Affinage

PKD1

Polycystin-1 · UniProt P98161

Length
4303 aa
Mass
462.5 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Polycystin-1 (PKD1) is a large (~400 kDa) plasma-membrane glycoprotein that governs epithelial tubule morphogenesis, cell adhesion, and mechanosensation, and whose dosage controls cystogenesis (PMID:8981910, PMID:9326937, PMID:15496422). It assembles with the cation channel polycystin-2/TRPP2 in a 1:3 stoichiometry through interacting C-terminal cytoplasmic tails, an arrangement requiring a homotrimeric TRPP2 coiled-coil that also promotes surface expression of both subunits (PMID:9192675, PMID:19556541). Cryo-EM resolves this complex as a domain-swapped, noncanonical TRP channel in which PKD1 contributes a voltage-gated ion channel fold with a broken S6 helix bearing cavity-facing positive charges, plus a five-transmembrane domain and a cytosolic PLAT domain (PMID:30093605). At the cell surface polycystin-1 partitions into the E-cadherin/catenin adhesion complex, co-precipitating with E-cadherin and alpha-, beta- and gamma-catenin (PMID:10562308). Its C-terminal tail is a signaling hub phosphorylated in vitro by PKA (Ser4252), c-Src (Tyr4237), and PRKX (Ser4166), the last of which rescues adhesion, migration, and branching defects in PKD1-deficient cells (PMID:10362514, PMID:17980165). Polycystin-1 supports cell survival and tubulogenic differentiation rather than simple cyst formation (PMID:11106764), and acts as a mechanosensor required for the osteoblast Ca2+ response to fluid shear and skeletal loading (PMID:21454365). Loss or reduction of PKD1 below a critical dosage threshold drives polycystic kidney disease and extends to pancreatic, hepatic, cardiovascular, and skeletal defects (PMID:9326937, PMID:15496422); downstream, PKD1 loss activates Galpha12 to disrupt cell-matrix and E-cadherin adhesion (genetic ablation of Galpha12 prevents cystogenesis) (PMID:27505895), elevates calpain activity that impairs lysosomal acidification and autophagic flux (PMID:32967521), and lowers collecting-duct intracellular Ca2+ and RhoA activity with altered AQP2 trafficking (PMID:17475819). PKD1 dosage is set by a reciprocal c-Myc feed-forward transcriptional loop (PMID:16449663, PMID:30388220), by p68/p53-mediated promoter repression (PMID:32724471), and post-transcriptionally by a 3'-UTR miR-17 element whose deletion raises polycystin-1 and alleviates cysts (PMID:35965273). Beyond the kidney, PKD1 is required for lymphatic vessel morphogenesis, brain ependymal planar cell polarity, and placental development (PMID:24767999, PMID:26245976, PMID:20862291).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1997 High

    Established the physical basis of the polycystin complex by showing PKD1 and PKD2 interact through their C-terminal tails, defining the molecular partnership underlying ADPKD.

    Evidence Co-immunoprecipitation and yeast two-hybrid with C-terminal tail constructs

    PMID:9192675

    Open questions at the time
    • Stoichiometry and structural arrangement not yet defined
    • Functional consequence of complex at the membrane unresolved
  2. 1996 Medium

    Defined polycystin-1 as a large plasma-membrane glycoprotein of renal, hepatic, and pancreatic ductal epithelia overexpressed in cysts, anchoring its tissue and subcellular context.

    Evidence Subcellular fractionation, immunohistochemistry, and EM with domain-specific antisera

    PMID:8981910

    Open questions at the time
    • Did not establish channel or adhesion function
    • Ciliary localization not addressed
  3. 1999 Medium

    Placed polycystin-1 in the E-cadherin/catenin adhesion complex and identified its C-terminal tail as a kinase substrate, linking it to junctional adhesion and intracellular signaling.

    Evidence Reciprocal co-IP and sucrose gradients for adhesion; in vitro phosphorylation by PKA and c-Src with site mutagenesis

    PMID:10362514 PMID:10562308

    Open questions at the time
    • In vivo significance of Ser4252/Tyr4237 phosphorylation not tested
    • Adhesion complex association not linked to channel function
  4. 1997 High

    Demonstrated through homozygous truncation that polycystin-1 is essential for tubular morphogenesis, with cysts arising during tubular elongation in mid-gestation.

    Evidence Pkd1 truncation knock-in mouse with timed developmental histopathology

    PMID:9326937

    Open questions at the time
    • Molecular mechanism of cystogenesis not defined
    • Perinatal lethality limited analysis of late-stage roles
  5. 2000 Medium

    Showed polycystin-1 promotes survival and tubulogenic differentiation rather than passive structural support, reframing it as a regulator of cell fate decisions.

    Evidence Stable PKD1 expression in MDCK cells with proliferation, apoptosis, and 3D tubulogenesis assays

    PMID:11106764

    Open questions at the time
    • Overexpression system may not reflect physiological signaling
    • Downstream effectors not identified
  6. 2004 High

    Established a dosage-threshold model of cystogenesis by showing that reducing Pkd1 to 13-20% of normal is sufficient to cause multi-organ cystic disease, with phenotype reversible upon restoration.

