{"gene":"PKD1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1997,"finding":"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.","method":"Co-immunoprecipitation and yeast two-hybrid using C-terminal cytoplasmic tail constructs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction mapped to specific domains, replicated across multiple labs in subsequent work","pmids":["9192675"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Biochemistry (co-IP, gel filtration), X-ray crystallography of the coiled-coil domain, and single-molecule fluorescence in live cell plasma membrane","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus single-molecule stoichiometry plus mutagenesis, multiple orthogonal methods in one study","pmids":["19556541"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Cryo-electron microscopy at 3.6 Å resolution","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution cryo-EM structure with functional domain assignment","pmids":["30093605"],"is_preprint":false},{"year":1996,"finding":"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.","method":"Subcellular fractionation, immunohistochemistry, electron microscopy using antisera against synthetic peptide and recombinant protein domains","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation and EM localization, single lab, multiple antibodies","pmids":["8981910"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Co-immunoprecipitation, sucrose density gradient fractionation, immunofluorescence co-localization","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus density gradient, single lab, two orthogonal methods","pmids":["10562308"],"is_preprint":false},{"year":1999,"finding":"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.","method":"In vitro phosphorylation assay with purified kinases and site-directed mutagenesis of PKD1-CTD fusion protein","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified kinases plus mutagenesis, single lab but multiple substrate mutations tested","pmids":["10362514"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Stable transfection of PKD1 cDNA in MDCK cells; proliferation assay, apoptosis assay, 3D tubulogenesis assay","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with defined functional readouts (proliferation, apoptosis, tubulogenesis), single lab","pmids":["11106764"],"is_preprint":false},{"year":1997,"finding":"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.","method":"Homologous recombination knock-in of truncating Pkd1 mutation in mice; histopathology and timed developmental analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — definitive loss-of-function mouse model with precise developmental staging, replicated by multiple groups","pmids":["9326937"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Targeted disruption with lacZ reporter to define expression; histopathology of embryos","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with defined developmental phenotype, single lab","pmids":["11593033"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Hypomorphic knock-in mouse model with intronic neomycin cassette causing aberrant splicing; restoration by cassette removal rescues phenotype","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dose-response with reversion control (cassette removal restores wild-type phenotype), multiple organ systems assessed","pmids":["15496422"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Conditional Pkd1 knockout mouse; immunostaining for pathway components; in vivo MEK inhibitor treatment with BrdU proliferation assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pathway activation with pharmacological rescue attempt, single lab; notable as a negative functional result for ERK causality","pmids":["18263604"],"is_preprint":false},{"year":2006,"finding":"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.","method":"BAC transgenic mouse with kidney-targeted Pkd1 overexpression; histopathology; c-Myc expression analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function mouse model with defined molecular downstream (c-Myc), single lab","pmids":["16449663"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ChIP assay, mouse genetic epistasis (c-Myc knockout in Pkd1-reduced and -increased models), transactivation assay with human c-MYC","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic epistasis, single lab, two orthogonal methods","pmids":["30388220"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Conditional knockout mouse; in vivo ulna loading; ex vivo fluid shear stress with Ca2+ imaging of isolated osteoblasts","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with in vivo and ex vivo functional readouts, single lab","pmids":["21454365"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Double-knockout mouse model (Pkd1 and Gna12); cell adhesion assays; genetic epistasis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo, single lab, clean phenotypic