Affinage

PDZK1

Na(+)/H(+) exchange regulatory cofactor NHE-RF3 · UniProt Q5T2W1

Length
519 aa
Mass
57.1 kDa
Annotated
2026-04-29
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDZK1 is a four-PDZ-domain scaffold protein that organizes multiprotein complexes at epithelial apical membranes and in endothelium, controlling the surface expression, membrane retention, and activity of diverse membrane transporters and signaling effectors. It directly binds the C-terminal PDZ-interaction motifs of transporters including NHE3, CFEX, Oatp1a1, OATP1A2, PEPT1, PEPT2, OCTN2, BCRP, NaPi-2c, and SMCT1/2 to promote their apical or basolateral localization and transport function, and loss of PDZK1 causes mislocalization and reduced activity of specific client proteins in kidney, intestine, and liver (PMID:16141316, PMID:15994332, PMID:18322073, PMID:21816982, PMID:21388960). Beyond transporter scaffolding, PDZK1 assembles signaling complexes—including a PLC-β3/somatostatin receptor ternary complex for Ca²⁺ mobilization and ERK activation, an SR-BI/Src complex for eNOS activation in endothelium, and a PTEN complex that suppresses PI3K/AKT signaling—and its scaffolding function is regulated by PKA-dependent phosphorylation at Ser-509 and by a head-to-tail intramolecular autoinhibitory association between its C-terminal tail and first PDZ domain (PMID:22528496, PMID:18174467, PMID:30930234, PMID:16174736, PMID:19173579). PDZK1 knockout mice exhibit increased serum cholesterol, impaired electroneutral Na⁺ absorption, defective endothelial repair after vascular injury, and—in bone marrow–derived macrophages—increased necroptosis and atherosclerotic necrotic core formation dependent on SR-BI/PI3K/Akt signaling (PMID:12556478, PMID:17347851, PMID:18174467, PMID:36353992).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    Identification of PDZK1 as a novel four-PDZ-domain protein in kidney proximal tubule brush border established the gene as a candidate epithelial scaffold.

    Evidence Yeast two-hybrid screen with MAP17 bait in human kidney cDNA library, with in situ hybridization confirming brush-border co-localization

    PMID:9461128

    Open questions at the time
    • No functional data on transport or signaling
    • Interaction partners beyond MAP17 unknown
    • Expression outside kidney not characterized
  2. 2003 High

    Generation of PDZK1 knockout mice revealed a mild phenotype (increased serum cholesterol, selective ion channel changes) and showed that many expected client proteins were not redistributed, indicating functional redundancy among PDZ scaffold proteins.

    Evidence Homologous recombination knockout mouse with serum chemistry, Western blot, and immunolocalization of candidate interactors

    PMID:12556478

    Open questions at the time
    • Source of hypercholesterolemia not mechanistically resolved
    • Identity of compensating PDZ proteins unclear
    • Tissue-specific contributions not dissected
  3. 2003 Medium

    Establishing that MAP17 anchors PDZK1 to the apical membrane (not vice versa) through PDZ domain 4 resolved the hierarchical assembly of the scaffold at the brush border.

    Evidence Yeast two-hybrid, in vitro binding, and immunofluorescence in opossum kidney cells showing PDZK1 apical localization depends on MAP17

    PMID:12837682

    Open questions at the time
    • Whether MAP17-independent anchoring exists in other tissues not tested
    • Structural basis of PDZ4-MAP17 interaction unresolved
  4. 2005 High

    Demonstration that PDZK1 is required in vivo for CFEX brush-border expression and Cl⁻-oxalate exchange, while NHE3 localization was unaffected, established client-selective scaffolding as PDZK1's primary mechanism for controlling transporter function in kidney.

    Evidence GST pull-down, immunocytochemistry, and brush-border membrane vesicle transport assays in PDZK1-null mice

    PMID:16141316

    Open questions at the time
    • Mechanism of selective client dependence (CFEX yes, NHE3 no) unknown
    • Whether PDZK1 stabilizes CFEX protein or only retains it at the surface not distinguished
  5. 2005 High

    Discovery that PKA phosphorylation of PDZK1 at Ser-509 is required for its ability to upregulate SR-BI protein levels provided the first post-translational regulatory mechanism for PDZK1 scaffold activity.

    Evidence In vitro PKA kinase assay, S509A mutagenesis abolishing SR-BI upregulation, glucagon administration in rats validating physiological PKA activation

    PMID:16174736

    Open questions at the time
    • Whether Ser-509 phosphorylation affects PDZK1 interactions with clients other than SR-BI not tested
    • Structural consequence of phosphorylation on PDZK1 conformation unknown
  6. 2005 High

    Showing that PDZK1 is required for basolateral membrane localization of Oatp1a1 in hepatocytes extended the scaffold's role beyond apical membranes and into liver organic anion transport.

