{"gene":"PDZK1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1998,"finding":"PDZK1 was identified as a novel PDZ domain-containing protein (519 amino acids, 63 kDa) that binds MAP17 via yeast two-hybrid screening. It is expressed in kidney, pancreas, liver, gastrointestinal tract, and adrenal cortex, and colocalizes with MAP17 in the brush border of proximal tubular epithelial cells.","method":"Yeast two-hybrid screening, in situ hybridization, immunolocalization","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid and colocalization, foundational identification paper with multiple methods in one lab","pmids":["9461128"],"is_preprint":false},{"year":1999,"finding":"PDZK1 interacts with the carboxy-terminal portion of cMOAT (MRP2), the canalicular multispecific organic anion transporter, as identified by yeast two-hybrid assay.","method":"Yeast two-hybrid system","journal":"Laboratory investigation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (yeast two-hybrid), not confirmed by orthogonal biochemical assay in this paper","pmids":["10496535"],"is_preprint":false},{"year":2003,"finding":"PDZK1 knockout mice show ~95% reduction of SR-BI protein in liver and 50% reduction in proximal intestine, but no reduction in steroidogenic organs, demonstrating tissue-specific, post-transcriptional control of SR-BI abundance by PDZK1. Loss of hepatic SR-BI caused elevated plasma total and HDL cholesterol and increased HDL particle size.","method":"Targeted gene knockout mouse model, Western blot, immunohistochemistry, plasma lipid analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined tissue-specific phenotype, multiple orthogonal methods, replicated across multiple subsequent studies","pmids":["14551195"],"is_preprint":false},{"year":2003,"finding":"PDZK1 forms a network in the brush border of renal proximal tubular cells, interacting via its individual PDZ domains with NaPi-IIa, NaPi-I (SLC17A1), NHE-3, OCTN1, CFEX, URAT1, D-AKAP2, and NHERF-1, as determined by yeast two-hybrid screens, pull-down assays, and blot overlays. All identified membrane proteins colocalize with PDZK1 at the brush border.","method":"Yeast two-hybrid, pull-down assays, blot overlays, immunohistochemistry","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple interactors confirmed by multiple in vitro methods in one lab, colocalization in native tissue","pmids":["14531806"],"is_preprint":false},{"year":2003,"finding":"MAP17 interacts specifically with the fourth PDZ domain of PDZK1 (but not other proximal tubular PDZ proteins), and MAP17 is required for apical localization of PDZK1 in opossum kidney cells, suggesting MAP17 is an apical anchoring site for PDZK1. MAP17 also associates with the NH2 terminus of NaPi-IIa within the PDZK1/NaPi-IIa/MAP17 complex.","method":"Yeast two-hybrid, in vitro binding assays, transfection studies in OK cells, immunofluorescence","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple in vitro and cell-based methods, single lab","pmids":["12837682"],"is_preprint":false},{"year":2003,"finding":"The small PDZK1-associated protein SPAP (MAP17/DD96) interacts with PDZK1 in vivo and its hepatic overexpression depletes PDZK1 in liver (in a proteasome-independent manner), which secondarily depletes SR-BI and raises plasma HDL. SPAP regulates PDZK1 turnover.","method":"In vivo protein interaction (co-IP), transgenic mouse overexpression, metabolic labeling, proteasome inhibition experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo identification with multiple orthogonal methods, single lab","pmids":["12754212"],"is_preprint":false},{"year":2003,"finding":"D-AKAP2 interacts with PDZK1 via PDZ domain 4, and this interaction anchors PKA to PDZK1 at the subapical pole of proximal tubular cells, potentially enabling PKA-mediated regulation of NaPi-IIa.","method":"Yeast two-hybrid, pull-down, co-immunoprecipitation from transfected OK cells, immunohistochemistry","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and pull-down confirmed, colocalization in native tissue, single lab","pmids":["14531807"],"is_preprint":false},{"year":2004,"finding":"PDZK1 interacts with URAT1 via URAT1's C-terminal PDZ motif and PDZ domains 1, 2, and 4 of PDZK1 (KD = 1.97–514 nM by surface plasmon resonance). This interaction enhances urate transport Vmax and increases surface expression of URAT1 in HEK293 cells. URAT1 and PDZK1 colocalize at the apical membrane of renal proximal tubular cells.","method":"Yeast two-hybrid, in vitro binding assay, surface plasmon resonance, co-immunoprecipitation, transport assay in HEK293 cells, surface biotinylation, immunolocalization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding with quantitative KD, transport reconstitution, surface expression measurement, multiple orthogonal methods, single lab","pmids":["15304510"],"is_preprint":false},{"year":2004,"finding":"PDZK1 directly interacts with OCTN2 via its C-terminal last four amino acids and stimulates carnitine uptake by a 6-fold increase in transport capacity, with minimal effect on cell-surface expression of OCTN2. PDZK1 and OCTN2 colocalize in kidney brush-border membranes. OCTN1 also interacts with PDZK1.","method":"Pull-down with recombinant C-terminal proteins, yeast two-hybrid, kidney brush-border membrane vesicle pull-down, immunohistochemistry, transport assay in double-transfected cells, surface biotinylation","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of transport, multiple orthogonal binding assays, deletion mutant confirms specificity","pmids":["15523054"],"is_preprint":false},{"year":2004,"finding":"Steady-state NaPi-IIa protein levels are reduced in PDZK1 knockout mice fed a high-phosphate diet, with higher urinary phosphate excretion, but localization of NaPi-IIa and acute regulation by PTH are not altered. Loss of PDZK1 also reduced CFEX/PAT1 abundance but increased NHERF1 in the brush border under high-Pi diet.","method":"PDZK1 knockout mice, Western blot, immunohistochemistry, urinary phosphate measurement, in vivo and in vitro PTH stimulation","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotype and multiple readouts, single lab","pmids":["15517343"],"is_preprint":false},{"year":2005,"finding":"PDZK1 is essential for normal brush-border expression and function of Cl−/anion exchanger CFEX (SLC26A6) in the renal proximal tubule. PDZK1-null mice show markedly reduced CFEX protein expression, reduced Cl−/oxalate exchange activity in brush-border membrane vesicles, and reduced oxalate-stimulated volume absorption. NHE3 brush-border expression is unaffected by loss of PDZK1. CFEX and NHE3 both bind PDZK1 through their C-terminal PDZ-interaction sites in vitro.","method":"GST pull-down with native brush-border membrane proteins, Western blot, immunocytochemistry, brush-border membrane vesicle transport assay, microperfused proximal tubule assay in PDZK1-null mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding, in vivo KO phenotype, functional transport assay, multiple orthogonal methods","pmids":["16141316"],"is_preprint":false},{"year":2005,"finding":"PDZK1 interacts with and is required for hepatocyte surface expression of rat Oatp1a1. In PDZK1 knockout mouse liver, Oatp1a1 protein level is near normal but redistributes to intracellular structures rather than the basolateral plasma membrane, causing delayed plasma disappearance of the Oatp1a1 ligand sulfobromophthalein. Oatp1a1 binds predominantly to the first and third PDZ domains of PDZK1.","method":"C-terminal peptide affinity isolation from liver cytosol, mass spectrometry, co-immunoprecipitation from cotransfected 293T cells and native rat liver, PDZK1 KO mouse study, immunofluorescence, in vivo substrate clearance assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo KO phenotype with functional consequence, multiple orthogonal binding/localization assays, mass spectrometry identification","pmids":["15994332"],"is_preprint":false},{"year":2005,"finding":"The C-terminal region of PDZK1 is required for upregulating SR-BI protein expression, and PDZK1 is phosphorylated by cAMP-dependent PKA at Ser-509 in this C-terminal region. A Ser-509→Ala mutant loses the ability to upregulate SR-BI. Glucagon administration to rats increases PDZK1 phosphorylation and hepatic SR-BI expression while decreasing plasma HDL.","method":"Metabolic labeling, phosphoamino acid analysis, point-mutation analysis, in vitro PKA phosphorylation assay, phospho-Ser-509-specific antibody, in vivo glucagon treatment in rats","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus mutagenesis plus in vivo hormonal regulation, multiple orthogonal methods","pmids":["16174736"],"is_preprint":false},{"year":2005,"finding":"PDZK1 interacts with SSTR5 at the plasma membrane (as opposed to PIST which retains SSTR5 in the Golgi). Removal of the PDZ ligand motif of SSTR5 does not affect agonist-dependent internalization or Golgi targeting but inhibits recycling of the receptor to the plasma membrane after agonist washout.","method":"Yeast two-hybrid, coexpression/colocalization studies, receptor trafficking assays with PDZ-motif deletion mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid and trafficking assays, functional consequence of PDZ-motif deletion, single lab","pmids":["16012170"],"is_preprint":false},{"year":2005,"finding":"PDZK1 (CAP70) binds to the C-terminal portion of inducible nitric oxide synthase (NOS2) via NOS2's four C-terminal amino acids. This interaction enhances both cytochrome c reductase and NO-synthase activities of NOS2, increases the population of active NOS2 dimers, and participates in correct apical subcellular targeting of NOS2 in polarized cells (dependent also on N-terminal palmitoylation of NOS2).","method":"Coimmunoprecipitation, in vitro enzymatic activity assays, dimer analysis, subcellular targeting assays in polarized cells","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, enzymatic assays, subcellular targeting experiment; single lab","pmids":["17507652"],"is_preprint":false},{"year":2005,"finding":"PDZK1 interacts with DRA (SLC26A3) at the intestinal brush border via DRA's C-terminal PDZ interaction motif, specifically through PDZK1's 2nd and 3rd PDZ domains. This is distinct from CFTR which interacts with PDZ1, PDZ3, and PDZ4 of PDZK1.","method":"Overlay assay with recombinant DRA C-terminus, pull-down, HEK cell co-transfection, immunostaining","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple in vitro methods identifying binding domains, confirmed in transfected cells, single lab","pmids":["15766278"],"is_preprint":false},{"year":2006,"finding":"PDZK1 interacts with PEPT2 via PEPT2's C-terminal PDZ motif; the 2nd and 3rd PDZ domains of PDZK1 bind PEPT2-CT (measured by surface plasmon resonance). PDZK1 coexpression increases surface expression of PEPT2 and enhances PEPT2 transport Vmax in HEK293 cells. PEPT2 and PDZK1 interact in native human kidney membrane fractions.","method":"Yeast two-hybrid, in vitro binding assay, surface plasmon resonance, co-immunoprecipitation from human kidney membrane fraction, transport assay, surface biotinylation","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro binding, transport reconstitution, native tissue confirmation, multiple orthogonal methods","pmids":["16738539"],"is_preprint":false},{"year":2006,"finding":"MAP17 coexpression with NHERF3 (PDZK1) or NHERF4 (but not NHERF1/2) induces internalization of NaPi-IIa, MAP17, and the PDZ protein to the trans-Golgi network (TGN) in a PKC-dependent manner. This cotransfection also prevents the adaptive upregulation of phosphate transport in response to low extracellular phosphate.","method":"Bacterial and mammalian two-hybrid, transfection studies in OK cells, immunofluorescence, transport assays, PKC inhibitor experiments","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-based trafficking assay with functional transport readout, pharmacological inhibition, single lab","pmids":["16926447"],"is_preprint":false},{"year":2007,"finding":"Loss of PDZK1 in murine proximal colonic enterocytes abolishes cAMP-mediated (forskolin) and Ca2+-dependent (ionomycin) inhibition of NHE3 activity without affecting NHE3 abundance or apical localization. NHE3 inhibition by hyperosmolarity is preserved in pdzk1−/− mice, indicating a selective role for PDZK1 in agonist-mediated NHE3 regulation.","method":"PDZK1 knockout mouse model, fluorometric NHE3 activity assay in isolated colonic crypts, quantitative PCR, Western blot, immunohistochemistry","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with specific functional readout, multiple assays, defined selectivity of phenotype","pmids":["17395628"],"is_preprint":false},{"year":2007,"finding":"In PDZK1-deficient small intestine, basal net Na+ absorption and its inhibition by forskolin are significantly reduced, and a mild reduction in maximal CFTR activation is observed. NHE3 mRNA is increased, suggesting increased NHE3 turnover, possibly due to reduced NHE3 membrane retention.","method":"PDZK1 knockout mouse model, short circuit current and ion flux measurements, 22Na+ fluxes, quantitative PCR, Western