rescue","pmids":["27505895"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Conditional knockout mice (Nestin-Cre); immunofluorescence localization in cilia; genetic epistasis with Pkd1/Vangl2 double heterozygotes","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with localization and genetic epistasis, single lab","pmids":["26245976"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Zebrafish ENU mutant screen; conditional Pkd1 mouse knockout; live imaging; immunofluorescence of lymphatic markers and junctional proteins","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent organism models (zebrafish + mouse) with cellular phenotype characterization","pmids":["24767999"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Noncystic Pkd1+/- mouse model; urine/plasma osmolality; isolated collecting duct Ca2+ imaging; AQP2 immunofluorescence; RhoA and ERK1/2 activity assays","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — haploinsufficiency model with multiple molecular endpoints, single lab","pmids":["17475819"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Genetic Pkd1 deletion in mIMCD3 cells and conditional knockout mouse; lysosomal pH assay; cathepsin activity assay; autophagy flux assay; calpain inhibitor rescue experiments","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent Pkd1-deficient cell models with pharmacological rescue, single lab","pmids":["32967521"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal models (cellular, ex vivo, in vivo, patient-derived) with genetic deletion of specific regulatory element and functional rescue","pmids":["35965273"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Structural analysis and functional assays of the GAIN domain (review synthesizing crystal structure and functional studies)","journal":"Trends in pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review synthesizing published structural data; no new direct experiment on PKD1 described in this abstract","pmids":["23850273"],"is_preprint":false},{"year":2007,"finding":"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.","method":"In vitro binding and phosphorylation assay; stable transfection in ADPKD epithelial cells; ureteric bud microinjection in embryonic kidney organ culture","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphorylation mapped to specific site plus functional rescue in two complementary cell/organ models, single lab","pmids":["17980165"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Western blot, qRT-PCR, immunostaining, ChIP assay in cystic renal cells and tissues; 3D culture cyst formation assay with p68 silencing","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus multiple molecular readouts, single lab, two orthogonal mechanisms demonstrated","pmids":["32724471"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Tetraploid aggregation placental rescue; Cre-mediated conditional deletion in endothelium (Tie2-Cre); histopathology","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two rescue strategies plus tissue-specific deletion, single lab","pmids":["20862291"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Mouse genetic cross of Pkd1+/- and Pkd2+/- animals; histopathology; immunostaining for polycystin-2 in cysts","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo with immunohistochemical validation, single lab","pmids":["12140187"],"is_preprint":false},{"year":2018,"finding":"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.","method":"RT-PCR, Western blotting with N-terminal antibody, Nanopore long-read sequencing of PKD1 transcripts","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal methods (RT-PCR, Western blot, long-read sequencing) confirming splice event, single lab","pmids":["30185468"],"is_preprint":false}],"current_model":"Polycystin-1 (PKD1) is a large plasma membrane glycoprotein that assembles with three PKD2/TRPP2 subunits into a noncanonical TRP-channel-like complex (1:3 stoichiometry, resolved by cryo-EM at 3.6 Å) via interacting C-terminal coiled-coil domains; the PKD1 VGIC fold contains a broken S6 helix with positively charged residues that likely gate cation permeation. Polycystin-1 localizes to primary cilia, plasma membranes, and cell-cell junctions where it interacts with the E-cadherin/catenin complex, and its C-terminal tail is phosphorylated by PKA (at Ser4252) and c-Src (at Tyr4237); its dosage is post-transcriptionally regulated by miR-17 via the 3'-UTR and transcriptionally controlled by a c-Myc feed-forward loop. Loss of PKD1 function triggers Gα12-dependent disruption of focal adhesion and E-cadherin adhesion, elevated calpain activity impairing lysosomal integrity and autophagic flux, decreased intracellular Ca2+ and RhoA activity in collecting duct cells, and deregulated proliferation/apoptosis leading to tubular cyst formation; PKD1 is also required for skeletal mechanosensing, lymphatic vessel morphogenesis, brain ependymal planar cell polarity, and placental development."