    Evidence C-terminal peptide affinity isolation, reciprocal Co-IP from rat liver, immunofluorescence and radiolabeled substrate clearance in PDZK1-KO mice

    PMID:15994332

    Open questions at the time
    • Whether PDZK1 similarly controls other hepatic Oatps not determined
    • Mechanism of PDZK1-dependent basolateral targeting versus apical targeting not distinguished
  7. 2007 High

    Functional studies in PDZK1-null colon and small intestine demonstrated that PDZK1 is essential for cAMP- and Ca²⁺-dependent regulation of NHE3 and for electroneutral Na⁺ absorption, establishing its role as a signaling scaffold that couples second messengers to transporter regulation.

    Evidence Fluorometric NHE3 transport assay in BCECF-loaded colonic crypts and ²²Na⁺ flux measurements in PDZK1⁻/⁻ small intestine

    PMID:17347851 PMID:17395628

    Open questions at the time
    • Identity of the Ca²⁺-sensing component in the PDZK1–NHE3 complex unknown
    • Whether PDZK1 recruits specific kinases or phosphatases to NHE3 not resolved
  8. 2008 High

    Discovery that PDZK1 is expressed in endothelium and required for HDL/SR-BI-induced Src activation, eNOS signaling, and vascular repair extended PDZK1's function from epithelial transport to cardiovascular signaling.

    Evidence Co-IP of Src–SR-BI, siRNA knockdown, eNOS activity assay, and carotid artery re-endothelialization in PDZK1⁻/⁻ mice with liver-specific reconstitution controls

    PMID:18174467

    Open questions at the time
    • How PDZK1 couples SR-BI to Src mechanistically not resolved
    • Whether PDZK1 interacts directly with eNOS in endothelium not tested
  9. 2008 High

    Extending the client repertoire to intestinal PEPT1 and OCTN2 with in vivo pharmacokinetic consequences showed that PDZK1 is a general determinant of drug and nutrient transporter bioavailability in the gut.

    Evidence Co-IP of PEPT1–PDZK1 from mouse small intestine, brush-border fractionation, and pharmacokinetic absorption studies in PDZK1⁻/⁻ mice

    PMID:18322073

    Open questions at the time
    • Whether PDZK1 loss alters transporter glycosylation or folding not examined
    • Contribution of other NHERF family members to compensation in gut not quantified
  10. 2009 Medium

    Identification of a head-to-tail intramolecular association (C-terminal tail binding PDZ1) revealed an autoinhibitory conformational switch that regulates PDZK1's intermolecular interactions, particularly with NHERF1.

    Evidence In vitro binding assays, size exclusion chromatography, and limited proteolysis showing compact conformation

    PMID:19173579

    Open questions at the time
    • Physiological signals that relieve autoinhibition not identified
    • Whether autoinhibition affects client transporter binding in cells not tested
    • Structural details of the compact conformation lacking
  11. 2012 High

    Assembly of a PDZK1–PLC-β3–SSTR ternary signaling complex that specifically transduces somatostatin into Ca²⁺ mobilization and ERK1/2 activation demonstrated that PDZK1 functions as a receptor-to-effector coupling scaffold, not merely a membrane retention factor.

    Evidence Co-IP of ternary complex, siRNA knockdown of PDZK1 or PLC-β3, Ca²⁺ mobilization and ERK phosphorylation assays

    PMID:22528496

    Open questions at the time
    • Whether PDZK1 scaffolds other GPCR–effector pairs unknown
    • Stoichiometry of the ternary complex not determined
  12. 2014 High

    Mechanistic dissection showing PDZK1 increases OATP1A2 surface expression by decreasing clathrin-dependent internalization and enhancing protein stability provided the first internalization-pathway-specific explanation for PDZK1's surface retention function.

    Evidence Surface biotinylation internalization assay with clathrin/caveolin inhibitors, cycloheximide chase, and functional transport assay in HEK293 cells

    PMID:24728453

    Open questions at the time
    • Whether clathrin-dependent internalization suppression applies to other PDZK1 clients not tested
    • Structural basis of how PDZK1 shields the internalization signal unknown
  13. 2019 High

    Demonstration that PDZK1 binds PTEN and inhibits its inhibitory phosphorylation, thereby enhancing PTEN-mediated suppression of PI3K/AKT, established PDZK1 as a modulator of tumor suppressor activity.

    Evidence Co-IP, GST pull-down, S380/T382/T383 phospho-specific immunoblotting, PDZK1 knockdown/overexpression, and xenograft proliferation assays in gastric cancer cells

    PMID:30930234

    Open questions at the time
    • Whether PDZK1-PTEN interaction occurs in normal epithelium or is cancer-specific not resolved
    • Identity of kinase whose access to PTEN is blocked by PDZK1 unknown
  14. 2022 High

    Bone marrow transplantation experiments established that PDZK1 in macrophages—not hepatocytes—mediates HDL/SR-BI protection against necroptosis and atherosclerotic necrotic core formation via PI3K/Akt, revealing a cell-autonomous anti-atherogenic function.

    Evidence Bone marrow reconstitution in PDZK1⁻/⁻ LDLR⁻/⁻ mice, macrophage necroptosis assays, PI3K inhibitor, RIPK3/MLKL immunohistochemistry

    PMID:36353992

    Open questions at the time
    • Whether PDZK1 directly scaffolds PI3K or Akt in macrophages not shown
    • Molecular partners downstream of SR-BI in macrophage PDZK1 complex not identified
  15. 2024 Medium

    PDZK1 deficiency in chondrocytes was linked to mitochondrial dysfunction and senescence through increased ubiquitination and degradation of Hmgcs2, revealing a non-scaffolding role in protein stability and mitochondrial homeostasis.