blot, immunohistochemistry","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO, electrophysiology and flux measurements, single lab","pmids":["17347851"],"is_preprint":false},{"year":2008,"finding":"PDZK1 is required for HDL/SR-BI signaling in endothelium: PDZK1 is needed for HDL activation of eNOS and endothelial cell migration, HDL/SR-BI-induced Src phosphorylation, and carotid reendothelialization after injury. PDZK1 does not regulate SR-BI abundance or plasma membrane localization in endothelium or HDL binding or cholesterol efflux. Src co-immunoprecipitates with SR-BI in a PDZK1-independent manner.","method":"Co-immunoprecipitation, siRNA knockdown, PDZK1−/− mouse model, carotid injury model, eNOS activity assay, cell migration assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO, in vitro and in vivo phenotypes, specific mechanistic distinction from liver (signaling vs. abundance), multiple methods","pmids":["18174467"],"is_preprint":false},{"year":2008,"finding":"PDZK1 is required for apical membrane localization of the intestinal mucin MUC17 (mouse Muc3(17)). In Pdzk1−/− mouse jejunum, Muc3(17) shows intracellular rather than brush-border staining. MUC17 C-terminal tail binds to three of four PDZ domains of PDZK1, and strong binding to PDZK1 was confirmed by GST pull-down and PDZ domain array screening.","method":"PDZ domain array screening, GST pull-down with mass spectrometry confirmation, immunostaining in Pdzk1−/− and WT mouse jejunum","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo localization in KO mouse, biochemical binding confirmed by MS, multiple methods, single lab","pmids":["17990980"],"is_preprint":false},{"year":2008,"finding":"All four PDZ domains of PDZK1 are required for normal hepatic SR-BI abundance, cell surface localization, and function. Truncation constructs lacking PDZ4 only partially restore SR-BI abundance without restoring cell surface localization. The C-terminal residues of PDZK1 beyond PDZ4 (including the putative PDZ-binding motif) are not required.","method":"PDZK1 KO mouse complementation with nested truncation transgenes, Western blot, immunohistochemistry, plasma cholesterol analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic domain truncation in vivo, multiple transgenes tested, functional readout, replicated across constructs","pmids":["19116202"],"is_preprint":false},{"year":2008,"finding":"Overexpression of only the PDZ1 domain of PDZK1 in wild-type mice dominantly reduces hepatic SR-BI protein by 75% and causes intracellular mislocalization of SR-BI, resulting in hypercholesterolemia. Full-length PDZK1 is required to restore normal SR-BI function in PDZK1 KO mice, while PDZ1 alone only partially restores SR-BI protein abundance without restoring cell surface expression.","method":"Liver-specific transgenic overexpression of PDZ1 domain and full-length PDZK1, Western blot, immunohistochemistry, plasma lipoprotein analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant-negative in vivo approach with defined molecular and functional phenotypes, complementary KO rescue experiment","pmids":["18544532"],"is_preprint":false},{"year":2008,"finding":"PDZK1 regulates intestinal solute carriers PEPT1 (Slc15a1) and OCTN2 (Slc22a5) in vivo. In pdzk1−/− mice, apical membrane localization of both transporters is reduced, their protein levels in brush-border membranes decrease, and PEPT1 localizes to intracellular vesicles. PDZK1 physically interacts with PEPT1 in mouse small intestine, and PDZK1 coexpression stimulates PEPT1 transport activity by increasing its expression level. GI absorption of cephalexin and carnitine are reduced in pdzk1−/− mice.","method":"PDZK1 KO mouse model, oral pharmacokinetics, immunohistochemistry, electron microscopy, Western blot, immunoprecipitation, transport assay in HEK293 cells","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO phenotype with functional absorption readout, direct interaction confirmed, transport reconstitution, multiple orthogonal methods","pmids":["18322073"],"is_preprint":false},{"year":2009,"finding":"PDZK1 undergoes an intramolecular head-to-tail self-association where the C-terminal tail interacts with the first PDZ domain. This intramolecular interaction causes a more compact conformation and negatively regulates the interaction of PDZK1's tail with the PDZ domains of EBP50/NHERF1. PDZK1 also undergoes modest homodimerization through its third PDZ domain. These interactions differ from the related scaffold EBP50 where intramolecular association regulates binding to PDZ domain ligands.","method":"In vitro binding assays, in vivo co-IP, biochemical characterization of self-association, conformational analysis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vitro and in vivo characterization of self-association with functional consequence, single lab","pmids":["19173579"],"is_preprint":false},{"year":2009,"finding":"NHERF3 (PDZK1) directly binds NHE3 C-terminus (amino acids 588–667) in vitro, colocalizes with NHE3 at the plasma membrane under basal conditions, and reconstitutes Ca2+-mediated inhibition of NHE3 activity. Elevated [Ca2+]i dissociates NHERF3 from NHE3, decreases NHE3 surface amount, and reduces NHE3 Vmax. NHERF3 shRNA knockdown in Caco-2BBe cells reduces basal NHE3 activity and brush-border NHE3 amount.","method":"In vitro binding assay, co-immunoprecipitation, confocal microscopy, FRET, shRNA knockdown, fluorometric NHE3 activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, functional reconstitution with NHERF3, multiple orthogonal methods (FRET, co-IP, transport assay, KD), single lab","pmids":["19535329"],"is_preprint":false},{"year":2009,"finding":"Pdzk1 ablation reduces basal but not FSK-stimulated duodenal HCO3− secretion in mice, while Nherf1 ablation strongly reduces both basal and FSK-stimulated secretion and blocks beta2-AR stimulation of CFTR. These data demonstrate differential roles of NHERF family members in CFTR regulation in vivo.","method":"Nherf1/Nherf2/Pdzk1 knockout mouse models, duodenal HCO3− secretion measurement, laser microdissection, quantitative PCR","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — three separate KO mouse models, direct secretory measurement, replicated specificity by comparison","pmids":["19221439"],"is_preprint":false},{"year":2010,"finding":"PDZK1 forms a regulated ternary complex with EBP50 and ezrin in vitro and in vivo. Complex formation is cooperative — ezrin positively influences the PDZK1/EBP50 interaction, and EBP50 PDZ domain occupancy enhances PDZK1 binding. PDZK1 shuttles from the nucleus (low confluence) to microvilli (high confluence), and when localized to microvilli can substitute for EBP50 in rescuing microvillar organization after EBP50 knockdown.","method":"In vitro ternary complex reconstitution, in vivo co-IP, live imaging of PDZK1 localization, EBP50 knockdown and rescue, confocal microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of ternary complex, in vivo validation, functional rescue experiment, multiple methods","pmids":["20237154"],"is_preprint":false},{"year":2010,"finding":"PDZK1 binding is required for optimal cell surface expression of Oatp1a1, while serine phosphorylation of Oatp1a1 at S634/S635 (upstream of the PDZ motif) regulates the balance between surface and intracellular pools. Phosphomimetic (EE) mutant internalizes rapidly; non-phosphorylatable (AA) mutant is retained at the surface by PDZK1. Extracellular ATP-stimulated phosphorylation in rat hepatocytes causes rapid Oatp1a1 internalization.","method":"Site-directed mutagenesis, surface biotinylation internalization assay, cotransfection with PDZK1, primary hepatocyte experiments with purinergic receptor stimulation","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus functional trafficking assay plus physiological stimulus, single lab","pmids":["21183661"],"is_preprint":false},{"year":2010,"finding":"PDZK1 is required for SR-BI-dependent HCV entry into hepatocytes. shRNA knockdown of PDZK1 reduces susceptibility to HCV infection, which is reversed by full-length PDZK1 but not the PDZ1 domain alone. Overexpression of SR-BI C-terminal cytoplasmic tail competes with endogenous PDZK1 and reduces HCV infection, only if the tail can interact with PDZK1.","method":"shRNA knockdown in hepatoma cells, HCV infection assay, overexpression of SR-BI cytoplasmic tail constructs, co-immunoprecipitation","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA KD with specific rescue and dominant-negative competition, functional infection readout, single lab","pmids":["20949066"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of PDZK1 PDZ1 bound to the 5-residue C-terminal SR-BI peptide (QEAKL) was solved by X-ray crystallography. Y20A and G21Y substitutions in the carboxylate-binding loop abrogate all binding; K14A and F22A substitutions do not significantly change binding affinity. The Y20A mutant at 10–20-fold overexpression still partially corrects SR-BI defects in PDZK1 KO mice, suggesting an additional binding site within PDZK1.","method":"X-ray crystallography (PDZ1–peptide complex), in vitro binding affinity measurements, mutagenesis in full-length PDZK1 transgenes, in vivo PDZK1 KO mouse complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus in vivo functional validation, multiple orthogonal methods","pmids":["20739281"],"is_preprint":false},{"year":2011,"finding":"PDZK1 is required for the stabilization of NaPi-2c (but not NaPi-2a) in the apical membrane of renal proximal tubules. FRET measurements show a stronger NHERF-1/NaPi-2a interaction than NHERF-1/NaPi-2c, while both NaPi-2c and NaPi-2a have similar FRET efficiencies with PDZK1. In pdzk1−/− mice on low-Pi diet, NaPi-2a is upregulated but NaPi-2c is not.","method":"PDZK1 KO mouse model, FRET in live cells, Western blot, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO plus FRET quantification of differential interactions, single lab","pmids":["21388960"],"is_preprint":false},{"year":2011,"finding":"PDZ3 of PDZK1 is a second functional binding site for the C-terminal SR-BI peptide (KD = 37.0 µM by ITC, ~10-fold lower affinity than PDZ1). PDZ3 binding is abrogated by Y253A mutation. A double PDZ1(Y20A)+PDZ3(Y253A) substitution abrogates all SR-BI binding and cannot correct SR-BI defects in PDZK1 KO mice, whereas the single PDZ3(Y253A) substitution fully corrects. Crystal structure of PDZ3-peptide complex determined at 1.5 Å.","method":"Isothermal titration calorimetry, X-ray crystallography (PDZ3–peptide complex), mutagenesis in transgenes, in vivo PDZK1 KO mouse complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, quantitative binding, in vivo functional rescue, systematic mutagenesis","pmids":["21602281"],"is_preprint":false},{"year":2011,"finding":"PDZK1 physically interacts with BCRP (breast cancer resistance protein) and promotes its apical membrane localization in small intestinal enterocytes. In pdzk1−/− mice, BCRP expression is reduced in brush-border membranes. PDZK1 coexpression in MDCK cells increases transcellular BCRP-mediated transport of cimetidine and enhances resistance to SN-38.","method":"PDZK1 KO mouse model, Western blot, immunohistochemistry, pull-down, immunoprecipitation, transcellular transport assay, cytotoxicity assay","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction confirmed, in vivo KO phenotype, functional transport reconstitution, multiple orthogonal methods","pmids":["21816982"],"is_preprint":false},{"year":2012,"finding":"PDZK1 forms a ternary complex with PLC-β3 and somatostatin receptors (SSTRs). PDZK1 specifically interacts with PLC-β3 (not PLC-β1) and with SSTRs. PDZK1-mediated complex formation is required for SST-induced PLC-β3 activation, intracellular Ca2+ mobilization, and subsequent ERK1/2 phosphorylation. PDZK1 knockdown abolishes these SST-induced responses.","method":"Co-immunoprecipitation, yeast two-hybrid screening, siRNA knockdown, Ca2+ mobilization assay, ERK1/2 phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of ternary complex, functional knockdown with specific signaling readouts, single lab","pmids":["22528496"],"is_preprint":false},{"year":2012,"finding":"PDZK1 upregulation in melanocytes increases tyrosinase expression and melanosome transfer to keratinocytes, while PDZK1 knockdown reduces estrogen-induced tyrosinase expression through regulation of estrogen receptor (ER-α and ER-β) expression. PDZK1-induced melanosome transfer involves phosphorylation of ERM proteins and Rac1, but not PAR-2, and is regulated by NHE, CFTR, and SLC26A3 ion transporters.","method":"Monocultures and cocultures of melanocytes/keratinocytes, PDZK1 overexpression and knockdown, biopsied skin specimens, Western blot","journal":"The Journal of investigative dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression/knockdown phenotype, indirect mechanistic inference","pmids":["22696060"],"is_preprint":false},{"year":2013,"finding":"PDZ4 domain of PDZK1 is necessary for hepatocyte cell-surface localization of PDZK1 in vivo (dependent on both PDZ4 and presence of SR-BI). PDZ4 does not bind the SR-BI target peptide canonically but binds phospholipid vesicles mimicking the plasma membrane by surface plasmon resonance, suggesting a noncanonical lipid-mediated membrane attachment role. Neither PDZ2, PDZ3, nor canonical peptide-binding activity of PDZ4 is necessary for SR-BI regulation.","method":"Domain deletion/replacement transgenic mice, immunohistochemistry, analytical ultracentrifugation, hydrogen-deuterium exchange mass spectrometry, surface plasmon resonance with lipid vesicles","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic in vivo domain analysis, biophysical characterization including HDX-MS and SPR with lipid vesicles, multiple orthogonal methods","pmids":["23720744"],"is_preprint":false},{"year":2013,"finding":"PDZK1 is required for trafficking of Oatp1a1 to the plasma membrane via selective recruitment of kinesin-1 (plus-end microtubule motor) to Oatp1a1-containing vesicles. In PDZK1 KO mice, Oatp1a1 vesicles instead recruit dynein (minus-end motor) and move predominantly toward the cell interior, resulting in intracellular accumulation.","method":"Vesicle isolation from WT and PDZK1 KO mouse liver, immunofluorescence for motor proteins on vesicles, in vitro microtubule motility assays with directionally marked microtubules","journal":"Drug metabolism and disposition","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro motility assay with defined directional readout, in vivo KO-derived vesicles, single lab","pmids":["24115750"],"is_preprint":false},{"year":2014,"finding":"PDZK1 interacts with the prostacyclin receptor (hIP) via a Class I PDZ ligand at hIP's C-terminus and PDZ domains 1, 3, and 4 of PDZK1. This interaction increases hIP cell surface expression and enhances cAMP generation. PDZK1 is required for cicaprost-induced endothelial cell migration and tube formation; siRNA knockdown of PDZK1 abolishes these effects but does not affect VEGF responses. PDZK1 phosphorylation at Ser-505 by PKA may dynamically regulate the interaction.