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1997,"claim":"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","pmids":["9192675"],"confidence":"High","gaps":["Stoichiometry and structural arrangement not yet defined","Functional consequence of complex at the membrane unresolved"]},{"year":1996,"claim":"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","pmids":["8981910"],"confidence":"Medium","gaps":["Did not establish channel or adhesion function","Ciliary localization not addressed"]},{"year":1999,"claim":"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","pmids":["10562308","10362514"],"confidence":"Medium","gaps":["In vivo significance of Ser4252/Tyr4237 phosphorylation not tested","Adhesion complex association not linked to channel function"]},{"year":1997,"claim":"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","pmids":["9326937"],"confidence":"High","gaps":["Molecular mechanism of cystogenesis not defined","Perinatal lethality limited analysis of late-stage roles"]},{"year":2000,"claim":"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","pmids":["11106764"],"confidence":"Medium","gaps":["Overexpression system may not reflect physiological signaling","Downstream effectors not identified"]},{"year":2004,"claim":"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","pmids":["15496422"],"confidence":"High","gaps":["Does not define which downstream pathway senses dosage","Cell-autonomous vs systemic contribution not separated"]},{"year":2007,"claim":"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","pmids":["17980165"],"confidence":"Medium","gaps":["In vivo requirement for Ser4166 phosphorylation untested","Mechanism linking phosphorylation to adhesion unresolved"]},{"year":2007,"claim":"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","pmids":["17475819"],"confidence":"Medium","gaps":["Causal chain from PKD1 to Ca2+ change not mechanistically resolved","Single lab, single allele"]},{"year":2009,"claim":"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","pmids":["19556541"],"confidence":"High","gaps":["Full-length complex architecture not yet visualized","Channel gating mechanism unresolved"]},{"year":2018,"claim":"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","pmids":["30093605"],"confidence":"High","gaps":["Truncated construct omits extracellular regions and the GAIN domain","Conducting state and physiological permeant not captured"]},{"year":2008,"claim":"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","pmids":["18263604"],"confidence":"Medium","gaps":["Negative result specific to this model and inhibitor dose","Did not identify the true causal pathway"]},{"year":2016,"claim":"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","pmids":["27505895"],"confidence":"Medium","gaps":["Mechanism coupling PKD1 loss to Galpha12 activation unresolved","Single lab"]},{"year":2020,"claim":"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","pmids":["32967521"],"confidence":"Medium","gaps":["Link from PKD1 to calcium influx driving calpain inferred, not proven","Contribution to cyst growth in vivo not quantified"]},{"year":2011,"claim":"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","pmids":["21454365"],"confidence":"Medium","gaps":["Whether mechanosensing requires the PKD2 channel partner not addressed","Molecular transduction step undefined"]},{"year":2014,"claim":"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","pmids":["24767999"],"confidence":"Medium","gaps":["Effector pathway in lymphatic cells not identified","Relationship to renal adhesion roles unresolved"]},{"year":2015,"claim":"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","pmids":["26245976"],"confidence":"Medium","gaps":["Biochemical link between PKD1 and Vangl2 not established","Channel role in PCP not tested"]},{"year":2010,"claim":"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","pmids":["20862291"],"confidence":"Medium","gaps":["Cell-autonomous placental mechanism incompletely resolved","Molecular effectors not defined"]},{"year":2006,"claim":"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","pmids":["16449663"],"confidence":"Medium","gaps":["Did not establish whether c-Myc is required for cysts","Mechanism of dosage sensitivity unresolved"]},{"year":2019,"claim":"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","pmids":["30388220"],"confidence":"Medium","gaps":["Direct cofactor requirements at the promoter only partly defined","Single lab"]},{"year":2020,"claim":"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","pmids":["32724471"],"confidence":"Medium","gaps":["Relative contribution of the two mechanisms unquantified","In vivo requirement not tested"]},{"year":2022,"claim":"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","pmids":["35965273"],"confidence":"High","gaps":["Endogenous regulators of miR-17 in patient tissue not fully mapped","Delivery strategy for therapeutic derepression unresolved"]},{"year":2018,"claim":"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","pmids":["30185468"],"confidence":"Medium","gaps":["Regulation of