    Evidence Chondrocyte-specific PDZK1 knockout, AAV rescue, mRNA sequencing, ubiquitination assay, mitochondrial function assays in mechanical overload OA model

    PMID:39019845

    Open questions at the time
    • Whether PDZK1 directly binds Hmgcs2 or acts indirectly not determined
    • Mechanism by which PDZK1 suppresses Hmgcs2 ubiquitination unknown
    • Relevance to PDZK1's canonical PDZ-scaffolding function unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the structural basis of PDZK1 autoinhibition and its relief by physiological signals, whether the clathrin-internalization-blocking mechanism generalizes across all transporter clients, how PDZK1 couples to PI3K/Akt in macrophages, and the full scope of client selectivity rules distinguishing PDZK1-dependent from PDZK1-independent targets.
  • No high-resolution structure of full-length PDZK1 or any client complex
  • Signal that relieves autoinhibition in vivo not identified
  • Systematic client dependency rules across tissues not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 10
Localization
GO:0005886 plasma membrane 7 GO:0005829 cytosol 1
Pathway
GO:0005215 transporter activity 7 R-HSA-382551 Transport of small molecules 7 R-HSA-162582 Signal Transduction 5 R-HSA-1430728 Metabolism 3
Partners
ABCG2NOS2PLCB3PTENSCARB1SLC26A6SLC9A3SLCO1A2
Complex memberships
PDZK1–PLC-β3–SSTR ternary complexPDZK1–SMCT1–URAT1 trimolecular complexPDZK1–SR-BI–Src endothelial complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PDZK1 was identified as a novel 519-amino acid protein containing four PDZ protein interaction domains, discovered by yeast two-hybrid screening of a human kidney cDNA library using MAP17 as bait. PDZK1 colocalized with MAP17 in the brush border of proximal tubular epithelial cells of the kidney. Yeast two-hybrid screening, in situ hybridization, co-localization Laboratory investigation Medium 9461128
2003 PDZK1 knockout mice lack overt phenotype but show modulation of selective ion channel expression in the kidney and increased serum cholesterol levels; PDZK1 loss did not significantly redistribute MAP17, cMOAT, or the type IIa Na/Pi cotransporter, suggesting functional compensation by other PDZ proteins. Homologous recombination knockout mouse, Western blot, serum cholesterol measurement Molecular and cellular biology High 12556478
2003 MAP17 interacts specifically with the fourth PDZ domain of PDZK1 (but not with other PDZ proteins in proximal tubular brush borders), and MAP17 acts as an apical anchoring site for PDZK1, as apical localization of PDZK1 is dependent on MAP17 but not vice versa. Yeast two-hybrid, in vitro binding assays, immunofluorescence, transfection in opossum kidney cells American journal of physiology. Renal physiology Medium 12837682
2003 PDZK1 anchors the dual-specific A-kinase anchoring protein D-AKAP2 to the subapical membrane of renal proximal tubular cells via PDZ domain 4 of PDZK1, thereby compartmentalizing PKA activity near NaPi-IIa to enable PTH-mediated regulation. Yeast two-hybrid, pull-down assays, co-immunoprecipitation from transfected OK cells, immunohistochemistry, real-time PCR Kidney international Medium 14531807
2005 PDZK1 is required for normal brush-border expression and function of the Cl-anion exchanger CFEX (SLC26A6/PAT1) in renal proximal tubule; PDZK1 directly binds NHE3 and CFEX via their C-terminal PDZ-interaction sites. Loss of PDZK1 markedly reduced CFEX protein expression and Cl-oxalate exchange activity, while NHE3 brush-border expression was unaffected. GST pull-down with native brush border membrane proteins, Western blot, immunocytochemistry, brush border membrane vesicle transport assay, microperfused proximal tubule volume absorption, PDZK1-null mice Proceedings of the National Academy of Sciences of the United States of America High 16141316
2005 PDZK1 controls hepatic SR-BI protein levels in a posttranscriptional manner; phosphorylation of PDZK1 at Ser-509 by PKA (stimulated by glucagon) is required for PDZK1 to upregulate SR-BI protein expression. Mutation of Ser-509 to Ala abolishes the ability of PDZK1 to upregulate SR-BI. Metabolic labeling, phosphoamino acid analysis, site-directed mutagenesis, in vitro kinase assay with PKA, cell culture overexpression, phospho-specific antibody, glucagon administration to rats Proceedings of the National Academy of Sciences of the United States of America High 16174736