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, cell migration assay, tube formation assay, cAMP assay, ligand binding assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, siRNA with specific functional readouts, multiple methods, single lab","pmids":["21653824"],"is_preprint":false},{"year":2014,"finding":"NHERF2 and NHERF3 (PDZK1) heterodimerize as the strongest NHERF-NHERF interaction, mediated by PDZ domains of NHERF2 and the C-terminal PDZ recognition motif of NHERF3. This heterodimerization is required for carbachol-mediated inhibition of NHE3 and allows simultaneous occupancy of NHERF2 PDZ domains by NHERF3 and another ligand (NHE3, α-actinin-4, or PKCα), forming NHE3 macrocomplexes.","method":"Pull-down, co-immunoprecipitation, FRET, FRAP, yeast three-hybrid, mutagenesis of NHERF3 C-terminal motif","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal interaction assays including FRET/FRAP, mutagenesis defining interaction domain, functional consequence, single lab","pmids":["24867958"],"is_preprint":false},{"year":2014,"finding":"PDZK1 interacts with OATP1A2 via the C-terminal PDZ-binding domain and increases OATP1A2 transport Vmax by increasing plasma membrane expression, reducing clathrin-dependent (but not caveolin-dependent) internalization, and enhancing protein stability. NHERF1 has similar effects.","method":"Co-immunoprecipitation, transport assay in HEK-293 cells, surface biotinylation, clathrin/caveolin pathway inhibitors, protein stability assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed, mechanistic pathway dissection, multiple methods, single lab","pmids":["24728453"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the D-AKAP2:PKA RII:PDZK1 ternary complex was determined. D-AKAP2 presents a disordered segment that adopts an α-helix to bind PKA RII and a β-strand to bind PDZK1's PDZ domain, nucleating a polyvalent scaffold. D-AKAP2:PKA binary complex formation is an important first step for high-affinity interaction with PDZK1, and the PDZK1 PDZ domain serves as a bridge between the kinase and membrane transporters.","method":"X-ray crystallography of ternary complex, surface plasmon resonance, biochemical binding assays","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of ternary complex, quantitative binding analysis, mechanistic insight into ordered complex assembly","pmids":["25348485"],"is_preprint":false},{"year":2015,"finding":"PDZK1 differentially regulates CRFR1 and 5-HT2AR: it interacts with CRFR1 in a PDZ-binding motif-dependent manner (redistributing PDZK1 to the plasma membrane) and with 5-HT2AR in a PDZ-binding motif-independent manner. PDZK1 selectively increases CRFR1-stimulated ERK1/2 phosphorylation but not cAMP signaling; it inhibits 5-HT2AR endocytosis and positively influences 5-HT2AR-stimulated inositol phosphate formation. PDZK1 has no effect on CRFR1 endocytosis.","method":"Co-immunoprecipitation, siRNA knockdown, ERK1/2 and cAMP signaling assays, internalization assays, inositol phosphate assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and siRNA with multiple functional readouts distinguishing PDZ-dependent and independent mechanisms, single lab","pmids":["25562428"],"is_preprint":false},{"year":2017,"finding":"PDZK1 inhibits renal cell carcinoma cell proliferation by suppressing SHP-1 phosphorylation at Tyr536. PDZK1 blocks the association between SHP-1 and PLCβ3, thereby preventing SHP-1 phosphorylation, which retards Akt phosphorylation and promotes STAT5 phosphorylation. These effects are validated in xenograft tumor studies.","method":"PDZK1 overexpression/knockdown in ccRCC cell lines, co-immunoprecipitation, Western blot for phospho-proteins, cell proliferation and migration assays, xenograft tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP defining complex disruption, phosphorylation readouts, in vivo xenograft, single lab","pmids":["28692056"],"is_preprint":false},{"year":2018,"finding":"PDZK1 interacts with OATP2B1 via the C-terminal PDZ-binding motif of OATP2B1 and increases OATP2B1 transport capacity (enhanced estrone 3-sulfate uptake) by increasing OATP2B1 membrane expression. Deletion of the C-terminal PDZ-binding motif reduces the effect of PDZK1.","method":"Co-expression and transport assay in HEK cells, Western blot for membrane fractions, C-terminal deletion mutant","journal":"European journal of pharmaceutical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-expression transport assay and Western blot only, no co-IP confirmation","pmids":["29752999"],"is_preprint":false},{"year":2018,"finding":"Full-length PDZK1 adopts an extended, asymmetric L-shaped domain organization in solution (not a flexible beads-on-string arrangement) as determined by small-angle X-ray scattering with hybrid modeling. The linker regions between PDZ domains play a central role in the spatial arrangement of the four domains. This architecture influences binding properties to membrane protein partners.","method":"Small-angle X-ray scattering (SAXS), deletion construct analysis, biochemical binding assays, hybrid modeling","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination with multiple deletion constructs and functional binding assays, systematic study","pmids":["30220543"],"is_preprint":false},{"year":2019,"finding":"PDZK1 identifies PTEN as a binding partner through PTEN's carboxyl terminus and PDZK1's PDZ domains. Direct interaction with PTEN inhibits PTEN phosphorylation at S380/T382/T383, enhancing PTEN's capacity to suppress PI3K/AKT activation, thereby inhibiting gastric cancer cell proliferation in vitro and in vivo.","method":"Co-immunoprecipitation, Western blot for PTEN phosphorylation, in vitro cell proliferation assay, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction identified, phosphorylation readout with functional consequence, in vivo xenograft, single lab","pmids":["30930234"],"is_preprint":false},{"year":2019,"finding":"PDZK1 is identified as a binding partner of SMCT1 and SMCT2 by yeast two-hybrid screen of a human kidney cDNA library. PDZK1 coexpression enhances nicotinate transport activity of SMCT1. PDZK1, SMCT1, and URAT1 form a tri-molecular complex in vitro and colocalize in renal proximal tubule in vivo.","method":"Yeast two-hybrid, transport assay in HEK293 cells, in vitro complex assembly, immunohistochemistry","journal":"The journal of physiological sciences : JPS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus transport assay plus in vitro complex, colocalization in native tissue, single lab","pmids":["30604288"],"is_preprint":false},{"year":2023,"finding":"Human OATP1B1 (but not OATP1B3) interacts with human PDZK1 via its PDZ-binding consensus motif at the C-terminus and PDZ domain 1 of PDZK1. Interaction with PDZK1 is required for OATP1B1 trafficking to the basolateral plasma membrane; truncation of the PDZ-binding motif results in predominantly intracellular localization.","method":"Co-immunoprecipitation from cotransfected 293T cells and normal human liver, domain-selective co-IP with individual PDZ domains, immunofluorescence in stably transfected HeLa cells with truncation mutant","journal":"Drug metabolism and disposition","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP from native human liver, domain specificity mapped, mutagenesis of PDZ motif with localization consequence, replicated in two cell systems","pmids":["37442606"],"is_preprint":false},{"year":2024,"finding":"PDZK1 loss in chondrocytes impairs mitochondrial function (decreased mtDNA content, increased ROS, accumulated damaged mitochondria) and induces chondrocyte senescence and cartilage degeneration. PDZK1 deficiency increases ubiquitination of Hmgcs2, suppressing its expression and thereby impairing mitochondrial function. Intra-articular AAV-PDZK1 rescues these defects.","method":"Pdzk1 chondrocyte-specific KO mouse model, mRNA sequencing, ubiquitination assay, mitochondrial function assays (ROS, mtDNA, membrane potential), in vivo AAV rescue, OA patient specimens","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with mechanistic pathway identification (Hmgcs2 ubiquitination), in vivo rescue, multiple functional readouts, single lab","pmids":["39019845"],"is_preprint":false},{"year":2024,"finding":"PDZK1 binds to EGFR and promotes EGFR degradation by enhancing EGFR binding to c-Cbl, while also inhibiting EGFR phosphorylation by hindering EGFR dimerization. These mechanisms suppress TNBC cell proliferation and sensitize TNBC cells to erlotinib in vitro and in vivo.","method":"Co-immunoprecipitation, Western blot for EGFR phosphorylation and ubiquitination, PDZK1 overexpression/knockdown, xenograft tumor model, erlotinib sensitivity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP defining interaction, functional mechanistic readouts (c-Cbl recruitment, dimerization inhibition), in vivo xenograft, single lab","pmids":["38604999"],"is_preprint":false}],"current_model":"PDZK1 is a multi-PDZ domain scaffold protein (with an extended L-shaped architecture) that localizes to apical brush borders and other plasma membranes in epithelial cells, where it directly binds the C-terminal PDZ motifs of a broad array of membrane transporters and receptors (including SR-BI, URAT1, OCTN2, PEPT1/2, NHE3, CFEX, Oatp1a1/1b1, BCRP, OATP1A2/2B1, OATP2B1, SMCT1/2, MUC17, prostacyclin receptor, somatostatin receptor, and EGFR) through canonical PDZ-domain interactions (primarily at PDZ1 and PDZ3, with PDZ4 providing noncanonical membrane attachment via lipid binding), thereby stabilizing these proteins at the plasma membrane, directing their intracellular trafficking (via selective recruitment of kinesin-1 over dynein), and modulating their activity; additionally, PDZK1 acts as a signaling scaffold by assembling ternary signaling complexes (e.g., PLC-β3/SSTRs, D-AKAP2/PKA) and mediating receptor-initiated signaling cascades (HDL/SR-BI→Src→eNOS in endothelium; PTEN dephosphorylation suppressing PI3K/AKT; SHP-1 phosphorylation control), and its own activity is regulated post-translationally by PKA phosphorylation at Ser-509, intramolecular head-to-tail self-association, and proteasome-dependent and -independent turnover."