this splicing event unknown","Functional impact of Trunc_PC1 protein product undefined"]},{"year":2002,"claim":"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","pmids":["12140187"],"confidence":"Medium","gaps":["Molecular basis of the synergy not defined","Two-hit and threshold contributions not separated"]},{"year":null,"claim":"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.","evidence":"No single study in the corpus links channel conductance to the downstream effector pathways","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,0,1]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,1]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[15]}],"pathway":[],"complexes":["polycystin-1/polycystin-2 (PKD1-TRPP2) channel complex","E-cadherin/catenin adhesion complex"],"partners":["PKD2","CDH1","CTNNB1","PRKACA","SRC","PRKX","GNA12","MYC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P98161","full_name":"Polycystin-1","aliases":["Autosomal dominant polycystic kidney disease 1 protein"],"length_aa":4303,"mass_kda":462.5,"function":"Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B (PubMed:27214281). Both PKD1 and PKD2 are required for channel activity (PubMed:27214281). Involved in renal tubulogenesis (PubMed:12482949). Involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (By similarity). Acts as a regulator of cilium length, together with PKD2 (By similarity). The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling (By similarity). The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling (By similarity). May be an ion-channel regulator. Involved in adhesive protein-protein and protein-carbohydrate interactions. Likely to be involved with polycystin-1-interacting protein 1 in the detection, sequestration and exocytosis of senescent mitochondria (PubMed:37681898)","subcellular_location":"Cell membrane; Cell projection, cilium; Endoplasmic reticulum; Golgi apparatus; Vesicle; Secreted, extracellular exosome","url":"https://www.uniprot.org/uniprotkb/P98161/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PKD1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":383,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PKD1","total_profiled":1310},"omim":[{"mim_id":"621445","title":"EXOSOMAL POLYCYSTIN 1-INTERACTING PROTEIN; EPCIP","url":"https://www.omim.org/entry/621445"},{"mim_id":"621164","title":"POLYCYSTIC KIDNEY DISEASE 9, SUSCEPTIBILITY TO; 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polycystic kidney disease patients.","date":"2002","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/12007219","citation_count":17,"is_preprint":false},{"pmid":"10231477","id":"PMC_10231477","title":"Characterisation and expression of the PKD-1 protein, polycystin, in renal and extrarenal tissues.","date":"1999","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/10231477","citation_count":16,"is_preprint":false},{"pmid":"29133434","id":"PMC_29133434","title":"PKD1 Promotes Functional Synapse Formation Coordinated with N-Cadherin in Hippocampus.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29133434","citation_count":16,"is_preprint":false},{"pmid":"34957500","id":"PMC_34957500","title":"Metformin induces lactate accumulation and accelerates renal cyst progression in Pkd1-deficient mice.","date":"2022","source":"Human molecular 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Ser203 by type I p21-activated kinase (PAK) regulates PKD1 localization.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28408623","citation_count":14,"is_preprint":false},{"pmid":"25445362","id":"PMC_25445362","title":"L1 modulates PKD1 phosphorylation in cerebellar granule neurons.","date":"2014","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/25445362","citation_count":14,"is_preprint":false},{"pmid":"35620448","id":"PMC_35620448","title":"Recessive PKD1 Mutations Are Associated With Febrile Seizures and Epilepsy With Antecedent Febrile Seizures and the Genotype-Phenotype Correlation.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35620448","citation_count":14,"is_preprint":false},{"pmid":"34980882","id":"PMC_34980882","title":"Generation of heterozygous PKD1 mutant pigs exhibiting early-onset renal cyst formation.","date":"2022","source":"Laboratory 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Additionally, the PKD2 C-terminal tail forms homodimers through a coiled-coil domain distinct from the PKD1-interaction region.