2005 PDZK1 interacts with organic anion transporter Oatp1a1 via its C-terminal PDZ-interaction site, predominantly at the first and third PDZ domains of PDZK1; PDZK1 is required for basolateral plasma membrane localization of Oatp1a1 in hepatocytes—in PDZK1 knockout liver, Oatp1a1 is retained in intracellular structures, impairing hepatic organic anion transport. C-terminal peptide affinity isolation, protein mass fingerprinting, co-immunoprecipitation from cotransfected 293T cells and native rat liver membranes, immunofluorescence, radiolabeled substrate plasma disappearance in PDZK1-KO mice The Journal of biological chemistry High 15994332
2005 PDZK1 (CAP70) interacts with the intestinal anion exchanger DRA via the DRA C-terminal PDZ interaction motif, binding at the 2nd and 3rd PDZ domains of PDZK1/CAP70, distinct from CFTR which binds PDZ1, PDZ3, and PDZ4. Overlay assay with recombinant DRA C-terminus, anti-CAP70 antibody identification, in vitro binding assays, co-immunoprecipitation in transfected HEK cells Biochemistry Medium 15766278
2005 PDZK1 interacts with SSTR5 (somatostatin receptor subtype 5) at the plasma membrane via the PDZ ligand motif at the C-terminus of SSTR5; PDZK1 is required for post-endocytic recycling of SSTR5 back to the plasma membrane after agonist-induced internalization. Yeast two-hybrid, co-localization studies, receptor recycling assay in transfected cells The Journal of biological chemistry Medium 16012170
2006 PDZK1 interacts with human PEPT2 (SLC15A2) via PDZ motif of the PEPT2 C-terminus, binding at the 2nd and 3rd PDZ domains of PDZK1; PDZK1 co-expression increases V(max) of glycylsarcosine transport by PEPT2 by increasing PEPT2 surface expression. Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation (human kidney membrane fraction), surface plasmon resonance for binding affinities, functional transport assay in HEK293 cells Kidney international High 16738539
2006 MAP17 interacts with all four NHERF family proteins (including PDZK1/NHERF3) and NaPi-IIa; co-expression of MAP17 with NHERF3 or NHERF4 (but not NHERF1/2) causes internalization of NaPi-IIa, MAP17, and the PDZ protein to the trans-Golgi network via a PKC-dependent mechanism. Bacterial and mammalian two-hybrid systems, functional studies in opossum kidney (OK) cells, PKC inhibitor/activator treatment, immunofluorescence American journal of physiology. Renal physiology Medium 16926447
2007 PDZK1 is required for cAMP- and Ca2+-dependent inhibition of NHE3 activity in native colonic enterocytes; PDZK1 ablation abolishes forskolin- and ionomycin-mediated inhibition of NHE3 while hyperosmolarity-mediated inhibition remains intact. PDZK1 loss does not alter NHE3 abundance or brush-border localization in colon. Fluorometric NHE3 transport assay in BCECF-loaded colonic crypts, Western blot, immunohistochemistry, qPCR, PDZK1-null mice The Journal of physiology High 17395628
2007 PDZK1 (CAP70) binds to inducible nitric oxide synthase (NOS2) via the four C-terminal amino acids of NOS2, enhancing NOS2 cytochrome c reductase and NO-synthase activities, increasing the population of active NOS2 dimers, and participating in apical targeting of NOS2 in polarized epithelial cells (in combination with N-terminal palmitoylation). Co-immunoprecipitation, enzyme activity assays, subcellular localization by immunofluorescence in polarized cells Molecular biology of the cell Medium 17507652
2007 PDZK1 ablation in mouse small intestine causes severe defect in electroneutral Na+ absorption and mild reduction of CFTR-mediated anion secretion; NHE3 brush-border expression is unaffected, but NHE3 mRNA is increased, suggesting increased NHE3 turnover due to reduced membrane retention without PDZK1. Short circuit current measurements, 22Na+ flux assays, qPCR, Western blot, immunohistochemistry in pdzk1-/- mice Pflugers Archiv : European journal of physiology High 17347851
2008 PDZK1 is expressed in endothelium and required for HDL/SR-BI-induced Src phosphorylation, endothelial NO synthase (eNOS) activation, and cell migration; PDZK1 is not required for SR-BI abundance, plasma membrane localization, HDL binding, or cholesterol efflux in endothelium. PDZK1-/- mice fail to re-endothelialize after carotid artery injury. Co-immunoprecipitation (Src-SR-BI interaction), siRNA knockdown, eNOS activity assay, cell migration assay, carotid artery re-endothelialization in PDZK1-/- mice (including liver-specific reconstitution controls), cell surface biotinylation Circulation research High 18174467