    Evidence Hypomorphic Pkd1 knock-in mouse with cassette-removal reversion control

    PMID:15496422

    Open questions at the time
    • Does not define which downstream pathway senses dosage
    • Cell-autonomous vs systemic contribution not separated
  7. 2007 Medium

    Connected PKD1 to additional kinase regulation and demonstrated functional rescue, showing PRKX phosphorylation of Ser4166 restores adhesion, migration, and branching in PKD1-deficient cells.

    Evidence In vitro binding/phosphorylation plus rescue in ADPKD cells and embryonic kidney organ culture

    PMID:17980165

    Open questions at the time
    • In vivo requirement for Ser4166 phosphorylation untested
    • Mechanism linking phosphorylation to adhesion unresolved
  8. 2007 Medium

    Linked polycystin-1 haploinsufficiency to dysregulated Ca2+ signaling and water handling, implicating it in collecting-duct RhoA activity and AQP2 trafficking even without cysts.

    Evidence Noncystic Pkd1+/- mouse with collecting-duct Ca2+ imaging, RhoA assays, and AQP2 immunofluorescence

    PMID:17475819

    Open questions at the time
    • Causal chain from PKD1 to Ca2+ change not mechanistically resolved
    • Single lab, single allele
  9. 2009 High

    Resolved the assembly stoichiometry as 1 PKD1 to 3 TRPP2 dependent on a TRPP2 coiled-coil trimer, explaining co-regulation of surface expression of both subunits.

    Evidence Co-IP, gel filtration, coiled-coil crystallography, and live-cell single-molecule fluorescence

    PMID:19556541

    Open questions at the time
    • Full-length complex architecture not yet visualized
    • Channel gating mechanism unresolved
  10. 2018 High

    Provided a near-atomic architecture of the PKD1-PKD2 complex, revealing PKD1's noncanonical TRP/VGIC fold and a broken, charge-bearing S6 helix that bears on cation permeation.

    Evidence Cryo-EM at 3.6 Å of truncated human PKD1-PKD2 complex

    PMID:30093605

    Open questions at the time
    • Truncated construct omits extracellular regions and the GAIN domain
    • Conducting state and physiological permeant not captured
  11. 2008 Medium

    Tested ERK/MAPK as a cyst driver and found it dispensable, redirecting the search for the causal effector of PKD1 loss away from ERK activation.

    Evidence Conditional Pkd1 knockout with in vivo MEK inhibition and BrdU proliferation readout

    PMID:18263604

    Open questions at the time
    • Negative result specific to this model and inhibitor dose
    • Did not identify the true causal pathway
  12. 2016 Medium

    Identified Galpha12 as a required downstream effector by showing its genetic ablation completely prevents cystogenesis in Pkd1-null kidneys via restored cell-matrix and E-cadherin adhesion.

    Evidence Pkd1/Gna12 double-knockout mouse with adhesion assays and genetic epistasis

    PMID:27505895

    Open questions at the time
    • Mechanism coupling PKD1 loss to Galpha12 activation unresolved
    • Single lab
  13. 2020 Medium

    Revealed a lysosomal/autophagy axis whereby PKD1 loss elevates calpain activity to impair lysosomal acidification and autophagic flux, rescuable by calpain inhibition.

    Evidence Pkd1-deleted mIMCD3 cells and conditional knockout mouse with lysosomal pH, cathepsin, autophagy flux, and calpain inhibitor rescue

    PMID:32967521

    Open questions at the time
    • Link from PKD1 to calcium influx driving calpain inferred, not proven
    • Contribution to cyst growth in vivo not quantified
  14. 2011 Medium

    Defined polycystin-1 as an essential skeletal mechanosensor required for osteoblast Ca2+ responses to fluid shear and the anabolic response to loading.

    Evidence Osteoblast/osteocyte conditional knockout with in vivo ulna loading and ex vivo shear-stress Ca2+ imaging

    PMID:21454365

    Open questions at the time
    • Whether mechanosensing requires the PKD2 channel partner not addressed
    • Molecular transduction step undefined
  15. 2014 Medium

    Extended PKD1 function to lymphatic vessel morphogenesis, showing it is dispensable for sprouting but required for migration, polarity, and adherens junctions of lymphatic endothelium.

    Evidence Zebrafish ENU mutant and conditional mouse knockout with live imaging and junctional marker immunofluorescence

    PMID:24767999

    Open questions at the time
    • Effector pathway in lymphatic cells not identified
    • Relationship to renal adhesion roles unresolved
  16. 2015 Medium

    Placed PKD1 in the planar cell polarity pathway by showing ciliary localization in radial glia and a requirement for asymmetric Vangl2 localization in ependymal PCP.