\",\n      \"method\": \"Co-immunoprecipitation and yeast two-hybrid using C-terminal cytoplasmic tail constructs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction mapped to specific domains, replicated across multiple labs in subsequent work\",\n      \"pmids\": [\"9192675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemistry (co-IP, gel filtration), X-ray crystallography of the coiled-coil domain, and single-molecule fluorescence in live cell plasma membrane\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus single-molecule stoichiometry plus mutagenesis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19556541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy at 3.6 Å resolution\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution cryo-EM structure with functional domain assignment\",\n      \"pmids\": [\"30093605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, immunohistochemistry, electron microscopy using antisera against synthetic peptide and recombinant protein domains\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation and EM localization, single lab, multiple antibodies\",\n      \"pmids\": [\"8981910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, sucrose density gradient fractionation, immunofluorescence co-localization\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus density gradient, single lab, two orthogonal methods\",\n      \"pmids\": [\"10562308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro phosphorylation assay with purified kinases and site-directed mutagenesis of PKD1-CTD fusion protein\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified kinases plus mutagenesis, single lab but multiple substrate mutations tested\",\n      \"pmids\": [\"10362514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Stable transfection of PKD1 cDNA in MDCK cells; proliferation assay, apoptosis assay, 3D tubulogenesis assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with defined functional readouts (proliferation, apoptosis, tubulogenesis), single lab\",\n      \"pmids\": [\"11106764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"Homologous recombination knock-in of truncating Pkd1 mutation in mice; histopathology and timed developmental analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — definitive loss-of-function mouse model with precise developmental staging, replicated by multiple groups\",\n      \"pmids\": [\"9326937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Targeted disruption with lacZ reporter to define expression; histopathology of embryos\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with defined developmental phenotype, single lab\",\n      \"pmids\": [\"11593033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Hypomorphic knock-in mouse model with intronic neomycin cassette causing aberrant splicing; restoration by cassette removal rescues phenotype\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dose-response with reversion control (cassette removal restores wild-type phenotype), multiple organ systems assessed\",\n      \"pmids\": [\"15496422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Pkd1 knockout mouse; immunostaining for pathway components; in vivo MEK inhibitor treatment with BrdU proliferation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pathway activation with pharmacological rescue attempt, single lab; notable as a negative functional result for ERK causality\",\n      \"pmids\": [\"18263604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"BAC transgenic mouse with kidney-targeted Pkd1 overexpression; histopathology; c-Myc expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function mouse model with defined molecular downstream (c-Myc), single lab\",\n      \"pmids\": [\"16449663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay, mouse genetic epistasis (c-Myc knockout in Pkd1-reduced and -increased models), transactivation assay with human c-MYC\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic epistasis, single lab, two orthogonal methods\",\n      \"pmids\": [\"30388220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mouse; in vivo ulna loading; ex vivo fluid shear stress with Ca2+ imaging of isolated osteoblasts\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with in vivo and ex vivo functional readouts, single lab\",\n      \"pmids\": [\"21454365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Double-knockout mouse model (Pkd1 and Gna12); cell adhesion assays; genetic epistasis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo, single lab, clean phenotypic rescue\",\n      \"pmids\": [\"27505895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice (Nestin-Cre); immunofluorescence localization in cilia; genetic epistasis with Pkd1/Vangl2 double heterozygotes\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with localization and genetic epistasis, single lab\",\n      \"pmids\": [\"26245976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Zebrafish ENU mutant screen; conditional Pkd1 mouse knockout; live imaging; immunofluorescence of lymphatic markers and junctional proteins\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent organism models (zebrafish + mouse) with cellular phenotype characterization\",\n      \"pmids\": [\"24767999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Noncystic Pkd1+/- mouse model; urine/plasma osmolality; isolated collecting duct Ca2+ imaging; AQP2 immunofluorescence; RhoA and ERK1/2 activity assays\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — haploinsufficiency model with multiple