2008 PDZK1 regulates intestinal oligopeptide transporter PEPT1 (Slc15a1) and carnitine transporter OCTN2 (Slc22a5): PDZK1 physically interacts with PEPT1, and loss of PDZK1 reduces apical membrane localization and protein levels of both transporters, delaying GI absorption of their substrates. Co-immunoprecipitation (PEPT1-PDZK1 from mouse small intestine), immunohistochemistry, Western blot of brush-border membranes, electron microscopy, pharmacokinetic studies in pdzk1-/- mice, functional transport assay in HEK293 cells Drug metabolism and disposition High 18322073
2009 PDZK1 undergoes head-to-tail intramolecular association: the C-terminal tail of PDZK1 interacts with its first PDZ domain, inducing a compact conformation. PDZK1 also forms modest homodimers via its third PDZ domain. The tail-PDZ1 intramolecular interaction does not affect binding of PDZ domain ligands of PDZK1 itself, but negatively regulates the interaction of PDZK1's tail with the PDZ domains of EBP50/NHERF1. In vitro binding assays, co-immunoprecipitation, size exclusion chromatography, limited proteolysis Biochemistry Medium 19173579
2009 PDZK1 (NHERF3) directly binds the NHE3 C-terminus (between amino acids 588-667), co-immunoprecipitates with NHE3 in vivo, co-localizes at the plasma membrane under basal conditions, and reconstitutes Ca2+-dependent inhibition of NHE3 activity by dissociating from NHE3 upon elevated intracellular Ca2+. NHERF3 knockdown reduces basal NHE3 activity and brush border expression in Caco-2BBe cells. In vitro binding assay, co-immunoprecipitation, confocal microscopy, FRET, fluorometric NHE3 transport assay, shRNA knockdown The Journal of biological chemistry High 19535329
2009 Pdzk1 ablation reduces basal HCO3- secretion in mouse duodenum but not FSK-stimulated secretion, distinguishing PDZK1's role from NHERF1 (obligatory for beta2-AR stimulation) and NHERF2 (mediates LPA inhibition of CFTR). PDZK1 reduction of basal CFTR-mediated secretion indicates a role in tonic CFTR regulation. Duodenal HCO3- secretion measurements, laser microdissection, qPCR, Nherf/Pdzk1 knockout mouse models The Journal of clinical investigation High 19221439
2010 PDZK1 binding (via C-terminal PDZ motif) promotes cell surface expression of Oatp1a1, and serine phosphorylation at S634/S635 (upstream of the PDZ motif) negatively regulates surface retention: phosphomimetic oatp1a1 remains intracellular even with PDZK1 co-expression. Extracellular ATP-induced phosphorylation of Oatp1a1 triggers rapid internalization in hepatocytes. Site-directed mutagenesis, transfection in HEK293T and HuH7 cells, surface biotinylation internalization assay, co-immunoprecipitation, confocal imaging, primary rat hepatocyte experiments American journal of physiology. Gastrointestinal and liver physiology High 21183661
2010 PDZK1 knockdown in hepatoma cells significantly reduces susceptibility to HCV infection; this effect requires more than just the first PDZ domain of PDZK1. PDZK1 facilitates HCV entry indirectly via its interaction with SR-BI, which serves as an HCV entry factor, and this interaction requires the C-terminal PDZ-interacting residue of SR-BI. Stable shRNA knockdown, PDZK1 overexpression rescue, GFP-SR-BI C-terminus chimera competition, HCV infection assay in Huh-7 cells PLoS pathogens Medium 20949066
2011 PDZK1 is required for apical membrane expression of NaPi-2c (but not NaPi-2a) in renal proximal tubule; FRET measurements show both NaPi-2a and NaPi-2c interact with PDZK1, but NaPi-2a shows stronger FRET with NHERF-1. In low-Pi adaptation, NaPi-2c/PDZK1 and NaPi-2a/NHERF-1 interactions increase, explaining differential regulation. Pdzk1-/- mice on low Pi diets, Western blot, immunofluorescence, FRET in transfected cells The Journal of biological chemistry High 21388960
2011 PDZK1 physically interacts with BCRP (breast cancer resistance protein) and is required for apical membrane localization of BCRP in mouse small intestine; PDZK1 co-expression in MDCKII/BCRP cells increases basal-to-apical transcellular transport and drug resistance to SN-38. Pull-down assay, co-immunoprecipitation, immunohistochemistry, Western blot of brush-border membranes, transcellular transport assay, cytotoxicity assay in MDCKII cells, pdzk1-/- mice pharmacokinetics Drug metabolism and disposition High 21816982