    Evidence Nestin-Cre conditional knockout with ciliary immunofluorescence and Pkd1/Vangl2 genetic epistasis

    PMID:26245976

    Open questions at the time
    • Biochemical link between PKD1 and Vangl2 not established
    • Channel role in PCP not tested
  17. 2010 Medium

    Demonstrated a requirement for PKD1 in placental development, with endothelial-specific deletion recapitulating a subset of vascular defects.

    Evidence Tetraploid aggregation rescue, Meox2-Cre and Tie2-Cre conditional deletions with histopathology

    PMID:20862291

    Open questions at the time
    • Cell-autonomous placental mechanism incompletely resolved
    • Molecular effectors not defined
  18. 2006 Medium

    Showed that Pkd1 overexpression also causes cystogenesis and upregulates c-Myc, establishing both excess and deficiency as pathogenic and naming c-Myc as a downstream node.

    Evidence BAC transgenic kidney-targeted Pkd1 overexpression with histopathology and c-Myc analysis

    PMID:16449663

    Open questions at the time
    • Did not establish whether c-Myc is required for cysts
    • Mechanism of dosage sensitivity unresolved
  19. 2019 Medium

    Closed the c-Myc-Pkd1 circuit by showing c-Myc directly binds the Pkd1 promoter and that c-Myc ablation attenuates cyst growth, defining a feed-forward regulatory loop.

    Evidence ChIP, genetic epistasis in Pkd1-dosage-altered mice, and human c-MYC transactivation assay

    PMID:30388220

    Open questions at the time
    • Direct cofactor requirements at the promoter only partly defined
    • Single lab
  20. 2020 Medium

    Identified p68 RNA helicase as a dual repressor of Pkd1, acting transcriptionally with p53 and post-transcriptionally by promoting repressive miRNA maturation.

    Evidence ChIP, qRT-PCR, immunostaining in cystic cells and 3D cyst assay with p68 silencing

    PMID:32724471

    Open questions at the time
    • Relative contribution of the two mechanisms unquantified
    • In vivo requirement not tested
  21. 2022 High

    Defined a therapeutically actionable post-transcriptional control whereby a 3'-UTR miR-17 element restrains the non-mutant PKD1 allele, and its deletion raises polycystin-1 and slows cysts.

    Evidence mRNA stability assays, miR-17 motif deletion mouse models, organoids, in vivo PKD models, and patient-derived cultures

    PMID:35965273

    Open questions at the time
    • Endogenous regulators of miR-17 in patient tissue not fully mapped
    • Delivery strategy for therapeutic derepression unresolved
  22. 2018 Medium

    Explained partial loss of full-length polycystin-1 in humans through abnormal alternative splicing at intron 21/22 polypyrimidine tracts, a mechanism absent in mouse.

    Evidence RT-PCR, N-terminal Western blot, and Nanopore long-read sequencing of human PKD1 transcripts

    PMID:30185468

    Open questions at the time
    • Regulation of this splicing event unknown
    • Functional impact of Trunc_PC1 protein product undefined
  23. 2002 Medium

    Provided genetic evidence for a polycystin dosage/threshold interaction by showing trans-heterozygous Pkd1+/-;Pkd2+/- mice exceed additive disease severity.

    Evidence Pkd1/Pkd2 mouse genetic cross with histopathology and polycystin-2 immunostaining