},"narrative":{"mechanistic_narrative":"PDZK1 is a four-PDZ-domain scaffold protein of epithelial apical brush borders and other plasma membranes that organizes membrane transporters, receptors, and signaling enzymes into functional complexes [PMID:9461128, PMID:14531806]. Through canonical PDZ interactions with the C-terminal motifs of partner proteins, it stabilizes a broad array of solute carriers and receptors at the cell surface, directs their trafficking, and tunes their transport activity: it controls hepatic and intestinal SR-BI abundance and thereby plasma HDL cholesterol [PMID:14551195], enhances urate, carnitine, and peptide transport by URAT1, OCTN2, and PEPT1/2 [PMID:15304510, PMID:15523054, PMID:16738539, PMID:18322073], maintains apical CFEX/SLC26A6 and NaPi-2c [PMID:16141316, PMID:21388960], and is required for membrane delivery of Oatp1a1, OATP1B1, BCRP, OATP1A2/2B1, and MUC17 [PMID:15994332, PMID:37442606, PMID:21816982, PMID:24728453, PMID:29752999, PMID:17990980]. Mechanistically, PDZK1 governs trafficking by selectively recruiting the plus-end motor kinesin-1 rather than dynein to transporter-containing vesicles [PMID:24115750], and it controls agonist-mediated regulation of NHE3 by cAMP and Ca2+ rather than basal NHE3 abundance [PMID:17395628, PMID:19535329]. Structural work shows the protein adopts an extended, asymmetric L-shaped architecture in solution [PMID:30220543], with PDZ1 and PDZ3 providing two functional binding sites for the SR-BI tail [PMID:20739281, PMID:21602281] and PDZ4 contributing a noncanonical lipid-mediated membrane attachment required for PDZK1's own surface localization [PMID:23720744]. Beyond transporter scaffolding, PDZK1 acts as a signaling platform: it is required for HDL/SR-BI activation of Src and eNOS in endothelium [PMID:18174467], assembles ternary complexes with PLC-β3/somatostatin receptors and with D-AKAP2/PKA [PMID:22528496, PMID:25348485], and modulates oncogenic signaling by stabilizing PTEN to suppress PI3K/AKT and by promoting c-Cbl-dependent EGFR degradation [PMID:30930234, PMID:38604999]. Its activity is regulated post-translationally by PKA phosphorylation at Ser-509, by an intramolecular head-to-tail self-association involving PDZ1, and by MAP17/SPAP-controlled turnover [PMID:16174736, PMID:19173579, PMID:12754212].","teleology":[{"year":1998,"claim":"Established PDZK1 as a multi-PDZ scaffold of epithelial brush borders, defining its tissue distribution and first binding partner before any function was known.","evidence":"Yeast two-hybrid identification via MAP17, in situ hybridization and immunolocalization in epithelial tissues","pmids":["9461128"],"confidence":"Medium","gaps":["No functional consequence of the MAP17 interaction defined","Binding not validated biochemically beyond yeast two-hybrid"]},{"year":2003,"claim":"Knockout mice showed PDZK1 post-transcriptionally controls SR-BI protein abundance in a tissue-specific manner, linking the scaffold to HDL cholesterol metabolism.","evidence":"Targeted Pdzk1 KO mouse, Western blot, immunohistochemistry, plasma lipid analysis","pmids":["14551195"],"confidence":"High","gaps":["Mechanism of SR-BI stabilization not resolved","Did not explain tissue specificity (liver/intestine vs steroidogenic organs)"]},{"year":2003,"claim":"Mapped PDZK1 as a hub of a renal brush-border transporter network and identified MAP17 as its apical anchor and D-AKAP2/PKA as a recruited kinase, framing PDZK1 as both organizer and signaling platform.","evidence":"Yeast two-hybrid, pull-down, blot overlay, co-IP and immunohistochemistry in renal/OK cell systems","pmids":["14531806","12837682","14531807","12754212"],"confidence":"Medium","gaps":["Many interactions defined only in vitro or by colocalization","Functional consequences for individual transporters not yet measured"]},{"year":2004,"claim":"Quantitative binding and transport reconstitution showed PDZK1 directly enhances transporter activity, not merely localization, establishing a causal scaffold-to-function link for URAT1 and OCTN2.","evidence":"Surface plasmon resonance KD measurement, co-IP, surface biotinylation, transport assays in HEK293 cells","pmids":["15304510","15523054"],"confidence":"High","gaps":["How surface stabilization vs intrinsic activity contributes differs between partners and was not fully separated","In vivo relevance to urate/carnitine handling not yet tested"]},{"year":2005,"claim":"In vivo KO studies extended the scaffold role to NaPi-IIa, CFEX, and basolateral Oatp1a1, revealing partner-specific outcomes from abundance loss to mistrafficking.","evidence":"Pdzk1 KO mice, brush-border membrane vesicle transport assays, microperfusion, peptide-affinity isolation with mass spectrometry, immunofluorescence","pmids":["15517343","16141316","15994332"],"confidence":"High","gaps":["Distinct fates of partners (degradation vs intracellular retention) mechanistically unexplained","NHE3 found unaffected, raising selectivity questions"]},{"year":2005,"claim":"Identified PKA phosphorylation at Ser-509 as a regulatory switch coupling hormonal (glucagon) signaling to PDZK1-dependent SR-BI expression.","evidence":"Metabolic labeling, phosphoamino acid analysis, S509A mutagenesis, in vitro PKA assay, phospho-specific antibody, in vivo glucagon treatment","pmids":["16174736"],"confidence":"High","gaps":["Structural mechanism by which Ser-509 phosphorylation alters scaffold function not defined","Generality to other partners untested"]},{"year":2005,"claim":"Showed PDZK1 controls receptor recycling and enzyme activity, broadening it from transporter scaffold to a regulator of GPCR trafficking (SSTR5) and NOS2 catalysis.","evidence":"Yeast two-hybrid, colocalization/trafficking assays with PDZ-motif deletions, co-IP, in vitro enzymatic and dimer assays","pmids":["16012170","17507652","15766278"],"confidence":"Medium","gaps":["NOS2 enzymatic enhancement not confirmed in vivo","DRA/CFTR domain assignments not functionally tested"]},{"year":2007,"claim":"KO physiology established that PDZK1 is required specifically for agonist-mediated (cAMP/Ca2+) regulation of NHE3 rather than its basal expression, refining its role to dynamic signaling control of ion transport.","evidence":"Pdzk1 KO mice, fluorometric NHE3 activity in colonic crypts, short-circuit current and ion flux measurements","pmids":["17395628","17347851"],"confidence":"High","gaps":["Molecular link between PDZK1 and the second-messenger machinery not defined","Whether NHE3 directly or indirectly engaged in vivo unresolved at this stage"]},{"year":2008,"claim":"Domain-dissection and dominant-negative experiments in vivo established that all four PDZ domains contribute to SR-BI regulation and that an isolated PDZ1 acts dominant-negatively, defining the multivalent logic of the scaffold.","evidence":"Nested truncation and PDZ1-only transgenes in WT and Pdzk1 KO mice, Western blot, immunohistochemistry, plasma lipoprotein analysis","pmids":["19116202","18544532"],"confidence":"High","gaps":["Why surface localization needs more than abundance restoration not mechanistically explained","Role of individual domains in other partners not addressed"]},{"year":2008,"claim":"Extended in vivo scaffold function to intestinal transport (PEPT1, OCTN2, MUC17) and CFTR-related secretion and to endothelial HDL/SR-BI signaling, separating a signaling role (eNOS/Src activation) from abundance control.","evidence":"Pdzk1 KO mice, oral pharmacokinetics, immunohistochemistry/EM, co-IP, carotid injury model, eNOS and migration assays","pmids":["18322073","17990980","18174467"],"confidence":"High","gaps":["How PDZK1 enables Src/eNOS signaling without affecting SR-BI abundance in endothelium unresolved","Src-SR-BI association shown PDZK1-independent, leaving the coupling step unclear"]},{"year":2009,"claim":"Defined autoregulation by intramolecular head-to-tail self-association and direct NHE3 binding that reconstitutes Ca2+-mediated inhibition, providing a molecular basis for the dynamic NHE3 control seen in KO mice.","evidence":"In vitro and in vivo binding/conformational assays; direct NHE3 binding, FRET, shRNA knockdown and NHE3 transport reconstitution in Caco-2BBe","pmids":["19173579","19535329","19221439"],"confidence":"High","gaps":["Trigger that relieves intramolecular self-association in vivo unknown","Differential NHERF-family roles in CFTR/HCO3- secretion not fully mechanistic"]},{"year":2010,"claim":"Crystal structure of PDZ1 bound to the SR-BI peptide plus mutagenesis revealed the binding chemistry and hinted at a second binding site, and PDZK1 was found necessary for SR-BI-dependent HCV entry.","evidence":"X-ray crystallography of PDZ1-peptide, carboxylate-loop mutagenesis with in vivo KO complementation, ternary complex reconstitution with EBP50/ezrin, HCV infection assays","pmids":["20739281","20237154","20949066","21183661"],"confidence":"High","gaps":["Y20A still partially functional in vivo implied an additional binding site not yet localized","Microvillar shuttling and nuclear localization of PDZK1 not mechanistically explained"]},{"year":2011,"claim":"Identified PDZ3 as the second functional SR-BI binding site and showed differential transporter selectivity (NaPi-2c vs NaPi-2a), resolving the redundancy implied by earlier mutagenesis.","evidence":"ITC, X-ray crystallography of PDZ3-peptide, double-mutant transgene complementation in KO mice, FRET interaction measurements","pmids":["21602281","21388960"],"confidence":"High","gaps":["Why two binding sites of unequal affinity are needed in vivo not defined","Basis of transporter selectivity between near-identical partners unresolved"]},{"year":2012,"claim":"Established PDZK1 as a signaling-complex organizer assembling PLC-β3 with somatostatin receptors to drive Ca2+ and ERK signaling, and linked it to pigmentation biology.","evidence":"Co-IP, yeast two-hybrid, siRNA knockdown, Ca2+ mobilization and ERK1/2 assays; melanocyte/keratinocyte coculture studies","pmids":["22528496","22696060"],"confidence":"Medium","gaps":["Pigmentation findings (idx 36) low-confidence and largely correlative","Direct vs indirect engagement of PLC-β3 within the SSTR complex not fully separated"]},{"year":2013,"claim":"Resolved a noncanonical, lipid-binding role for PDZ4 in anchoring PDZK1 itself to the membrane and defined kinesin-1 recruitment as the mechanism of partner trafficking.","evidence":"Domain replacement transgenic mice, HDX-MS and SPR with lipid vesicles; vesicle isolation from KO liver, motor-protein immunofluorescence, in vitro microtubule motility assays","pmids":["23720744","24115750"],"confidence":"High","gaps":["How PDZK1 biases the kinesin-vs-dynein choice molecularly is unknown","Whether PDZ4 lipid binding is regulated dynamically untested"]},{"year":2014,"claim":"Determined the D-AKAP2:PKA RII:PDZK1 ternary structure showing ordered, polyvalent assembly, and mapped further transporter/receptor partners and NHERF2 heterodimerization that build macrocomplexes.","evidence":"X-ray crystallography of ternary complex with SPR; co-IP, FRET/FRAP, yeast three-hybrid, transport and signaling assays for hIP, OATP1A2, CRFR1/5-HT2AR, NHERF2","pmids":["25348485","21653824","24728453","24867958","25562428"],"confidence":"High","gaps":["Stoichiometry and dynamics of higher-order macrocomplexes in vivo unclear","Receptor-specific PDZ-dependent vs -independent modes (e.g., 5-HT2AR) not structurally explained"]},{"year":2017,"claim":"Extended PDZK1 to tumor-suppressive signaling by showing it disrupts SHP-1/PLCβ3 association to alter Akt/STAT5 signaling and restrain renal carcinoma growth.","evidence":"Overexpression/knockdown in ccRCC lines, co-IP, phospho-protein Western blots, proliferation/migration assays, xenografts","pmids":["28692056"],"confidence":"Medium","gaps":["Direct vs scaffold-mediated effect on SHP-1 phosphorylation not separated","Single-lab xenograft model"]},{"year":2019,"claim":"Defined PDZK1 as a stabilizer of PTEN that suppresses PI3K/AKT and as a renal scaffold for SMCT1/2-URAT1 complexes, broadening both its oncologic and transport-organizing roles.","evidence":"Co-IP and PTEN phospho-Western with proliferation assays and xenografts; yeast two-hybrid, transport assay, in vitro complex assembly, immunohistochemistry for SMCT/URAT1","pmids":["30930234","30604288"],"confidence":"Medium","gaps":["How PDZK1 binding blocks PTEN C-terminal phosphorylation mechanistically unknown","SMCT/URAT1 tri-complex function in vivo untested"]},{"year":2023,"claim":"Demonstrated PDZK1 is required for basolateral trafficking of human OATP1B1 (but not OATP1B3) via PDZ1, confirming human-relevant partner selectivity in hepatic drug uptake.","evidence":"Co-IP from cotransfected 293T cells and human liver, domain-selective co-IP, immunofluorescence with PDZ-motif truncation in HeLa","pmids":["37442606"],"confidence":"High","gaps":["Basis for OATP1B1 vs OATP1B3 discrimination not defined","In vivo consequence for drug disposition not tested"]},{"year":2024,"claim":"Identified non-epithelial roles in mitochondrial homeostasis: PDZK1 limits Hmgcs2 ubiquitination to preserve chondrocyte mitochondrial function and promotes c-Cbl-mediated EGFR degradation to restrain breast cancer.","evidence":"Chondrocyte-specific KO mice with mRNA-seq, ubiquitination and mitochondrial assays and AAV rescue; co-IP, EGFR phospho/ubiquitination assays, xenografts and erlotinib sensitivity","pmids":["39019845","38604999"],"confidence":"Medium","gaps":["How a brush-border scaffold influences Hmgcs2 ubiquitination mechanistically unresolved","Whether EGFR/Hmgcs2 effects involve canonical PDZ binding not established"]},{"year":null,"claim":"How PDZK1 integrates its multivalent, conformationally regulated architecture to dynamically select among dozens of partners and bias trafficking, signaling, or degradation outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking intramolecular self-association and Ser-509 phosphorylation to partner-specific outcomes","Trigger relieving autoinhibition in vivo unknown","Mechanism of kinesin-vs-dynein motor selection undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,7,16,42]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8,16,14,51]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[37]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,10,11,26,49]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[28,38]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[28]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[11,24,38]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[7,8,16,24,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[20,35,39,47]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[11,38,49]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]}],"complexes":["PDZK1/SR-BI complex","D-AKAP2:PKA RII:PDZK1 ternary complex","PLC-β3/SSTR/PDZK1 signaling complex","PDZK1/EBP50/ezrin ternary complex"],"partners":["SCARB1","URAT1","SLC22A5","MAP17","SLCO1A1","NHE3","AKAP10","NHERF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T2W1","full_name":"Na(+)/H(+) exchange regulatory cofactor NHE-RF3","aliases":["CFTR-associated protein of 70 kDa","Na(+)/H(+) exchanger regulatory factor 3","Na/Pi cotransporter C-terminal-associated protein 1","NaPi-Cap1","PDZ domain-containing protein 1","Sodium-hydrogen exchanger regulatory factor 3"],"length_aa":519,"mass_kda":57.1,"function":"A scaffold protein that connects plasma membrane proteins and regulatory components, regulating their surface expression in epithelial cells apical domains. May be involved in the coordination of a diverse range of regulatory processes for ion transport and second messenger cascades. In complex with NHERF1, may cluster proteins that are functionally dependent in a mutual fashion and modulate the trafficking and the activity of the associated membrane proteins. May play a role in the cellular mechanisms associated with multidrug resistance through its interaction with ABCC2 and PDZK1IP1. May potentiate the CFTR chloride channel activity. Required for normal cell-surface expression of SCARB1. Plays a role in maintaining normal plasma cholesterol levels via its effects on SCARB1. Plays a role in the normal localization and function of the chloride-anion exchanger SLC26A6 to the plasma membrane in the brush border of the proximal tubule of the kidney. May be involved in the regulation of proximal tubular Na(+)-dependent inorganic phosphate cotransport therefore playing an important role in tubule function (By similarity)","subcellular_location":"Membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q5T2W1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDZK1","classification":"Not Classified","n_dependent_lines":186,"n_total_lines":1208,"dependency_fraction":0.15397350993377484},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDZK1","total_profiled":1310},"omim":[{"mim_id":"611736","title":"GREB1 PROTEIN","url":"https://www.omim.org/entry/611736"},{"mim_id":"607762","title":"KIRRE-LIKE NEPHRIN FAMILY ADHESION MOLECULE 2; KIRREL2","url":"https://www.omim.org/entry/607762"},{"mim_id":"607761","title":"KIRRE-LIKE NEPHRIN FAMILY 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Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28724612","citation_count":16,"is_preprint":false},{"pmid":"24115750","id":"PMC_24115750","title":"Oatp1a1 requires PDZK1 to traffic to the plasma membrane by selective recruitment of microtubule-based motor proteins.","date":"2013","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/24115750","citation_count":14,"is_preprint":false},{"pmid":"23720744","id":"PMC_23720744","title":"Noncanonical role of the PDZ4 domain of the adaptor protein PDZK1 in the regulation of the hepatic high density lipoprotein receptor scavenger receptor class B, type I (SR-BI).","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23720744","citation_count":14,"is_preprint":false},{"pmid":"28223944","id":"PMC_28223944","title":"IL-1β-Induced Downregulation of the Multifunctional PDZ Adaptor PDZK1 Is Attenuated by ERK Inhibition, RXRα, or PPARα Stimulation in Enterocytes.","date":"2017","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28223944","citation_count":14,"is_preprint":false},{"pmid":"28882822","id":"PMC_28882822","title":"Both NHERF3 and NHERF2 are necessary for multiple aspects of acute regulation of NHE3 by elevated Ca2+, cGMP, and lysophosphatidic acid.","date":"2017","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28882822","citation_count":13,"is_preprint":false},{"pmid":"16054660","id":"PMC_16054660","title":"Interactions between CAP70 and actinfilin are important for integrity of actin cytoskeleton structures in neurons.","date":"2005","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16054660","citation_count":13,"is_preprint":false},{"pmid":"28133487","id":"PMC_28133487","title":"Upregulation of PDZK1 by Calculus Bovis Sativus May Play an Important Role in Restoring Biliary Transport Function in Intrahepatic Cholestasis.","date":"2017","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/28133487","citation_count":12,"is_preprint":false},{"pmid":"38604999","id":"PMC_38604999","title":"PDZK1 suppresses TNBC development and sensitizes TNBC cells to erlotinib via the EGFR pathway.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38604999","citation_count":11,"is_preprint":false},{"pmid":"38158021","id":"PMC_38158021","title":"Downregulation of PDZK1 by TGF-β1 promotes renal fibrosis via inducing epithelial-mesenchymal transition of renal tubular cells.","date":"2023","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38158021","citation_count":11,"is_preprint":false},{"pmid":"26550347","id":"PMC_26550347","title":"Genetic polymorphisms in the PDZK1 gene and susceptibility to gout in male Han Chinese: a case-control study.","date":"2015","source":"International journal of clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26550347","citation_count":11,"is_preprint":false},{"pmid":"26183824","id":"PMC_26183824","title":"Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis.","date":"2015","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26183824","citation_count":11,"is_preprint":false},{"pmid":"18403724","id":"PMC_18403724","title":"Coexpression of CLA-1 and human PDZK1 in murine liver modulates HDL cholesterol metabolism.","date":"2008","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18403724","citation_count":11,"is_preprint":false},{"pmid":"19710538","id":"PMC_19710538","title":"Systematic analysis of a simple adaptor protein PDZK1: ligand identification, interaction and functional prediction of complex.","date":"2009","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19710538","citation_count":11,"is_preprint":false},{"pmid":"38822145","id":"PMC_38822145","title":"PDZK1 confers sensitivity to sunitinib in clear cell renal cell carcinoma by suppressing the PDGFR-β pathway.","date":"2024","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38822145","citation_count":10,"is_preprint":false},{"pmid":"31365292","id":"PMC_31365292","title":"NHERF3 is necessary for Escherichia coli heat-stable enterotoxin-induced inhibition of NHE3: differences in signaling in mouse small intestine and Caco-2 cells.","date":"2019","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31365292","citation_count":10,"is_preprint":false},{"pmid":"36052278","id":"PMC_36052278","title":"HBV Infection-Related PDZK1 Plays an Oncogenic Role by Regulating the PI3K-Akt Pathway and Fatty Acid Metabolism and Enhances Immunosuppression.","date":"2022","source":"Journal of immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/36052278","citation_count":10,"is_preprint":false},{"pmid":"25348485","id":"PMC_25348485","title":"D-AKAP2:PKA RII:PDZK1 ternary complex structure: insights from the nucleation of a polyvalent scaffold.","date":"2014","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/25348485","citation_count":9,"is_preprint":false},{"pmid":"30220543","id":"PMC_30220543","title":"Probing the Architecture of a Multi-PDZ Domain Protein: Structure of PDZK1 in Solution.","date":"2018","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/30220543","citation_count":9,"is_preprint":false},{"pmid":"36420358","id":"PMC_36420358","title":"Mechanism of PDZK1 in Hepatocellular Carcinoma Complicated with Hyperuricemia.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36420358","citation_count":8,"is_preprint":false},{"pmid":"17390218","id":"PMC_17390218","title":"Interaction of carboxyl-terminal peptides of cytosolic-tail of apactin with PDZ domains of NHERF/EBP50 and PDZK-1/CAP70.","date":"2007","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17390218","citation_count":8,"is_preprint":false},{"pmid":"37442606","id":"PMC_37442606","title":"Interaction of Human OATP1B1 with PDZK1 Is Required for Its Trafficking to the Hepatocyte Plasma Membrane.","date":"2023","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/37442606","citation_count":8,"is_preprint":false},{"pmid":"28928085","id":"PMC_28928085","title":"PDZ domain containing protein 1 (PDZK1), a modulator of membrane proteins, is regulated by the nuclear receptor THRβ.","date":"2017","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/28928085","citation_count":8,"is_preprint":false},{"pmid":"23457445","id":"PMC_23457445","title":"Molecular analysis of the prostacyclin receptor's interaction with the PDZ1 domain of its adaptor protein PDZK1.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23457445","citation_count":8,"is_preprint":false},{"pmid":"35066758","id":"PMC_35066758","title":"Roles of circ_0000135/miR-140-3p/PDZK1 network in cervical cancer.","date":"2022","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/35066758","citation_count":6,"is_preprint":false},{"pmid":"35727731","id":"PMC_35727731","title":"PDZK1 Interacting Protein 1 Promotes the Progression of Papillary Thyroid Cancer.","date":"2022","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35727731","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57635,"output_tokens":14021,"usd":0.19161,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25901,"output_tokens":7009,"usd":0.152365,"stage2_stop_reason":"end_turn"},"total_usd":0.343975,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"PDZK1 was identified as a novel PDZ domain-containing protein (519 amino acids, 63 kDa) that binds MAP17 via yeast two-hybrid screening. It is expressed in kidney, pancreas, liver, gastrointestinal tract, and adrenal cortex, and colocalizes with MAP17 in the brush border of proximal tubular epithelial cells.\",\n      \"method\": \"Yeast two-hybrid screening, in situ hybridization, immunolocalization\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid and colocalization, foundational identification paper with multiple methods in one lab\",\n      \"pmids\": [\"9461128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PDZK1 interacts with the carboxy-terminal portion of cMOAT (MRP2), the canalicular multispecific organic anion transporter, as identified by yeast two-hybrid assay.\",\n      \"method\": \"Yeast two-hybrid system\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (yeast two-hybrid), not confirmed by orthogonal biochemical assay in this paper\",\n      \"pmids\": [\"10496535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PDZK1 knockout mice show ~95% reduction of SR-BI protein in liver and 50% reduction in proximal intestine, but no reduction in steroidogenic organs, demonstrating tissue-specific, post-transcriptional control of SR-BI abundance by PDZK1. Loss of hepatic SR-BI caused elevated plasma total and HDL cholesterol and increased HDL particle size.\",\n      \"method\": \"Targeted gene knockout mouse model, Western blot, immunohistochemistry, plasma lipid analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined tissue-specific phenotype, multiple orthogonal methods, replicated across multiple subsequent studies\",\n      \"pmids\": [\"14551195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PDZK1 forms a network in the brush border of renal proximal tubular cells, interacting via its individual PDZ domains with NaPi-IIa, NaPi-I (SLC17A1), NHE-3, OCTN1, CFEX, URAT1, D-AKAP2, and NHERF-1, as determined by yeast two-hybrid screens, pull-down assays, and blot overlays. All identified membrane proteins colocalize with PDZK1 at the brush border.\",\n      \"method\": \"Yeast two-hybrid, pull-down assays, blot overlays, immunohistochemistry\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple interactors confirmed by multiple in vitro methods in one lab, colocalization in native tissue\",\n      \"pmids\": [\"14531806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MAP17 interacts specifically with the fourth PDZ domain of PDZK1 (but not other proximal tubular PDZ proteins), and MAP17 is required for apical localization of PDZK1 in opossum kidney cells, suggesting MAP17 is an apical anchoring site for PDZK1. MAP17 also associates with the NH2 terminus of NaPi-IIa within the PDZK1/NaPi-IIa/MAP17 complex.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays, transfection studies in OK cells, immunofluorescence\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple in vitro and cell-based methods, single lab\",\n      \"pmids\": [\"12837682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The small PDZK1-associated protein SPAP (MAP17/DD96) interacts with PDZK1 in vivo and its hepatic overexpression depletes PDZK1 in liver (in a proteasome-independent manner), which secondarily depletes SR-BI and raises plasma HDL. SPAP regulates PDZK1 turnover.