molecular endpoints, single lab\",\n      \"pmids\": [\"17475819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic Pkd1 deletion in mIMCD3 cells and conditional knockout mouse; lysosomal pH assay; cathepsin activity assay; autophagy flux assay; calpain inhibitor rescue experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent Pkd1-deficient cell models with pharmacological rescue, single lab\",\n      \"pmids\": [\"32967521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal models (cellular, ex vivo, in vivo, patient-derived) with genetic deletion of specific regulatory element and functional rescue\",\n      \"pmids\": [\"35965273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Structural analysis and functional assays of the GAIN domain (review synthesizing crystal structure and functional studies)\",\n      \"journal\": \"Trends in pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review synthesizing published structural data; no new direct experiment on PKD1 described in this abstract\",\n      \"pmids\": [\"23850273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding and phosphorylation assay; stable transfection in ADPKD epithelial cells; ureteric bud microinjection in embryonic kidney organ culture\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro phosphorylation mapped to specific site plus functional rescue in two complementary cell/organ models, single lab\",\n      \"pmids\": [\"17980165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot, qRT-PCR, immunostaining, ChIP assay in cystic renal cells and tissues; 3D culture cyst formation assay with p68 silencing\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus multiple molecular readouts, single lab, two orthogonal mechanisms demonstrated\",\n      \"pmids\": [\"32724471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Tetraploid aggregation placental rescue; Cre-mediated conditional deletion in endothelium (Tie2-Cre); histopathology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two rescue strategies plus tissue-specific deletion, single lab\",\n      \"pmids\": [\"20862291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse genetic cross of Pkd1+/- and Pkd2+/- animals; histopathology; immunostaining for polycystin-2 in cysts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo with immunohistochemical validation, single lab\",\n      \"pmids\": [\"12140187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR, Western blotting with N-terminal antibody, Nanopore long-read sequencing of PKD1 transcripts\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal methods (RT-PCR, Western blot, long-read sequencing) confirming splice event, single lab\",\n      \"pmids\": [\"30185468\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Polycystin-1 (PKD1) is a large plasma membrane glycoprotein that assembles with three PKD2/TRPP2 subunits into a noncanonical TRP-channel-like complex (1:3 stoichiometry, resolved by cryo-EM at 3.6 Å) via interacting C-terminal coiled-coil domains; the PKD1 VGIC fold contains a broken S6 helix with positively charged residues that likely gate cation permeation. Polycystin-1 localizes to primary cilia, plasma membranes, and cell-cell junctions where it interacts with the E-cadherin/catenin complex, and its C-terminal tail is phosphorylated by PKA (at Ser4252) and c-Src (at Tyr4237); its dosage is post-transcriptionally regulated by miR-17 via the 3'-UTR and transcriptionally controlled by a c-Myc feed-forward loop. Loss of PKD1 function triggers Gα12-dependent disruption of focal adhesion and E-cadherin adhesion, elevated calpain activity impairing lysosomal integrity and autophagic flux, decreased intracellular Ca2+ and RhoA activity in collecting duct cells, and deregulated proliferation/apoptosis leading to tubular cyst formation; PKD1 is also required for skeletal mechanosensing, lymphatic vessel morphogenesis, brain ependymal planar cell polarity, and placental development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#3, #7, #9]. 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 [#0, #1]. 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 [#2]. 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 [#4]. 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 [#5, #21]. Polycystin-1 supports cell survival and tubulogenic differentiation rather than simple cyst formation [#6], and acts as a mechanosensor required for the osteoblast Ca2+ response to fluid shear and skeletal loading [#13]. Loss or reduction of PKD1 below a critical dosage threshold drives polycystic kidney disease and extends to pancreatic, hepatic, cardiovascular, and skeletal defects [#7, #9]; downstream, PKD1 loss activates Galpha12 to disrupt cell-matrix and E-cadherin adhesion (genetic ablation of Galpha12 prevents cystogenesis) [#14], elevates calpain activity that impairs lysosomal acidification and autophagic flux [#18], and lowers collecting-duct intracellular Ca2+ and RhoA activity with altered AQP2 trafficking [#17]. PKD1 dosage is