    PMID:12140187

    Open questions at the time
    • Molecular basis of the synergy not defined
    • Two-hit and threshold contributions not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the structurally resolved PKD1-PKD2 channel translates ion conduction or mechanical/ciliary cues into the adhesion, Ca2+, Galpha12, calpain, and transcriptional outputs that control tubule size remains unresolved.
  • Conducting state and physiological permeant of PKD1 unknown
  • Direct mechanism coupling PKD1 to Galpha12 activation undefined
  • Whether ciliary, junctional, and channel pools have distinct functions unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0060089 molecular transducer activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005929 cilium 1
Partners
CDH1CTNNB1GNA12MYCPKD2PRKACAPRKXSRC
Complex memberships
E-cadherin/catenin adhesion complexpolycystin-1/polycystin-2 (PKD1-TRPP2) channel complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PKD1 (polycystin-1) and PKD2 interact through their C-terminal cytoplasmic tails; this interaction upregulates PKD1 but not PKD2 expression. Additionally, the PKD2 C-terminal tail forms homodimers through a coiled-coil domain distinct from the PKD1-interaction region. Co-immunoprecipitation and yeast two-hybrid using C-terminal cytoplasmic tail constructs Proceedings of the National Academy of Sciences of the United States of America High 9192675
2009 The PKD1-PKD2 (TRPP2) complex assembles in a 1:3 stoichiometry (one PKD1 to three PKD2). A homotrimeric coiled-coil domain in the TRPP2/PKD2 C-terminus is required for complex assembly; mutations disrupting this trimer abolish both the full-length TRPP2 trimer and the TRPP2/PKD1 complex and diminish surface expression of both proteins. Biochemistry (co-IP, gel filtration), X-ray crystallography of the coiled-coil domain, and single-molecule fluorescence in live cell plasma membrane Proceedings of the National Academy of Sciences of the United States of America High 19556541
2018 Cryo-EM structure of truncated human PKD1-PKD2 complex at 3.6 Å reveals a 1:3 assembly with domain-swapped, noncanonical TRP channel architecture. PKD1 contains a voltage-gated ion channel (VGIC) fold; the S6 helix is broken in the middle (S6a resembles pore helix 1; S6b has three positively charged cavity-facing residues that may block cation permeation). A five-transmembrane helix domain and a cytosolic PLAT domain were also resolved in PKD1. Cryo-electron microscopy at 3.6 Å resolution Science (New York, N.Y.) High 30093605
1996 Polycystin-1 (PKD1 gene product) is an ~400 kDa glycoprotein that localizes predominantly to plasma membranes of renal tubular epithelia, hepatic bile ductules, and pancreatic ducts, with lower abundance in adult versus fetal epithelia; it is overexpressed in ADPKD cysts. Subcellular fractionation, immunohistochemistry, electron microscopy using antisera against synthetic peptide and recombinant protein domains The Journal of clinical investigation Medium 8981910
1999 Polycystin-1 co-localizes with E-cadherin and alpha-, beta-, and gamma-catenin; it co-precipitates with these proteins and co-migrates on sucrose density gradients, placing it in the E-cadherin/catenin cell-adhesion complex. It does not associate with the focal adhesion component focal adhesion kinase. Co-immunoprecipitation, sucrose density gradient fractionation, immunofluorescence co-localization The Journal of clinical investigation Medium 10562308
1999 The polycystin-1 C-terminal domain (CTD) is phosphorylated by cAMP-dependent protein kinase (PKA) at Ser4252 and by c-Src at Tyr4237 in vitro; PKA phosphorylation is enhanced by cAMP and blocked by PKA inhibitors; Y4237F mutation abolishes c-Src phosphorylation. In vitro phosphorylation assay with purified kinases and site-directed mutagenesis of PKD1-CTD fusion protein Biochemical and biophysical research communications High 10362514
2000 Expression of human PKD1 in MDCK cells slows their growth, protects them from apoptosis, and causes spontaneous formation of branching tubules rather than simple cysts, demonstrating that polycystin-1 regulates both cell survival and tubulogenic differentiation. Stable transfection of PKD1 cDNA in MDCK cells; proliferation assay, apoptosis assay, 3D tubulogenesis assay Molecular cell Medium 11106764
1997 Homozygous Pkd1 truncation in mice causes perinatal lethality with massively enlarged cystic kidneys and pancreatic ductal cysts; cyst formation begins at E15.5 in proximal tubules, indicating polycystin-1 is required for normal morphogenesis during tubular elongation and maturation. Homologous recombination knock-in of truncating Pkd1 mutation in mice; histopathology and timed developmental analysis Nature genetics High 9326937