\",\n      \"method\": \"In vivo protein interaction (co-IP), transgenic mouse overexpression, metabolic labeling, proteasome inhibition experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo identification with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"12754212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"D-AKAP2 interacts with PDZK1 via PDZ domain 4, and this interaction anchors PKA to PDZK1 at the subapical pole of proximal tubular cells, potentially enabling PKA-mediated regulation of NaPi-IIa.\",\n      \"method\": \"Yeast two-hybrid, pull-down, co-immunoprecipitation from transfected OK cells, immunohistochemistry\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and pull-down confirmed, colocalization in native tissue, single lab\",\n      \"pmids\": [\"14531807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PDZK1 interacts with URAT1 via URAT1's C-terminal PDZ motif and PDZ domains 1, 2, and 4 of PDZK1 (KD = 1.97–514 nM by surface plasmon resonance). This interaction enhances urate transport Vmax and increases surface expression of URAT1 in HEK293 cells. URAT1 and PDZK1 colocalize at the apical membrane of renal proximal tubular cells.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, surface plasmon resonance, co-immunoprecipitation, transport assay in HEK293 cells, surface biotinylation, immunolocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding with quantitative KD, transport reconstitution, surface expression measurement, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"15304510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PDZK1 directly interacts with OCTN2 via its C-terminal last four amino acids and stimulates carnitine uptake by a 6-fold increase in transport capacity, with minimal effect on cell-surface expression of OCTN2. PDZK1 and OCTN2 colocalize in kidney brush-border membranes. OCTN1 also interacts with PDZK1.\",\n      \"method\": \"Pull-down with recombinant C-terminal proteins, yeast two-hybrid, kidney brush-border membrane vesicle pull-down, immunohistochemistry, transport assay in double-transfected cells, surface biotinylation\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of transport, multiple orthogonal binding assays, deletion mutant confirms specificity\",\n      \"pmids\": [\"15523054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Steady-state NaPi-IIa protein levels are reduced in PDZK1 knockout mice fed a high-phosphate diet, with higher urinary phosphate excretion, but localization of NaPi-IIa and acute regulation by PTH are not altered. Loss of PDZK1 also reduced CFEX/PAT1 abundance but increased NHERF1 in the brush border under high-Pi diet.\",\n      \"method\": \"PDZK1 knockout mice, Western blot, immunohistochemistry, urinary phosphate measurement, in vivo and in vitro PTH stimulation\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotype and multiple readouts, single lab\",\n      \"pmids\": [\"15517343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDZK1 is essential for normal brush-border expression and function of Cl−/anion exchanger CFEX (SLC26A6) in the renal proximal tubule. PDZK1-null mice show markedly reduced CFEX protein expression, reduced Cl−/oxalate exchange activity in brush-border membrane vesicles, and reduced oxalate-stimulated volume absorption. NHE3 brush-border expression is unaffected by loss of PDZK1. CFEX and NHE3 both bind PDZK1 through their C-terminal PDZ-interaction sites in vitro.\",\n      \"method\": \"GST pull-down with native brush-border membrane proteins, Western blot, immunocytochemistry, brush-border membrane vesicle transport assay, microperfused proximal tubule assay in PDZK1-null mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding, in vivo KO phenotype, functional transport assay, multiple orthogonal methods\",\n      \"pmids\": [\"16141316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDZK1 interacts with and is required for hepatocyte surface expression of rat Oatp1a1. In PDZK1 knockout mouse liver, Oatp1a1 protein level is near normal but redistributes to intracellular structures rather than the basolateral plasma membrane, causing delayed plasma disappearance of the Oatp1a1 ligand sulfobromophthalein. Oatp1a1 binds predominantly to the first and third PDZ domains of PDZK1.\",\n      \"method\": \"C-terminal peptide affinity isolation from liver cytosol, mass spectrometry, co-immunoprecipitation from cotransfected 293T cells and native rat liver, PDZK1 KO mouse study, immunofluorescence, in vivo substrate clearance assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo KO phenotype with functional consequence, multiple orthogonal binding/localization assays, mass spectrometry identification\",\n      \"pmids\": [\"15994332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The C-terminal region of PDZK1 is required for upregulating SR-BI protein expression, and PDZK1 is phosphorylated by cAMP-dependent PKA at Ser-509 in this C-terminal region. A Ser-509→Ala mutant loses the ability to upregulate SR-BI. Glucagon administration to rats increases PDZK1 phosphorylation and hepatic SR-BI expression while decreasing plasma HDL.\",\n      \"method\": \"Metabolic labeling, phosphoamino acid analysis, point-mutation analysis, in vitro PKA phosphorylation assay, phospho-Ser-509-specific antibody, in vivo glucagon treatment in rats\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus mutagenesis plus in vivo hormonal regulation, multiple orthogonal methods\",\n      \"pmids\": [\"16174736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDZK1 interacts with SSTR5 at the plasma membrane (as opposed to PIST which retains SSTR5 in the Golgi). Removal of the PDZ ligand motif of SSTR5 does not affect agonist-dependent internalization or Golgi targeting but inhibits recycling of the receptor to the plasma membrane after agonist washout.\",\n      \"method\": \"Yeast two-hybrid, coexpression/colocalization studies, receptor trafficking assays with PDZ-motif deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid and trafficking assays, functional consequence of PDZ-motif deletion, single lab\",\n      \"pmids\": [\"16012170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDZK1 (CAP70) binds to the C-terminal portion of inducible nitric oxide synthase (NOS2) via NOS2's four C-terminal amino acids. This interaction enhances both cytochrome c reductase and NO-synthase activities of NOS2, increases the population of active NOS2 dimers, and participates in correct apical subcellular targeting of NOS2 in polarized cells (dependent also on N-terminal palmitoylation of NOS2).\",\n      \"method\": \"Coimmunoprecipitation, in vitro enzymatic activity assays, dimer analysis, subcellular targeting assays in polarized cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, enzymatic assays, subcellular targeting experiment; single lab\",\n      \"pmids\": [\"17507652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDZK1 interacts with DRA (SLC26A3) at the intestinal brush border via DRA's C-terminal PDZ interaction motif, specifically through PDZK1's 2nd and 3rd PDZ domains. This is distinct from CFTR which interacts with PDZ1, PDZ3, and PDZ4 of PDZK1.\",\n      \"method\": \"Overlay assay with recombinant DRA C-terminus, pull-down, HEK cell co-transfection, immunostaining\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple in vitro methods identifying binding domains, confirmed in transfected cells, single lab\",\n      \"pmids\": [\"15766278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PDZK1 interacts with PEPT2 via PEPT2's C-terminal PDZ motif; the 2nd and 3rd PDZ domains of PDZK1 bind PEPT2-CT (measured by surface plasmon resonance). PDZK1 coexpression increases surface expression of PEPT2 and enhances PEPT2 transport Vmax in HEK293 cells. PEPT2 and PDZK1 interact in native human kidney membrane fractions.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, surface plasmon resonance, co-immunoprecipitation from human kidney membrane fraction, transport assay, surface biotinylation\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro binding, transport reconstitution, native tissue confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"16738539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MAP17 coexpression with NHERF3 (PDZK1) or NHERF4 (but not NHERF1/2) induces internalization of NaPi-IIa, MAP17, and the PDZ protein to the trans-Golgi network (TGN) in a PKC-dependent manner. This cotransfection also prevents the adaptive upregulation of phosphate transport in response to low extracellular phosphate.\",\n      \"method\": \"Bacterial and mammalian two-hybrid, transfection studies in OK cells, immunofluorescence, transport assays, PKC inhibitor experiments\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based trafficking assay with functional transport readout, pharmacological inhibition, single lab\",\n      \"pmids\": [\"16926447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of PDZK1 in murine proximal colonic enterocytes abolishes cAMP-mediated (forskolin) and Ca2+-dependent (ionomycin) inhibition of NHE3 activity without affecting NHE3 abundance or apical localization. NHE3 inhibition by hyperosmolarity is preserved in pdzk1−/− mice, indicating a selective role for PDZK1 in agonist-mediated NHE3 regulation.\",\n      \"method\": \"PDZK1 knockout mouse model, fluorometric NHE3 activity assay in isolated colonic crypts, quantitative PCR, Western blot, immunohistochemistry\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with specific functional readout, multiple assays, defined selectivity of phenotype\",\n      \"pmids\": [\"17395628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In PDZK1-deficient small intestine, basal net Na+ absorption and its inhibition by forskolin are significantly reduced, and a mild reduction in maximal CFTR activation is observed. NHE3 mRNA is increased, suggesting increased NHE3 turnover, possibly due to reduced NHE3 membrane retention.\",\n      \"method\": \"PDZK1 knockout mouse model, short circuit current and ion flux measurements, 22Na+ fluxes, quantitative PCR, Western blot, immunohistochemistry\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO, electrophysiology and flux measurements, single lab\",\n      \"pmids\": [\"17347851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PDZK1 is required for HDL/SR-BI signaling in endothelium: PDZK1 is needed for HDL activation of eNOS and endothelial cell migration, HDL/SR-BI-induced Src phosphorylation, and carotid reendothelialization after injury. PDZK1 does not regulate SR-BI abundance or plasma membrane localization in endothelium or HDL binding or cholesterol efflux. Src co-immunoprecipitates with SR-BI in a PDZK1-independent manner.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, PDZK1−/− mouse model, carotid injury model, eNOS activity assay, cell migration assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO, in vitro and in vivo phenotypes, specific mechanistic distinction from liver (signaling vs. abundance), multiple methods\",\n      \"pmids\": [\"18174467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PDZK1 is required for apical membrane localization of the intestinal mucin MUC17 (mouse Muc3(17)). In Pdzk1−/− mouse jejunum, Muc3(17) shows intracellular rather than brush-border staining. MUC17 C-terminal tail binds to three of four PDZ domains of PDZK1, and strong binding to PDZK1 was confirmed by GST pull-down and PDZ domain array screening.\",\n      \"method\": \"PDZ domain array screening, GST pull-down with mass spectrometry confirmation, immunostaining in Pdzk1−/− and WT mouse jejunum\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo localization in KO mouse, biochemical binding confirmed by MS, multiple methods, single lab\",\n      \"pmids\": [\"17990980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"All four PDZ domains of PDZK1 are required for normal hepatic SR-BI abundance, cell surface localization, and function. Truncation constructs lacking PDZ4 only partially restore SR-BI abundance without restoring cell surface localization. The C-terminal residues of PDZK1 beyond PDZ4 (including the putative PDZ-binding motif) are not required.\",\n      \"method\": \"PDZK1 KO mouse complementation with nested truncation transgenes, Western blot, immunohistochemistry, plasma cholesterol analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic domain truncation in vivo, multiple transgenes tested, functional readout, replicated across constructs\",\n      \"pmids\": [\"19116202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Overexpression of only the PDZ1 domain of PDZK1 in wild-type mice dominantly reduces hepatic SR-BI protein by 75% and causes intracellular mislocalization of SR-BI, resulting in hypercholesterolemia. Full-length PDZK1 is required to restore normal SR-BI function in PDZK1 KO mice, while PDZ1 alone only partially restores SR-BI protein abundance without restoring cell surface expression.