2012 PDZK1 specifically interacts with PLC-β3 (not PLC-β1) and assembles a ternary complex with PLC-β3 and somatostatin receptors (SSTRs), enabling specific activation of PLC-β3 by somatostatin. Disruption of this ternary complex inhibits SST-induced PLC activation, intracellular Ca2+ mobilization, and ERK1/2 phosphorylation. PDZ protein screen, co-immunoprecipitation, siRNA knockdown of PDZK1 or PLC-β3, Ca2+ mobilization assay, ERK1/2 phosphorylation assay The Journal of biological chemistry High 22528496
2013 PDZK1 expression in breast cancer cells promotes estrogen-mediated cell proliferation through enhancement of c-Myc expression; PDZK1 interacts with the Src/ER-α/EGFR complex and enhances EGFR-stimulated MEK/ERK1/2 signaling. PDZK1 expression is indirectly regulated by ER-α stimulation, requiring IGF-1R function. siRNA knockdown, ectopic overexpression, co-immunoprecipitation, proliferation assay, immunoblotting for signaling intermediates, tissue microarrays Molecular medicine Medium 23821363
2014 PDZK1 directly interacts with OATP1A2 via its C-terminal PDZ-binding domain and increases OATP1A2 surface expression by decreasing clathrin-dependent (but not caveolin-dependent) internalization, and by enhancing OATP1A2 protein stability, resulting in increased V(max) of estrone-3-sulfate transport. Co-immunoprecipitation, surface biotinylation, internalization assay with clathrin/caveolin inhibitors, cycloheximide chase for stability, transport functional assay in HEK293 cells PloS one High 24728453
2017 PDZK1 inhibits SHP-1 phosphorylation at Tyr536 by blocking the association between SHP-1 and PLCβ3, thereby promoting STAT5 phosphorylation and retarding Akt phosphorylation in renal cell carcinoma cells. PDZK1 overexpression and knockdown models, co-immunoprecipitation, immunoblotting for phosphoproteins, xenograft tumor studies Oncogene Medium 28692056
2018 HNF4A directly binds the rs1967017 region of the PDZK1 promoter/enhancer and transcriptionally regulates PDZK1 expression; siRNA depletion of HNF4A reduces endogenous PDZK1 in HepG2 cells. The urate-increasing T allele of rs1967017 strengthens the HNF4A binding site, enhancing PDZK1 expression. siRNA knockdown, luciferase reporter assay, ChIP (HNF4A binding), zebrafish transgenic reporter, eQTL analysis Human molecular genetics Medium 30124855
2019 PDZK1 directly binds PTEN through its PDZ domains interacting with the PTEN C-terminus, and this interaction inhibits phosphorylation of PTEN at the S380/T382/T383 cluster, thereby enhancing PTEN's capacity to suppress PI3K/AKT signaling and gastric cancer cell proliferation. Co-immunoprecipitation, GST pull-down, site-directed mutagenesis, PDZK1 knockdown and overexpression, phospho-specific immunoblotting, in vitro and in vivo (xenograft) proliferation assays Cancer letters High 30930234
2019 PDZK1 interacts with sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) via their C-terminal PDZ motifs; PDZK1 co-expression enhances nicotinate transport activity in SMCT1-expressing HEK293 cells. PDZK1, SMCT1, and URAT1 assemble into a trimolecular complex in vitro and co-localize in renal proximal tubule in vivo. Yeast two-hybrid, co-immunoprecipitation, functional transport assay in HEK293 cells, immunohistochemistry The journal of physiological sciences Medium 30604288
2022 HDL-mediated protection against macrophage necroptosis requires SR-B1 and PDZK1 in a PI3K/Akt pathway-dependent manner; PDZK1 knockout in bone marrow-derived cells (not liver) increases atherosclerosis and necrotic core formation, which is reversed by restoring PDZK1 in BM-derived cells. Bone marrow transplantation reconstitution, PDZK1-/- LDLRKO mice, macrophage necroptosis assay, PI3K inhibitor, immunohistochemistry for RIPK3/MLKL Arteriosclerosis, thrombosis, and vascular biology High 36353992
2024 PDZK1 deficiency in chondrocytes impairs mitochondrial function (decreased mtDNA content, increased ROS, accumulation of damaged mitochondria) during mechanical overload by increasing ubiquitination and thereby reducing expression of Hmgcs2; PDZK1 loss exacerbates mechanical overload-induced chondrocyte senescence and cartilage degeneration. Pdzk1 chondrocyte knockout and AAV-PDZK1 intraarticular injection, mRNA sequencing, ubiquitination assay, mitochondrial function assays (ROS, mtDNA content, mitochondrial morphology), mechanical overload OA model Bone research Medium 39019845