2001 Pkd1 deletion in mice (del17-21betageo allele) causes embryonic lethality at E13.5–14.5 due to primary cardiovascular defects (double outflow right ventricle, disorganized myocardium, abnormal AV septation) and severe skeletal abnormalities, revealing essential roles for polycystin-1 in cardiovascular and skeletal development coincident with sites of high Pkd1 expression. Targeted disruption with lacZ reporter to define expression; histopathology of embryos Proceedings of the National Academy of Sciences of the United States of America Medium 11593033
2004 Reduction of Pkd1 expression to 13–20% of normal (hypomorphic Pkd1nl allele) is sufficient to cause bilateral polycystic kidneys, pancreatic and liver bile duct dilatations, and cardiovascular abnormalities in viable mice, demonstrating that PKD1 dosage below a critical threshold drives cystogenesis independently of complete loss of heterozygosity. Hypomorphic knock-in mouse model with intronic neomycin cassette causing aberrant splicing; restoration by cassette removal rescues phenotype Human molecular genetics High 15496422
2008 Kidney-specific inactivation of Pkd1 activates the MAPK/ERK pathway (Ras through MEK1/2, ERK1/2, to P90RSK) focally in cystic segments, but pharmacological inhibition of MEK1/2 with U0126 at doses sufficient to reduce phospho-ERK1/2 does not prevent cyst formation, indicating ERK activation is not the primary driver of cyst growth in this model. Conditional Pkd1 knockout mouse; immunostaining for pathway components; in vivo MEK inhibitor treatment with BrdU proliferation assay Human molecular genetics Medium 18263604
2006 Overexpression of wild-type Pkd1 in kidney (2–15-fold) is sufficient to trigger cystogenesis and renal failure in transgenic mice, and is accompanied by striking upregulation of renal c-Myc, identifying c-Myc as a downstream effector of Pkd1 pathways in vivo. BAC transgenic mouse with kidney-targeted Pkd1 overexpression; histopathology; c-Myc expression analysis Molecular and cellular biology Medium 16449663
2019 c-Myc directly binds the Pkd1 promoter (ChIP-confirmed) with RNA pol II and active chromatin-modifying co-factors to stimulate Pkd1/polycystin-1 transcription during cystogenesis, establishing a reciprocal feed-forward regulatory loop between c-Myc and Pkd1. Genetic ablation of c-Myc in Pkd1-dosage-altered mice significantly attenuates cyst growth. ChIP assay, mouse genetic epistasis (c-Myc knockout in Pkd1-reduced and -increased models), transactivation assay with human c-MYC Human molecular genetics Medium 30388220
2011 Conditional deletion of Pkd1 in osteoblasts/osteocytes (Dmp1-Cre) impairs the anabolic response to mechanical loading; Pkd1-null osteoblasts fail to show cytosolic Ca2+ increases in response to fluid shear stress, identifying polycystin-1 as an essential skeletal mechanosensor. Conditional knockout mouse; in vivo ulna loading; ex vivo fluid shear stress with Ca2+ imaging of isolated osteoblasts FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 21454365
2016 Pkd1 knockout promotes Gα12 activation, which then decreases cell-matrix adhesion (focal adhesion function) and cell-cell adhesion (E-cadherin function); genetic ablation of Gα12 in Pkd1-knockout mice completely prevents kidney cystogenesis, establishing Gα12 as a required downstream effector of polycystin-1 loss in the kidney. Double-knockout mouse model (Pkd1 and Gna12); cell adhesion assays; genetic epistasis Journal of cell science Medium 27505895
2015 Pkd1 and Pkd2 localize to primary cilia of radial glial cells (RGCs) in the brain ventricular epithelium; conditional ablation of Pkd1 or Pkd2 disrupts planar cell polarity (PCP) development in RGCs and ependymal cells, including asymmetric localization of PCP protein Vangl2, placing Pkd1 in the same pathway as Vangl2 for establishing ependymal PCP. Conditional knockout mice (Nestin-Cre); immunofluorescence localization in cilia; genetic epistasis with Pkd1/Vangl2 double heterozygotes The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 26245976
2014 Pkd1 is required for lymphatic vessel morphogenesis: loss of Pkd1a in zebrafish (lyc1 mutant) and Pkd1 in mice does not impair initial lymphatic precursor sprouting but blocks ongoing migration and network morphogenesis, with individual lymphatic endothelial cells showing defective polarity, elongation, and adherens junctions. Zebrafish ENU mutant screen; conditional Pkd1 mouse knockout; live imaging; immunofluorescence of lymphatic markers and junctional proteins Cell reports Medium 24767999