\",\n      \"method\": \"Liver-specific transgenic overexpression of PDZ1 domain and full-length PDZK1, Western blot, immunohistochemistry, plasma lipoprotein analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant-negative in vivo approach with defined molecular and functional phenotypes, complementary KO rescue experiment\",\n      \"pmids\": [\"18544532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PDZK1 regulates intestinal solute carriers PEPT1 (Slc15a1) and OCTN2 (Slc22a5) in vivo. In pdzk1−/− mice, apical membrane localization of both transporters is reduced, their protein levels in brush-border membranes decrease, and PEPT1 localizes to intracellular vesicles. PDZK1 physically interacts with PEPT1 in mouse small intestine, and PDZK1 coexpression stimulates PEPT1 transport activity by increasing its expression level. GI absorption of cephalexin and carnitine are reduced in pdzk1−/− mice.\",\n      \"method\": \"PDZK1 KO mouse model, oral pharmacokinetics, immunohistochemistry, electron microscopy, Western blot, immunoprecipitation, transport assay in HEK293 cells\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO phenotype with functional absorption readout, direct interaction confirmed, transport reconstitution, multiple orthogonal methods\",\n      \"pmids\": [\"18322073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PDZK1 undergoes an intramolecular head-to-tail self-association where the C-terminal tail interacts with the first PDZ domain. This intramolecular interaction causes a more compact conformation and negatively regulates the interaction of PDZK1's tail with the PDZ domains of EBP50/NHERF1. PDZK1 also undergoes modest homodimerization through its third PDZ domain. These interactions differ from the related scaffold EBP50 where intramolecular association regulates binding to PDZ domain ligands.\",\n      \"method\": \"In vitro binding assays, in vivo co-IP, biochemical characterization of self-association, conformational analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vitro and in vivo characterization of self-association with functional consequence, single lab\",\n      \"pmids\": [\"19173579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NHERF3 (PDZK1) directly binds NHE3 C-terminus (amino acids 588–667) in vitro, colocalizes with NHE3 at the plasma membrane under basal conditions, and reconstitutes Ca2+-mediated inhibition of NHE3 activity. Elevated [Ca2+]i dissociates NHERF3 from NHE3, decreases NHE3 surface amount, and reduces NHE3 Vmax. NHERF3 shRNA knockdown in Caco-2BBe cells reduces basal NHE3 activity and brush-border NHE3 amount.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, confocal microscopy, FRET, shRNA knockdown, fluorometric NHE3 activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, functional reconstitution with NHERF3, multiple orthogonal methods (FRET, co-IP, transport assay, KD), single lab\",\n      \"pmids\": [\"19535329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Pdzk1 ablation reduces basal but not FSK-stimulated duodenal HCO3− secretion in mice, while Nherf1 ablation strongly reduces both basal and FSK-stimulated secretion and blocks beta2-AR stimulation of CFTR. These data demonstrate differential roles of NHERF family members in CFTR regulation in vivo.\",\n      \"method\": \"Nherf1/Nherf2/Pdzk1 knockout mouse models, duodenal HCO3− secretion measurement, laser microdissection, quantitative PCR\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three separate KO mouse models, direct secretory measurement, replicated specificity by comparison\",\n      \"pmids\": [\"19221439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDZK1 forms a regulated ternary complex with EBP50 and ezrin in vitro and in vivo. Complex formation is cooperative — ezrin positively influences the PDZK1/EBP50 interaction, and EBP50 PDZ domain occupancy enhances PDZK1 binding. PDZK1 shuttles from the nucleus (low confluence) to microvilli (high confluence), and when localized to microvilli can substitute for EBP50 in rescuing microvillar organization after EBP50 knockdown.\",\n      \"method\": \"In vitro ternary complex reconstitution, in vivo co-IP, live imaging of PDZK1 localization, EBP50 knockdown and rescue, confocal microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of ternary complex, in vivo validation, functional rescue experiment, multiple methods\",\n      \"pmids\": [\"20237154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDZK1 binding is required for optimal cell surface expression of Oatp1a1, while serine phosphorylation of Oatp1a1 at S634/S635 (upstream of the PDZ motif) regulates the balance between surface and intracellular pools. Phosphomimetic (EE) mutant internalizes rapidly; non-phosphorylatable (AA) mutant is retained at the surface by PDZK1. Extracellular ATP-stimulated phosphorylation in rat hepatocytes causes rapid Oatp1a1 internalization.\",\n      \"method\": \"Site-directed mutagenesis, surface biotinylation internalization assay, cotransfection with PDZK1, primary hepatocyte experiments with purinergic receptor stimulation\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus functional trafficking assay plus physiological stimulus, single lab\",\n      \"pmids\": [\"21183661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDZK1 is required for SR-BI-dependent HCV entry into hepatocytes. shRNA knockdown of PDZK1 reduces susceptibility to HCV infection, which is reversed by full-length PDZK1 but not the PDZ1 domain alone. Overexpression of SR-BI C-terminal cytoplasmic tail competes with endogenous PDZK1 and reduces HCV infection, only if the tail can interact with PDZK1.\",\n      \"method\": \"shRNA knockdown in hepatoma cells, HCV infection assay, overexpression of SR-BI cytoplasmic tail constructs, co-immunoprecipitation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA KD with specific rescue and dominant-negative competition, functional infection readout, single lab\",\n      \"pmids\": [\"20949066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of PDZK1 PDZ1 bound to the 5-residue C-terminal SR-BI peptide (QEAKL) was solved by X-ray crystallography. Y20A and G21Y substitutions in the carboxylate-binding loop abrogate all binding; K14A and F22A substitutions do not significantly change binding affinity. The Y20A mutant at 10–20-fold overexpression still partially corrects SR-BI defects in PDZK1 KO mice, suggesting an additional binding site within PDZK1.\",\n      \"method\": \"X-ray crystallography (PDZ1–peptide complex), in vitro binding affinity measurements, mutagenesis in full-length PDZK1 transgenes, in vivo PDZK1 KO mouse complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus in vivo functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"20739281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDZK1 is required for the stabilization of NaPi-2c (but not NaPi-2a) in the apical membrane of renal proximal tubules. FRET measurements show a stronger NHERF-1/NaPi-2a interaction than NHERF-1/NaPi-2c, while both NaPi-2c and NaPi-2a have similar FRET efficiencies with PDZK1. In pdzk1−/− mice on low-Pi diet, NaPi-2a is upregulated but NaPi-2c is not.\",\n      \"method\": \"PDZK1 KO mouse model, FRET in live cells, Western blot, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO plus FRET quantification of differential interactions, single lab\",\n      \"pmids\": [\"21388960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDZ3 of PDZK1 is a second functional binding site for the C-terminal SR-BI peptide (KD = 37.0 µM by ITC, ~10-fold lower affinity than PDZ1). PDZ3 binding is abrogated by Y253A mutation. A double PDZ1(Y20A)+PDZ3(Y253A) substitution abrogates all SR-BI binding and cannot correct SR-BI defects in PDZK1 KO mice, whereas the single PDZ3(Y253A) substitution fully corrects. Crystal structure of PDZ3-peptide complex determined at 1.5 Å.\",\n      \"method\": \"Isothermal titration calorimetry, X-ray crystallography (PDZ3–peptide complex), mutagenesis in transgenes, in vivo PDZK1 KO mouse complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, quantitative binding, in vivo functional rescue, systematic mutagenesis\",\n      \"pmids\": [\"21602281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDZK1 physically interacts with BCRP (breast cancer resistance protein) and promotes its apical membrane localization in small intestinal enterocytes. In pdzk1−/− mice, BCRP expression is reduced in brush-border membranes. PDZK1 coexpression in MDCK cells increases transcellular BCRP-mediated transport of cimetidine and enhances resistance to SN-38.\",\n      \"method\": \"PDZK1 KO mouse model, Western blot, immunohistochemistry, pull-down, immunoprecipitation, transcellular transport assay, cytotoxicity assay\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction confirmed, in vivo KO phenotype, functional transport reconstitution, multiple orthogonal methods\",\n      \"pmids\": [\"21816982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDZK1 forms a ternary complex with PLC-β3 and somatostatin receptors (SSTRs). PDZK1 specifically interacts with PLC-β3 (not PLC-β1) and with SSTRs. PDZK1-mediated complex formation is required for SST-induced PLC-β3 activation, intracellular Ca2+ mobilization, and subsequent ERK1/2 phosphorylation. PDZK1 knockdown abolishes these SST-induced responses.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid screening, siRNA knockdown, Ca2+ mobilization assay, ERK1/2 phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of ternary complex, functional knockdown with specific signaling readouts, single lab\",\n      \"pmids\": [\"22528496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDZK1 upregulation in melanocytes increases tyrosinase expression and melanosome transfer to keratinocytes, while PDZK1 knockdown reduces estrogen-induced tyrosinase expression through regulation of estrogen receptor (ER-α and ER-β) expression. PDZK1-induced melanosome transfer involves phosphorylation of ERM proteins and Rac1, but not PAR-2, and is regulated by NHE, CFTR, and SLC26A3 ion transporters.\",\n      \"method\": \"Monocultures and cocultures of melanocytes/keratinocytes, PDZK1 overexpression and knockdown, biopsied skin specimens, Western blot\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression/knockdown phenotype, indirect mechanistic inference\",\n      \"pmids\": [\"22696060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PDZ4 domain of PDZK1 is necessary for hepatocyte cell-surface localization of PDZK1 in vivo (dependent on both PDZ4 and presence of SR-BI). PDZ4 does not bind the SR-BI target peptide canonically but binds phospholipid vesicles mimicking the plasma membrane by surface plasmon resonance, suggesting a noncanonical lipid-mediated membrane attachment role. Neither PDZ2, PDZ3, nor canonical peptide-binding activity of PDZ4 is necessary for SR-BI regulation.\",\n      \"method\": \"Domain deletion/replacement transgenic mice, immunohistochemistry, analytical ultracentrifugation, hydrogen-deuterium exchange mass spectrometry, surface plasmon resonance with lipid vesicles\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic in vivo domain analysis, biophysical characterization including HDX-MS and SPR with lipid vesicles, multiple orthogonal methods\",\n      \"pmids\": [\"23720744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PDZK1 is required for trafficking of Oatp1a1 to the plasma membrane via selective recruitment of kinesin-1 (plus-end microtubule motor) to Oatp1a1-containing vesicles. In PDZK1 KO mice, Oatp1a1 vesicles instead recruit dynein (minus-end motor) and move predominantly toward the cell interior, resulting in intracellular accumulation.\",\n      \"method\": \"Vesicle isolation from WT and PDZK1 KO mouse liver, immunofluorescence for motor proteins on vesicles, in vitro microtubule motility assays with directionally marked microtubules\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro motility assay with defined directional readout, in vivo KO-derived vesicles, single lab\",\n      \"pmids\": [\"24115750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDZK1 interacts with the prostacyclin receptor (hIP) via a Class I PDZ ligand at hIP's C-terminus and PDZ domains 1, 3, and 4 of PDZK1. This interaction increases hIP cell surface expression and enhances cAMP generation. PDZK1 is required for cicaprost-induced endothelial cell migration and tube formation; siRNA knockdown of PDZK1 abolishes these effects but does not affect VEGF responses. PDZK1 phosphorylation at Ser-505 by PKA may dynamically regulate the interaction.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, cell migration assay, tube formation assay, cAMP assay, ligand binding assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, siRNA with specific functional readouts, multiple methods, single lab\",\n      \"pmids\": [\"21653824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NHERF2 and NHERF3 (PDZK1) heterodimerize as the strongest NHERF-NHERF interaction, mediated by PDZ domains of NHERF2 and the C-terminal PDZ recognition motif of NHERF3. This heterodimerization is required for carbachol-mediated inhibition of NHE3 and allows simultaneous occupancy of NHERF2 PDZ domains by NHERF3 and another ligand (NHE3, α-actinin-4, or PKCα), forming NHE3 macrocomplexes.