOLOGICAL PROCESS cardiovascular
    text ion
    PATHWAY
    metabolism
    signaling
    a component
  • heterodimerizing with PKD2, 3 PKD2 and 1 PKD1 (disruption of the complex PKD1/PKD2 is involved in the pathogenesis of cyst formation through a mechanosensor action in renal primary cilia for fluid flow)
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • PKD2
  • RGS7
  • talin, vinculin, p130Cas, FAK, alpha-actinin, paxillin, pp60c-src, E-cadherin, beta- and gamma-catenin
  • collagens type I, II and IV
  • Cytokeratins K8 and K18, Vimentin, and desmin (
  • extracellular matrix, ECM (
  • Protein kinase-X (
  • ITPR1 (
  • interaction between the PKD1 polyproline motif and the NPHP1 SH3 domain
  • STAT3 (
  • binds a multimeric protein complex consisting of several GTPases (ARF4, RAB6, RAB11) and the GTPase-activating protein (GAP), ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) in the Golgi, which facilitates vesicle budding and Golgi exocytosis
  • its cytoplasmic tail associates with the transcription factors TPX2 and STAT6
  • interaction of polycystin-1 (PKD1) and GNA12 is important for development of kidney cysts in autosomal dominant polycystic kidney disease (ADPKD)
  • CDH1/CTNNB1 signaling pathway is regulated by PKD1 and GNA12 via ADAM10
  • GNAT1, NPHP3, and PKD1 bind with high affinity to UNC119, whereas a peptide derived from a non-ciliary localizing protein (SRC) has low affinity
  • PKD1 enhances the stability of CDH2 on cell membrane and promotes synapse morphogenesis and synaptic plasticity in an activity-dependent manner
  • cell & other
    REGULATION
    Other cleavage is modulated by PKD2 expression
    regilated by PKD2 (its expression is required for the movement of PKD1 to the plasma and ciliary membranes)
    ASSOCIATED DISORDERS
    corresponding disease(s) PKTS , PKD
    related resource Polycystickidneyresearchfoundation
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional somatic mutation      
    in PKD2 cysts (modification of disease severity)
    constitutional     --low  
    in renal cysts
    constitutional     --low  
    in aortic dissection
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
  • PRKX can restore normal function to PKD1-deficient kidneys (
  • pyrimethamine or similar drugs may be an attractive therapy for human ADPKD
  • SystemTypeDisorderPubmed
    cancerurinary 
    Treatment with pyrimethamine decreases cell proliferation in human ADPKD cells and blocks renal cyst formation in an adult and a neonatal PKD mouse model
    cancerurinary 
    a specific STAT3 inhibitor, S3I-201, reduces cyst formation and growth in a neonatal PKD mouse model
    ANIMAL & CELL MODELS
  • disruption of the PKD1 gene in mice leads to cystic kidneys and embryonic or perinatal death (
  • Pkd1(del34) -/- and Pkd1(L) -/- mice have cysts but no cardiac abnormalities, although vascular fragility was reported in the latter (
  • Pkd1(del17-21betageo) +/- adult mice develop renal and hepatic cysts, Pkd1(del17-21betageo) -/- embryos die at embryonic days 13.5-14.5 from a primary cardiovascular defect that includes double outflow right ventricle, disorganized myocardium, and abnormal atrio-ventricular septation, and skeletal development is also severely compromised (
  • mice that overexpress polycystin-1 develop renal cysts (
  • targeted mouse mutant with a homozygous null mutation in Pkd1 develop aggressive and severe renal and pancreatic cystic disease but also polyhydramnios, hydrops fetalis, spina bifida occulta and osteochondrodysplasia (
  • targeted mouse mutant with a heterozygoous null mutation in Pkd1 develop adult-onset pancreatic disease (
  • mouse with a homozygous targeted deletion of exons 2-6 of Pkd1 develop hydrops, cardiac conotruncal defects and renal cystogenesis (
  • Pkd1(+/-), Pkd2 (+/-) and Pkd1(+/-) : Pkd2 (+/-) mice, the renal cystic lesion was mild and variable with no adverse effect on survival at 1 year (
  • mouse model with a hypomorphic Pkd1 allele, Pkd1(nl), are viable, showing bilaterally enlarged polycystic, kidneys dilatations of pancreatic and liver bile ducts, and cardiovascular abnormalities (
  • inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months (
  • transgenic mice from a Pkd1-BAC modified by introducing a silent tag develop tubular and glomerular cysts leading to renal insufficiency, renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis hepatic fibrosis and approximately 15% intrahepatic cysts of the bile ducts affecting females preferentially and a significant proportion of mice developed cardiac anomalies with severe left-ventricular hypertrophy, marked aortic arch distention and/or valvular stenosis and calcification (
  • mouse models of PC-1, a knock-in (KI) mutant line and a hair cell-specific inducible Cre-mediated knock-out line exhibit normal mechanoelectrical transduction channel function at neonatal ages despite hearing loss and ultrastructural abnormalities of sterecilia that remain properly polarized at adult ages (
  • treatment with pioglitazone improved survival of Pkd1(-/-) embryos and ameliorated the cardiac defects and the degree of renal cystogenesis (