2007 Pkd1 haploinsufficiency in non-cystic mice causes a syndrome of inappropriate antidiuresis, associated with decreased intracellular Ca2+ concentration in isolated collecting duct cells, decreased RhoA activity, and enhanced apical recruitment of phospho-Ser256-AQP2, revealing a role for polycystin-1 in regulating Ca2+ signaling and AQP2 trafficking in the collecting duct. Noncystic Pkd1+/- mouse model; urine/plasma osmolality; isolated collecting duct Ca2+ imaging; AQP2 immunofluorescence; RhoA and ERK1/2 activity assays Journal of the American Society of Nephrology : JASN Medium 17475819
2020 Loss of Pkd1 causes diminished lysosomal acidification, reduced CTSB/cathepsin B processing, impaired autophagosomal-lysosomal fusion, and enhanced extracellular CTSB secretion; these defects are driven by elevated CAPN (calpain) activity (likely from higher calcium influx), and are rescued by calpain inhibitors, establishing a lysosomal function for PKD1 that keeps calpain activity in check. Genetic Pkd1 deletion in mIMCD3 cells and conditional knockout mouse; lysosomal pH assay; cathepsin activity assay; autophagy flux assay; calpain inhibitor rescue experiments Autophagy Medium 32967521
2022 mRNAs from the non-inactivated PKD1 allele are repressed via a 3'-UTR miR-17 binding element; deletion of this motif (Pkd1Δ17) improves mRNA stability, raises polycystin-1 levels, and alleviates cyst growth in cellular, ex vivo, and mouse PKD models. Pkd2 is likewise inhibited via its 3'-UTR miR-17 motif, and Pkd2Δ17-induced polycystin-2 derepression retards cyst growth in Pkd1-mutant models. mRNA stability assays; miR-17 motif deletion mouse models (Pkd1Δ17, Pkd2Δ17); ex vivo organoid cultures; in vivo mouse PKD models; patient-derived ADPKD primary cultures Nature communications High 35965273
2013 The GAIN (GPCR autoproteolysis-inducing) domain structure, which incorporates the GPS motif, is present in PKD1 and related proteins and mediates autoproteolytic cleavage; structural analysis of the GAIN domain reveals the GPS motif as a linchpin for multiple receptor signals. Structural analysis and functional assays of the GAIN domain (review synthesizing crystal structure and functional studies) Trends in pharmacological sciences Low 23850273
2007 Protein kinase X (PRKX) binds to and phosphorylates the polycystin-1 C-terminal domain at Ser4166 in vitro; constitutively active PRKX rescues adhesion and migration defects in human ADPKD epithelial cells and restores normal branching morphogenesis in PKD1-inhibited mouse embryonic kidney organ culture. In vitro binding and phosphorylation assay; stable transfection in ADPKD epithelial cells; ureteric bud microinjection in embryonic kidney organ culture Biochimica et biophysica acta Medium 17980165
2020 RNA helicase p68 represses Pkd1 gene expression via two mechanisms: (1) binding to the Pkd1 promoter together with p53 to repress transcription (ChIP-confirmed), and (2) promoting expression and maturation of miR-17, miR-200c, and miR-182 (via a Drosha-p68 complex) that post-transcriptionally suppress Pkd1 mRNA. Western blot, qRT-PCR, immunostaining, ChIP assay in cystic renal cells and tissues; 3D culture cyst formation assay with p68 silencing Theranostics Medium 32724471
2010 Pkd1 and Pkd2 are required for normal placental development; histopathological analysis shows labyrinth layer abnormalities in Pkd1-null placentas from E12.5. Tetraploid aggregation rescue and Meox2-Cre conditional Pkd1 inactivation both improve viability of Pkd1-null embryos. Endothelial cell-specific deletion of Pkd1 or Pkd2 recapitulates a subset of placental vascular findings. Tetraploid aggregation placental rescue; Cre-mediated conditional deletion in endothelium (Tie2-Cre); histopathology PloS one Medium 20862291
2002 Trans-heterozygous Pkd1+/-;Pkd2+/- mice develop cystic disease more severe than predicted by simple additive effects of single heterozygotes, supporting a genetic modifier/threshold role for the trans-polycystin gene. ~70% of Pkd2+/- kidney cysts show uniform loss of polycystin-2, consistent with a two-hit mechanism. Mouse genetic cross of Pkd1+/- and Pkd2+/- animals; histopathology; immunostaining for polycystin-2 in cysts Human molecular genetics Medium 12140187
2018 Human PKD1 undergoes abnormal alternative splicing across the polypyrimidine tracts in introns 21 and 22, generating a truncated polycystin-1 product (Trunc_PC1); 28.8–61.5% of PKD1 transcripts terminate early, reducing full-length PC1 levels from normal alleles. This mechanism does not occur in mouse Pkd1, which lacks equivalent polypyrimidine tracts. RT-PCR, Western blotting with N-terminal antibody, Nanopore long-read sequencing of PKD1 transcripts Journal of the American Society of Nephrology : JASN Medium 30185468