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex. Nature 374 15201901
2009 Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice. The Journal of clinical investigation 303 19221439
2004 The PCNA-RFC families of DNA clamps and clamp loaders. Progress in nucleic acid research and molecular biology 270 15210332
1997 Proliferating cell nuclear antigen: more than a clamp for DNA polymerases. BioEssays : news and reviews in molecular, cellular and developmental biology 211 9394619
2016 Molecular force spectroscopy with a DNA origami-based nanoscopic force clamp. Science (New York, N.Y.) 194 27846560
2001 Interaction of the beta sliding clamp with MutS, ligase, and DNA polymerase I. Proceedings of the National Academy of Sciences of the United States of America 193 11459978
2008 Structure of a sliding clamp on DNA. Cell 187 18191219
2012 Opening and closing of the bacterial RNA polymerase clamp. Science (New York, N.Y.) 183 22859489
2006 The checkpoint clamp activates Mec1 kinase during initiation of the DNA damage checkpoint. Molecular cell 159 17189191
2011 How a DNA polymerase clamp loader opens a sliding clamp. Science (New York, N.Y.) 145 22194570
1998 Clamping down on clamps and clamp loaders--the eukaryotic replication factor C. European journal of biochemistry 135 9660172
1998 Identification and partial characterization of PDZK1: a novel protein containing PDZ interaction domains. Laboratory investigation; a journal of technical methods and pathology 119 9461128
2021 Cohesin mediates DNA loop extrusion by a "swing and clamp" mechanism. Cell 112 34624221
2006 Dendritic patch-clamp recording. Nature protocols 107 17406407
2013 Replication clamps and clamp loaders. Cold Spring Harbor perspectives in biology 105 23545418
2013 The CLAMP protein links the MSL complex to the X chromosome during Drosophila dosage compensation. Genes & development 101 23873939
2020 FANCD2-FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair. Nature structural & molecular biology 98 32066963
2008 The scavenger receptor class B type I adaptor protein PDZK1 maintains endothelial monolayer integrity. Circulation research 98 18174467
2003 Targeted disruption of the PDZK1 gene by homologous recombination. Molecular and cellular biology 92 12556478
2009 Voltage-clamp and current-clamp recordings from mammalian DRG neurons. Nature protocols 91 19617882
2013 PDZK1 is a novel factor in breast cancer that is indirectly regulated by estrogen through IGF-1R and promotes estrogen-mediated growth. Molecular medicine (Cambridge, Mass.) 86 23821363
2003 The topoisomerase IIbeta circular clamp arrests transcription and signals a 26S proteasome pathway. Proceedings of the National Academy of Sciences of the United States of America 84 12629207
2004 Overexpression of PDZK1 within the 1q12-q22 amplicon is likely to be associated with drug-resistance phenotype in multiple myeloma. The American journal of pathology 83 15215163
2011 Rediscovering sperm ion channels with the patch-clamp technique. Molecular human reproduction 81 21642646
2003 The diverse spectrum of sliding clamp interacting proteins. FEBS letters 81 12832034
2006 The Clp1 protein is required for clamp formation and pathogenic development of Ustilago maydis. The Plant cell 79 16920779
2012 Clamp loader ATPases and the evolution of DNA replication machinery. BMC biology 78 22520345
2012 The RFC clamp loader: structure and function. Sub-cellular biochemistry 75 22918590
2009 Role of the adaptor protein PDZK1 in controlling the HDL receptor SR-BI. Current opinion in lipidology 66 19421056
2005 Interactions with PDZ domain proteins PIST/GOPC and PDZK1 regulate intracellular sorting of the somatostatin receptor subtype 5. The Journal of biological chemistry 64 16012170
2001 The ring-type polymerase sliding clamp family. Genome biology 62 11178284
1979 Voltage clamp analysis of embryonic heart cell aggregates. The Journal of general physiology 61 438769
2005 Interaction with PDZK1 is required for expression of organic anion transporting protein 1A1 on the hepatocyte surface. The Journal of biological chemistry 57 15994332
2017 Design and applications of a clamp for Green Fluorescent Protein with picomolar affinity. Scientific reports 56 29176615
2006 Convergent evolution of clamp-like binding sites in diverse chaperones. Nature structural & molecular biology 56 17021621
2019 Loss of PDZK1 expression activates PI3K/AKT signaling via PTEN phosphorylation in gastric cancer. Cancer letters 55 30930234
2007 NHE3 inhibition by cAMP and Ca2+ is abolished in PDZ-domain protein PDZK1-deficient murine enterocytes. The Journal of physiology 54 17395628
2007 The patch clamp technique: principles and technical considerations. Journal of veterinary cardiology : the official journal of the European Society of Veterinary Cardiology 54 17689466
2005 Role of PDZK1 in membrane expression of renal brush border ion exchangers. Proceedings of the National Academy of Sciences of the United States of America 53 16141316
2003 Interactions of MAP17 with the NaPi-IIa/PDZK1 protein complex in renal proximal tubular cells. American journal of physiology. Renal physiology 51 12837682
2020 Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release. Proceedings of the National Academy of Sciences of the United States of America 49 32015138
2015 Force-controlled patch clamp of beating cardiac cells. Nano letters 48 25639960
2006 Interaction of MAP17 with NHERF3/4 induces translocation of the renal Na/Pi IIa transporter to the trans-Golgi. American journal of physiology. Renal physiology 48 16926447
2005 Regulation of SR-BI protein levels by phosphorylation of its associated protein, PDZK1. Proceedings of the National Academy of Sciences of the United States of America 48 16174736
2003 PDZK1: II. an anchoring site for the PKA-binding protein D-AKAP2 in renal proximal tubular cells. Kidney international 48 14531807
2013 A clamp-like biohybrid catalyst for DNA oxidation. Nature chemistry 47 24153373
2004 The clamp-loading complex for processive DNA replication. Nature structural & molecular biology 47 15208692
2007 Down regulation of small intestinal ion transport in PDZK1- (CAP70/NHERF3) deficient mice. Pflugers Archiv : European journal of physiology 46 17347851