set by a reciprocal c-Myc feed-forward transcriptional loop [#11, #12], by p68/p53-mediated promoter repression [#22], and post-transcriptionally by a 3'-UTR miR-17 element whose deletion raises polycystin-1 and alleviates cysts [#19]. Beyond the kidney, PKD1 is required for lymphatic vessel morphogenesis, brain ependymal planar cell polarity, and placental development [#16, #15, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation and yeast two-hybrid with C-terminal tail constructs\",\n      \"pmids\": [\"9192675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural arrangement not yet defined\", \"Functional consequence of complex at the membrane unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Subcellular fractionation, immunohistochemistry, and EM with domain-specific antisera\",\n      \"pmids\": [\"8981910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish channel or adhesion function\", \"Ciliary localization not addressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal co-IP and sucrose gradients for adhesion; in vitro phosphorylation by PKA and c-Src with site mutagenesis\",\n      \"pmids\": [\"10562308\", \"10362514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo significance of Ser4252/Tyr4237 phosphorylation not tested\", \"Adhesion complex association not linked to channel function\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated through homozygous truncation that polycystin-1 is essential for tubular morphogenesis, with cysts arising during tubular elongation in mid-gestation.\",\n      \"evidence\": \"Pkd1 truncation knock-in mouse with timed developmental histopathology\",\n      \"pmids\": [\"9326937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of cystogenesis not defined\", \"Perinatal lethality limited analysis of late-stage roles\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed polycystin-1 promotes survival and tubulogenic differentiation rather than passive structural support, reframing it as a regulator of cell fate decisions.\",\n      \"evidence\": \"Stable PKD1 expression in MDCK cells with proliferation, apoptosis, and 3D tubulogenesis assays\",\n      \"pmids\": [\"11106764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system may not reflect physiological signaling\", \"Downstream effectors not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Hypomorphic Pkd1 knock-in mouse with cassette-removal reversion control\",\n      \"pmids\": [\"15496422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define which downstream pathway senses dosage\", \"Cell-autonomous vs systemic contribution not separated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected PKD1 to additional kinase regulation and demonstrated functional rescue, showing PRKX phosphorylation of Ser4166 restores adhesion, migration, and branching in PKD1-deficient cells.\",\n      \"evidence\": \"In vitro binding/phosphorylation plus rescue in ADPKD cells and embryonic kidney organ culture\",\n      \"pmids\": [\"17980165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo requirement for Ser4166 phosphorylation untested\", \"Mechanism linking phosphorylation to adhesion unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked polycystin-1 haploinsufficiency to dysregulated Ca2+ signaling and water handling, implicating it in collecting-duct RhoA activity and AQP2 trafficking even without cysts.\",\n      \"evidence\": \"Noncystic Pkd1+/- mouse with collecting-duct Ca2+ imaging, RhoA assays, and AQP2 immunofluorescence\",\n      \"pmids\": [\"17475819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from PKD1 to Ca2+ change not mechanistically resolved\", \"Single lab, single allele\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, gel filtration, coiled-coil crystallography, and live-cell single-molecule fluorescence\",\n      \"pmids\": [\"19556541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length complex architecture not yet visualized\", \"Channel gating mechanism unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM at 3.6 Å of truncated human PKD1-PKD2 complex\",\n      \"pmids\": [\"30093605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Truncated construct omits extracellular regions and the GAIN domain\", \"Conducting state and physiological permeant not captured\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional Pkd1 knockout with in vivo MEK inhibition and BrdU proliferation readout\",\n      \"pmids\": [\"18263604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result specific to this model and inhibitor dose\", \"Did not identify the true causal pathway\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pkd1/Gna12 double-knockout mouse with adhesion assays and genetic epistasis\",\n      \"pmids\": [\"27505895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling PKD1 loss to Galpha12 activation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a lysosomal/autophagy axis whereby PKD1 loss elevates calpain activity to impair lysosomal acidification and autophagic flux, rescuable by calpain inhibition.