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proceedings of the National Academy of Sciences of the United States of America 426 9192675
2013 Type of PKD1 mutation influences renal outcome in ADPKD. Journal of the American Society of Nephrology : JASN 418 23431072
1997 Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation. Nature genetics 378 9326937
2004 Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Human molecular genetics 260 15496422
2001 Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene. Proceedings of the National Academy of Sciences of the United States of America 249 11593033
2008 Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Human molecular genetics 241 18263604
2018 Structure of the human PKD1-PKD2 complex. Science (New York, N.Y.) 221 30093605
1999 Polycystin-1, the PKD1 gene product, is in a complex containing E-cadherin and the catenins. The Journal of clinical investigation 182 10562308
2000 Polycystin-1, the gene product of PKD1, induces resistance to apoptosis and spontaneous tubulogenesis in MDCK cells. Molecular cell 181 11106764
1996 Identification and localization of polycystin, the PKD1 gene product. The Journal of clinical investigation 168 8981910
2000 Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. American journal of human genetics 162 11115377
2009 Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proceedings of the National Academy of Sciences of the United States of America 152 19556541
2004 PKD1/PKCmu promotes alphavbeta3 integrin recycling and delivery to nascent focal adhesions. The EMBO journal 151 15192707
2012 Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Human mutation 146 22508176
2006 Overexpression of PKD1 causes polycystic kidney disease. Molecular and cellular biology 119 16449663
2014 Identification of Biomarkers for PKD1 Using Urinary Exosomes. Journal of the American Society of Nephrology : JASN 115 25475747
2002 Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. Human molecular genetics 109 12140187
2002 Expression of PKD1 and PKD2 transcripts and proteins in human embryo and during normal kidney development. The American journal of pathology 103 11891195
2011 Conditional deletion of Pkd1 in osteocytes disrupts skeletal mechanosensing in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 102 21454365
2008 Pkd1 inactivation induced in adulthood produces focal cystic disease. Journal of the American Society of Nephrology : JASN 81 18776127
1999 Polycystin-1 expression in PKD1, early-onset PKD1, and TSC2/PKD1 cystic tissue. Kidney international 81 10504485
2013 Matching structure with function: the GAIN domain of adhesion-GPCR and PKD1-like proteins. Trends in pharmacological sciences 79 23850273
1998 Gene conversion is a likely cause of mutation in PKD1. Human molecular genetics 78 9668165
2014 Pkd1 regulates lymphatic vascular morphogenesis during development. Cell reports 75 24767999
2009 Pkd1 haploinsufficiency increases renal damage and induces microcyst formation following ischemia/reperfusion. Journal of the American Society of Nephrology : JASN 75 19833899
2010 Pkd1 and Pkd2 are required for normal placental development. PloS one 73 20862291
2015 Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease. Journal of the American Society of Nephrology : JASN 69 26139440
2022 PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression. Nature communications 60 35965273
2018 Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in Pkd1-Deficient Mice. Journal of the American Society of Nephrology : JASN 58 30042193
2007 PKD1 haploinsufficiency causes a syndrome of inappropriate antidiuresis in mice. Journal of the American Society of Nephrology : JASN 58 17475819
2001 Pkd1 unusual DNA conformations are recognized by nucleotide excision repair. The Journal of biological chemistry 56 11279140
2002 Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1. Current opinion in nephrology and hypertension 55 11981261
2006 CCK causes PKD1 activation in pancreatic acini by signaling through PKC-delta and PKC-independent pathways. Biochimica et biophysica acta 51 17306383
1999 Identification of phosphorylation sites in the PKD1-encoded protein C-terminal domain. Biochemical and biophysical research communications 51 10362514
2011 A missense mutation in PKD1 attenuates the severity of renal disease. Kidney international 50 22031115
1999 DNA structural transitions within the PKD1 gene. Nucleic acids research 50 10373576
2004 Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2). European journal of human genetics : EJHG 49 14872199
2015 Mechanosensory Genes Pkd1 and Pkd2 Contribute to the Planar Polarization of Brain Ventricular Epithelium. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 26245976
2017 Detecting PKD1 variants in polycystic kidney disease patients by single-molecule long-read sequencing. Human mutation 45 28378423
2018 Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure. eLife 44 30511640
1999 Murine Pkd1 is a developmentally regulated gene from morula to adulthood: role in tissue condensation and patterning. Developmental dynamics : an official publication of the American Association of Anatomists 44 10213389
2019 Synergistic Genetic Interactions between Pkhd1 and Pkd1 Result in an ARPKD-Like Phenotype in Murine Models. Journal of the American Society of Nephrology : JASN 42 31427367
2007 Pkd1 and Nek8 mutations affect cell-cell adhesion and cilia in cysts formed in kidney organ cultures. American journal of physiology. Renal physiology 42 17928412
2004 PKD1 intron 21: triplex DNA formation and effect on replication. Nucleic acids research 38 14990751
2000 Distinct and common developmental expression patterns of the murine Pkd2 and Pkd1 genes. Mechanisms of development 36 10781953
1997 Mutation detection in the repeated part of the PKD1 gene. American journal of human genetics 35 9345095
1995 The PKD1 gene produces a developmentally regulated protein in mesenchyme and vasculature. Nature medicine 35 7585067
2011 Protein kinase D1 (PKD1) activation mediates a compensatory protective response during early stages of oxidative stress-induced neuronal degeneration. Molecular neurodegeneration 34 21696630
2010 Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 34 21115670
2020 EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats. Translational neuroscience 33 33335755
2019 Silencing of long non-coding RNA H19 downregulates CTCF to protect against atherosclerosis by upregulating PKD1 expression in ApoE knockout mice. Aging 33 31757932
2020 Loss of PKD1/polycystin-1 impairs lysosomal activity in a CAPN (calpain)-dependent manner. Autophagy 32 32967521