2010 The SR-BI partner PDZK1 facilitates hepatitis C virus entry. PLoS pathogens 45 20949066
2008 Distinct domains of complexins bind SNARE complexes and clamp fusion in vitro. The Journal of biological chemistry 44 18499660
2024 PDZK1 protects against mechanical overload-induced chondrocyte senescence and osteoarthritis by targeting mitochondrial function. Bone research 43 39019845
2008 PDZK1 regulates two intestinal solute carriers (Slc15a1 and Slc22a5) in mice. Drug metabolism and disposition: the biological fate of chemicals 43 18322073
2005 The CFTR associated protein CAP70 interacts with the apical Cl-/HCO3- exchanger DRA in rabbit small intestinal mucosa. Biochemistry 43 15766278
2015 The sliding clamp tethers the endonuclease domain of MutL to DNA. Nucleic acids research 42 26384423
2005 Regulation of SR-BI-mediated high-density lipoprotein metabolism by the tissue-specific adaptor protein PDZK1. Current opinion in lipidology 42 15767854
2008 Influence of PDZK1 on lipoprotein metabolism and atherosclerosis. Biochimica et biophysica acta 41 18342019
2011 Role of PDZK1 protein in apical membrane expression of renal sodium-coupled phosphate transporters. The Journal of biological chemistry 40 21388960
2011 PDZK1 regulates breast cancer resistance protein in small intestine. Drug metabolism and disposition: the biological fate of chemicals 39 21816982
2017 Human CTF18-RFC clamp-loader complexed with non-synthesising DNA polymerase ε efficiently loads the PCNA sliding clamp. Nucleic acids research 38 28199690
2016 Cleaning patch-clamp pipettes for immediate reuse. Scientific reports 38 27725751
2022 Studying Synaptic Connectivity and Strength with Optogenetics and Patch-Clamp Electrophysiology. International journal of molecular sciences 36 36232917
2009 The scaffold protein PDZK1 undergoes a head-to-tail intramolecular association that negatively regulates its interaction with EBP50. Biochemistry 36 19173579
2004 Combining optical tweezers and patch clamp for studies of cell membrane electromechanics. The Review of scientific instruments 36 21412445
2001 Replication protein A as a "fidelity clamp" for DNA polymerase alpha. The Journal of biological chemistry 36 11278525
2020 Eukaryotic clamp loaders and unloaders in the maintenance of genome stability. Experimental & molecular medicine 35 33339954
2008 The voltage-clamp fluorometry technique. Methods in molecular biology (Clifton, N.J.) 34 18998096
1977 Membrane currents examined under voltage clamp in cultured neuroblastoma cells. Science (New York, N.Y.) 34 557842
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2006 The PDZ domain protein PDZK1 interacts with human peptide transporter PEPT2 and enhances its transport activity. Kidney international 33 16738539
2017 PDZK1 inhibits the development and progression of renal cell carcinoma by suppression of SHP-1 phosphorylation. Oncogene 32 28692056
2012 Downregulation of the NHE3-binding PDZ-adaptor protein PDZK1 expression during cytokine-induced inflammation in interleukin-10-deficient mice. PloS one 32 22848392
2009 NHERF3 (PDZK1) contributes to basal and calcium inhibition of NHE3 activity in Caco-2BBe cells. The Journal of biological chemistry 32 19535329
2003 DNA relaxation by human topoisomerase I occurs in the closed clamp conformation of the protein. Proceedings of the National Academy of Sciences of the United States of America 32 12711735
2018 A non-coding genetic variant maximally associated with serum urate levels is functionally linked to HNF4A-dependent PDZK1 expression. Human molecular genetics 31 30124855
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2005 Fenofibrate induces a novel degradation pathway for scavenger receptor B-I independent of PDZK1. The Journal of biological chemistry 30 15837786
2022 Structure of the human RAD17-RFC clamp loader and 9-1-1 checkpoint clamp bound to a dsDNA-ssDNA junction. Nucleic acids research 28 35819203
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2014 PDZK1 and NHERF1 regulate the function of human organic anion transporting polypeptide 1A2 (OATP1A2) by modulating its subcellular trafficking and stability. PloS one 28 24728453
2012 PDZ domain-containing 1 (PDZK1) protein regulates phospholipase C-β3 (PLC-β3)-specific activation of somatostatin by forming a ternary complex with PLC-β3 and somatostatin receptors. The Journal of biological chemistry 28 22528496
2010 PDZK1 binding and serine phosphorylation regulate subcellular trafficking of organic anion transport protein 1a1. American journal of physiology. Gastrointestinal and liver physiology 28 21183661
2013 Sperm patch-clamp. Methods in enzymology 27 23522465
2013 Type IA topoisomerase inhibition by clamp closure. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 23612788
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2016 The essential Drosophila CLAMP protein differentially regulates non-coding roX RNAs in male and females. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 25 27995349
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2015 Conformational Changes of the Clamp of the Protein Translocation ATPase SecA. Journal of molecular biology 23 25982945
2019 IL-1β functionally attenuates ABCG2 and PDZK1 expression in HK-2 cells partially through NF-ĸB activation. Cell biology international 22 30632646
2016 Common variant of PDZ domain containing 1 (PDZK1) gene is associated with gout susceptibility: A replication study and meta-analysis in Japanese population. Drug metabolism and pharmacokinetics 22 27720648
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2008 Regulation of the human PDZK1 expression by peroxisome proliferator-activated receptor alpha. FEBS letters 19 18955051
2022 Apolipoprotein A1 Protects Against Necrotic Core Development in Atherosclerotic Plaques: PDZK1-Dependent High-Density Lipoprotein Suppression of Necroptosis in Macrophages. Arteriosclerosis, thrombosis, and vascular biology 18 36353992
2013 Giant liposome preparation for imaging and patch-clamp electrophysiology. Journal of visualized experiments : JoVE 18 23851612
2007 Binding of CAP70 to inducible nitric oxide synthase and implications for the vectorial release of nitric oxide in polarized cells. Molecular biology of the cell 18 17507652