\",\n      \"evidence\": \"Pkd1-deleted mIMCD3 cells and conditional knockout mouse with lysosomal pH, cathepsin, autophagy flux, and calpain inhibitor rescue\",\n      \"pmids\": [\"32967521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link from PKD1 to calcium influx driving calpain inferred, not proven\", \"Contribution to cyst growth in vivo not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined polycystin-1 as an essential skeletal mechanosensor required for osteoblast Ca2+ responses to fluid shear and the anabolic response to loading.\",\n      \"evidence\": \"Osteoblast/osteocyte conditional knockout with in vivo ulna loading and ex vivo shear-stress Ca2+ imaging\",\n      \"pmids\": [\"21454365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mechanosensing requires the PKD2 channel partner not addressed\", \"Molecular transduction step undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended PKD1 function to lymphatic vessel morphogenesis, showing it is dispensable for sprouting but required for migration, polarity, and adherens junctions of lymphatic endothelium.\",\n      \"evidence\": \"Zebrafish ENU mutant and conditional mouse knockout with live imaging and junctional marker immunofluorescence\",\n      \"pmids\": [\"24767999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector pathway in lymphatic cells not identified\", \"Relationship to renal adhesion roles unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Nestin-Cre conditional knockout with ciliary immunofluorescence and Pkd1/Vangl2 genetic epistasis\",\n      \"pmids\": [\"26245976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical link between PKD1 and Vangl2 not established\", \"Channel role in PCP not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated a requirement for PKD1 in placental development, with endothelial-specific deletion recapitulating a subset of vascular defects.\",\n      \"evidence\": \"Tetraploid aggregation rescue, Meox2-Cre and Tie2-Cre conditional deletions with histopathology\",\n      \"pmids\": [\"20862291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-autonomous placental mechanism incompletely resolved\", \"Molecular effectors not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"BAC transgenic kidney-targeted Pkd1 overexpression with histopathology and c-Myc analysis\",\n      \"pmids\": [\"16449663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether c-Myc is required for cysts\", \"Mechanism of dosage sensitivity unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP, genetic epistasis in Pkd1-dosage-altered mice, and human c-MYC transactivation assay\",\n      \"pmids\": [\"30388220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cofactor requirements at the promoter only partly defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified p68 RNA helicase as a dual repressor of Pkd1, acting transcriptionally with p53 and post-transcriptionally by promoting repressive miRNA maturation.\",\n      \"evidence\": \"ChIP, qRT-PCR, immunostaining in cystic cells and 3D cyst assay with p68 silencing\",\n      \"pmids\": [\"32724471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of the two mechanisms unquantified\", \"In vivo requirement not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"mRNA stability assays, miR-17 motif deletion mouse models, organoids, in vivo PKD models, and patient-derived cultures\",\n      \"pmids\": [\"35965273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulators of miR-17 in patient tissue not fully mapped\", \"Delivery strategy for therapeutic derepression unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"RT-PCR, N-terminal Western blot, and Nanopore long-read sequencing of human PKD1 transcripts\",\n      \"pmids\": [\"30185468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulation of this splicing event unknown\", \"Functional impact of Trunc_PC1 protein product undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Provided genetic evidence for a polycystin dosage/threshold interaction by showing trans-heterozygous Pkd1+/-;Pkd2+/- mice exceed additive disease severity.\",\n      \"evidence\": \"Pkd1/Pkd2 mouse genetic cross with histopathology and polycystin-2 immunostaining\",\n      \"pmids\": [\"12140187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the synergy not defined\", \"Two-hit and threshold contributions not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No single study in the corpus links channel conductance to the downstream effector pathways\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 0, 1]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 1]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\"polycystin-1/polycystin-2 (PKD1-TRPP2) channel complex\", \"E-cadherin/catenin adhesion complex\"],\n    \"partners\": [\"PKD2\", \"CDH1\", \"CTNNB1\", \"PRKACA\", \"SRC\", \"PRKX\", \"GNA12\", \"MYC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}