2021 Detection of PKD1 and PKD2 Somatic Variants in Autosomal Dominant Polycystic Kidney Cyst Epithelial Cells by Whole-Genome Sequencing. Journal of the American Society of Nephrology : JASN 31 34716216
2010 Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension. Laboratory investigation; a journal of technical methods and pathology 31 20856231
2007 PKD1, PKD2, and their substrate Kidins220 regulate neurotensin secretion in the BON human endocrine cell line. The Journal of biological chemistry 31 18048355
2007 PKD1 inhibits cancer cells migration and invasion via Wnt signaling pathway in vitro. Cell biochemistry and function 30 17437318
2014 Nedd9 restrains renal cystogenesis in Pkd1-/- mice. Proceedings of the National Academy of Sciences of the United States of America 29 25139996
2013 VEGF-PKD1-HDAC7 signaling promotes endothelial progenitor cell migration and tube formation. Microvascular research 28 24189120
2008 Protein kinase D1 (PKD1) influences androgen receptor (AR) function in prostate cancer cells. Biochemical and biophysical research communications 28 18602367
2019 Deciphering the Role of Protein Kinase D1 (PKD1) in Cellular Proliferation. Molecular cancer research : MCR 27 31311827
2008 Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease. European journal of clinical investigation 25 18257781
2021 Patients with Protein-Truncating PKD1 Mutations and Mild ADPKD. Clinical journal of the American Society of Nephrology : CJASN 24 33602752
2021 An Oxidative Stress-Related Gene Pair (CCNB1/PKD1), Competitive Endogenous RNAs, and Immune-Infiltration Patterns Potentially Regulate Intervertebral Disc Degeneration Development. Frontiers in immunology 24 34858418
2019 c-Myc is a regulator of the PKD1 gene and PC1-induced pathogenesis. Human molecular genetics 24 30388220
2016 Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout. Kidney international 24 27475230
2015 PKD1 protein is involved in reactive oxygen species-mediated mitochondrial depolarization in cooperation with protein kinase Cδ (PKCδ). The Journal of biological chemistry 22 25759386
2015 Small heat shock protein 20 (Hsp20) facilitates nuclear import of protein kinase D 1 (PKD1) during cardiac hypertrophy. Cell communication and signaling : CCS 22 25889640
2014 Protein kinase D1 (PKD1) phosphorylation promotes dopaminergic neuronal survival during 6-OHDA-induced oxidative stress. PloS one 22 24806360
2020 RNA helicase p68 inhibits the transcription and post-transcription of Pkd1 in ADPKD. Theranostics 20 32724471
2016 Gα12 is required for renal cystogenesis induced by Pkd1 inactivation. Journal of cell science 20 27505895
2012 PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma. International journal of oncology 20 22426824
2011 Molecular analysis of TSC2/PKD1 contiguous gene deletion syndrome. The Kobe journal of medical sciences 20 22169896
2021 ANXA10 promotes melanoma metastasis by suppressing E3 ligase TRIM41-directed PKD1 degradation. Cancer letters 19 34324862
2019 Caffeine Accelerates Cystic Kidney Disease in a Pkd1-Deficient Mouse Model. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 30977988
2011 Differential expression of PKD1 and PKD2 in gastric cancer and analysis of PKD1 and PKD2 function in the model system. Experimental oncology 19 22217708
2020 Inhibition of the BCL6/miR-31/PKD1 axis attenuates oxidative stress-induced neuronal damage. Experimental neurology 18 33189730
2013 Different regulation of physiological and tumor angiogenesis in zebrafish by protein kinase D1 (PKD1). PloS one 18 23874489
2012 Conditional mesenchymal disruption of pkd1 results in osteopenia and polycystic kidney disease. PloS one 18 23029375
2011 High Resolution Melt analysis for mutation screening in PKD1 and PKD2. BMC nephrology 18 22008521
2007 Protein kinase X (PRKX) can rescue the effects of polycystic kidney disease-1 gene (PKD1) deficiency. Biochimica et biophysica acta 18 17980165
2005 Differential expression of Cux-1 and p21 in polycystic kidneys from Pkd1 null and cpk mice. Kidney international 18 15673290
2002 Mutation analysis in PKD1 of Japanese autosomal dominant polycystic kidney disease patients. Human mutation 17 12007219
2022 Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice. Human molecular genetics 16 34957500
2021 Dysfunctional EGFR and oxidative stress-induced PKD1 signaling drive formation of DCLK1+ pancreatic stem cells. iScience 16 33521594
2018 Human-Specific Abnormal Alternative Splicing of Wild-Type PKD1 Induces Premature Termination of Polycystin-1. Journal of the American Society of Nephrology : JASN 16 30185468
2017 PKD1 Promotes Functional Synapse Formation Coordinated with N-Cadherin in Hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 16 29133434
1999 Characterisation and expression of the PKD-1 protein, polycystin, in renal and extrarenal tissues. Kidney international 16 10231477
2023 Atypical splicing variants in PKD1 explain most undiagnosed typical familial ADPKD. NPJ genomic medicine 15 37419908
2019 A role for PKD1 in insulin secretion downstream of P2Y1 receptor activation in mouse and human islets. Physiological reports 15 31591827
2018 PKD1 is a potential biomarker and therapeutic target in triple-negative breast cancer. Oncotarget 15 29796183
2014 Genkwadaphnin induces IFN-γ via PKD1/NF-κB/STAT1 dependent pathway in NK-92 cells. PloS one 15 25517939
2022 Generation of heterozygous PKD1 mutant pigs exhibiting early-onset renal cyst formation. Laboratory investigation; a journal of technical methods and pathology 14 34980882
2022 Recessive PKD1 Mutations Are Associated With Febrile Seizures and Epilepsy With Antecedent Febrile Seizures and the Genotype-Phenotype Correlation. Frontiers in molecular neuroscience 14 35620448
2017 Protein kinase D1 (PKD1) phosphorylation on Ser203 by type I p21-activated kinase (PAK) regulates PKD1 localization. The Journal of biological chemistry 14 28408623
2014 L1 modulates PKD1 phosphorylation in cerebellar granule neurons. Neuroscience letters 14 25445362
2009 p38delta and PKD1: kinase switches for insulin secretion. Cell 14 19167323
2023 Hypomorphic PKD1 Alleles Impact Disease Variability in Autosomal Dominant Polycystic Kidney Disease. Kidney360 12 36706243
2022 Phosphorylation-dependent positive feedback on the oxytocin receptor through the kinase PKD1 contributes to long-term social memory. Science signaling 12 35104164
2021 Loss of PKD1 and PKD2 share common effects on intracellular Ca2+ signaling. Cell calcium 12 33915319
2021 Smoking accelerates renal cystic disease and worsens cardiac phenotype in Pkd1-deficient mice. Scientific reports 12 34262092

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