\",\n      \"method\": \"Pull-down, co-immunoprecipitation, FRET, FRAP, yeast three-hybrid, mutagenesis of NHERF3 C-terminal motif\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal interaction assays including FRET/FRAP, mutagenesis defining interaction domain, functional consequence, single lab\",\n      \"pmids\": [\"24867958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDZK1 interacts with OATP1A2 via the C-terminal PDZ-binding domain and increases OATP1A2 transport Vmax by increasing plasma membrane expression, reducing clathrin-dependent (but not caveolin-dependent) internalization, and enhancing protein stability. NHERF1 has similar effects.\",\n      \"method\": \"Co-immunoprecipitation, transport assay in HEK-293 cells, surface biotinylation, clathrin/caveolin pathway inhibitors, protein stability assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed, mechanistic pathway dissection, multiple methods, single lab\",\n      \"pmids\": [\"24728453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the D-AKAP2:PKA RII:PDZK1 ternary complex was determined. D-AKAP2 presents a disordered segment that adopts an α-helix to bind PKA RII and a β-strand to bind PDZK1's PDZ domain, nucleating a polyvalent scaffold. D-AKAP2:PKA binary complex formation is an important first step for high-affinity interaction with PDZK1, and the PDZK1 PDZ domain serves as a bridge between the kinase and membrane transporters.\",\n      \"method\": \"X-ray crystallography of ternary complex, surface plasmon resonance, biochemical binding assays\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of ternary complex, quantitative binding analysis, mechanistic insight into ordered complex assembly\",\n      \"pmids\": [\"25348485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDZK1 differentially regulates CRFR1 and 5-HT2AR: it interacts with CRFR1 in a PDZ-binding motif-dependent manner (redistributing PDZK1 to the plasma membrane) and with 5-HT2AR in a PDZ-binding motif-independent manner. PDZK1 selectively increases CRFR1-stimulated ERK1/2 phosphorylation but not cAMP signaling; it inhibits 5-HT2AR endocytosis and positively influences 5-HT2AR-stimulated inositol phosphate formation. PDZK1 has no effect on CRFR1 endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ERK1/2 and cAMP signaling assays, internalization assays, inositol phosphate assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and siRNA with multiple functional readouts distinguishing PDZ-dependent and independent mechanisms, single lab\",\n      \"pmids\": [\"25562428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PDZK1 inhibits renal cell carcinoma cell proliferation by suppressing SHP-1 phosphorylation at Tyr536. PDZK1 blocks the association between SHP-1 and PLCβ3, thereby preventing SHP-1 phosphorylation, which retards Akt phosphorylation and promotes STAT5 phosphorylation. These effects are validated in xenograft tumor studies.\",\n      \"method\": \"PDZK1 overexpression/knockdown in ccRCC cell lines, co-immunoprecipitation, Western blot for phospho-proteins, cell proliferation and migration assays, xenograft tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP defining complex disruption, phosphorylation readouts, in vivo xenograft, single lab\",\n      \"pmids\": [\"28692056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PDZK1 interacts with OATP2B1 via the C-terminal PDZ-binding motif of OATP2B1 and increases OATP2B1 transport capacity (enhanced estrone 3-sulfate uptake) by increasing OATP2B1 membrane expression. Deletion of the C-terminal PDZ-binding motif reduces the effect of PDZK1.\",\n      \"method\": \"Co-expression and transport assay in HEK cells, Western blot for membrane fractions, C-terminal deletion mutant\",\n      \"journal\": \"European journal of pharmaceutical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-expression transport assay and Western blot only, no co-IP confirmation\",\n      \"pmids\": [\"29752999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Full-length PDZK1 adopts an extended, asymmetric L-shaped domain organization in solution (not a flexible beads-on-string arrangement) as determined by small-angle X-ray scattering with hybrid modeling. The linker regions between PDZ domains play a central role in the spatial arrangement of the four domains. This architecture influences binding properties to membrane protein partners.\",\n      \"method\": \"Small-angle X-ray scattering (SAXS), deletion construct analysis, biochemical binding assays, hybrid modeling\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination with multiple deletion constructs and functional binding assays, systematic study\",\n      \"pmids\": [\"30220543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDZK1 identifies PTEN as a binding partner through PTEN's carboxyl terminus and PDZK1's PDZ domains. Direct interaction with PTEN inhibits PTEN phosphorylation at S380/T382/T383, enhancing PTEN's capacity to suppress PI3K/AKT activation, thereby inhibiting gastric cancer cell proliferation in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for PTEN phosphorylation, in vitro cell proliferation assay, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction identified, phosphorylation readout with functional consequence, in vivo xenograft, single lab\",\n      \"pmids\": [\"30930234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDZK1 is identified as a binding partner of SMCT1 and SMCT2 by yeast two-hybrid screen of a human kidney cDNA library. PDZK1 coexpression enhances nicotinate transport activity of SMCT1. PDZK1, SMCT1, and URAT1 form a tri-molecular complex in vitro and colocalize in renal proximal tubule in vivo.\",\n      \"method\": \"Yeast two-hybrid, transport assay in HEK293 cells, in vitro complex assembly, immunohistochemistry\",\n      \"journal\": \"The journal of physiological sciences : JPS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus transport assay plus in vitro complex, colocalization in native tissue, single lab\",\n      \"pmids\": [\"30604288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human OATP1B1 (but not OATP1B3) interacts with human PDZK1 via its PDZ-binding consensus motif at the C-terminus and PDZ domain 1 of PDZK1. Interaction with PDZK1 is required for OATP1B1 trafficking to the basolateral plasma membrane; truncation of the PDZ-binding motif results in predominantly intracellular localization.\",\n      \"method\": \"Co-immunoprecipitation from cotransfected 293T cells and normal human liver, domain-selective co-IP with individual PDZ domains, immunofluorescence in stably transfected HeLa cells with truncation mutant\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP from native human liver, domain specificity mapped, mutagenesis of PDZ motif with localization consequence, replicated in two cell systems\",\n      \"pmids\": [\"37442606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDZK1 loss in chondrocytes impairs mitochondrial function (decreased mtDNA content, increased ROS, accumulated damaged mitochondria) and induces chondrocyte senescence and cartilage degeneration. PDZK1 deficiency increases ubiquitination of Hmgcs2, suppressing its expression and thereby impairing mitochondrial function. Intra-articular AAV-PDZK1 rescues these defects.\",\n      \"method\": \"Pdzk1 chondrocyte-specific KO mouse model, mRNA sequencing, ubiquitination assay, mitochondrial function assays (ROS, mtDNA, membrane potential), in vivo AAV rescue, OA patient specimens\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with mechanistic pathway identification (Hmgcs2 ubiquitination), in vivo rescue, multiple functional readouts, single lab\",\n      \"pmids\": [\"39019845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDZK1 binds to EGFR and promotes EGFR degradation by enhancing EGFR binding to c-Cbl, while also inhibiting EGFR phosphorylation by hindering EGFR dimerization. These mechanisms suppress TNBC cell proliferation and sensitize TNBC cells to erlotinib in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for EGFR phosphorylation and ubiquitination, PDZK1 overexpression/knockdown, xenograft tumor model, erlotinib sensitivity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP defining interaction, functional mechanistic readouts (c-Cbl recruitment, dimerization inhibition), in vivo xenograft, single lab\",\n      \"pmids\": [\"38604999\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDZK1 is a multi-PDZ domain scaffold protein (with an extended L-shaped architecture) that localizes to apical brush borders and other plasma membranes in epithelial cells, where it directly binds the C-terminal PDZ motifs of a broad array of membrane transporters and receptors (including SR-BI, URAT1, OCTN2, PEPT1/2, NHE3, CFEX, Oatp1a1/1b1, BCRP, OATP1A2/2B1, OATP2B1, SMCT1/2, MUC17, prostacyclin receptor, somatostatin receptor, and EGFR) through canonical PDZ-domain interactions (primarily at PDZ1 and PDZ3, with PDZ4 providing noncanonical membrane attachment via lipid binding), thereby stabilizing these proteins at the plasma membrane, directing their intracellular trafficking (via selective recruitment of kinesin-1 over dynein), and modulating their activity; additionally, PDZK1 acts as a signaling scaffold by assembling ternary signaling complexes (e.g., PLC-β3/SSTRs, D-AKAP2/PKA) and mediating receptor-initiated signaling cascades (HDL/SR-BI→Src→eNOS in endothelium; PTEN dephosphorylation suppressing PI3K/AKT; SHP-1 phosphorylation control), and its own activity is regulated post-translationally by PKA phosphorylation at Ser-509, intramolecular head-to-tail self-association, and proteasome-dependent and -independent turnover.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDZK1 is a four-PDZ-domain scaffold protein of epithelial apical brush borders and other plasma membranes that organizes membrane transporters, receptors, and signaling enzymes into functional complexes [#0, #3]. Through canonical PDZ interactions with the C-terminal motifs of partner proteins, it stabilizes a broad array of solute carriers and receptors at the cell surface, directs their trafficking, and tunes their transport activity: it controls hepatic and intestinal SR-BI abundance and thereby plasma HDL cholesterol [#2], enhances urate, carnitine, and peptide transport by URAT1, OCTN2, and PEPT1/2 [#7, #8, #16, #24], maintains apical CFEX/SLC26A6 and NaPi-2c [#10, #32], and is required for membrane delivery of Oatp1a1, OATP1B1, BCRP, OATP1A2/2B1, and MUC17 [#11, #49, #34, #41, #45, #21]. Mechanistically, PDZK1 governs trafficking by selectively recruiting the plus-end motor kinesin-1 rather than dynein to transporter-containing vesicles [#38], and it controls agonist-mediated regulation of NHE3 by cAMP and Ca2+ rather than basal NHE3 abundance [#18, #26]. Structural work shows the protein adopts an extended, asymmetric L-shaped architecture in solution [#46], with PDZ1 and PDZ3 providing two functional binding sites for the SR-BI tail [#31, #33] and PDZ4 contributing a noncanonical lipid-mediated membrane attachment required for PDZK1's own surface localization [#37]. Beyond transporter scaffolding, PDZK1 acts as a signaling platform: it is required for HDL/SR-BI activation of Src and eNOS in endothelium [#20], assembles ternary complexes with PLC-\\u03b23/somatostatin receptors and with D-AKAP2/PKA [#35, #42], and modulates oncogenic signaling by stabilizing PTEN to suppress PI3K/AKT and by promoting c-Cbl-dependent EGFR degradation [#47, #51]. Its activity is regulated post-translationally by PKA phosphorylation at Ser-509, by an intramolecular head-to-tail self-association involving PDZ1, and by MAP17/SPAP-controlled turnover [#12, #25, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established PDZK1 as a multi-PDZ scaffold of epithelial brush borders, defining its tissue distribution and first binding partner before any function was known.\",\n      \"evidence\": \"Yeast two-hybrid identification via MAP17, in situ hybridization and immunolocalization in epithelial tissues\",\n      \"pmids\": [\"9461128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of the MAP17 interaction defined\", \"Binding not validated biochemically beyond yeast two-hybrid\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Knockout mice showed PDZK1 post-transcriptionally controls SR-BI protein abundance in a tissue-specific manner, linking the scaffold to HDL cholesterol metabolism.\",\n      \"evidence\": \"Targeted Pdzk1 KO mouse, Western blot, immunohistochemistry, plasma lipid analysis\",\n      \"pmids\": [\"14551195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of SR-BI stabilization not resolved\", \"Did not explain tissue specificity (liver/intestine vs steroidogenic organs)\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped PDZK1 as a hub of a renal brush-border transporter network and identified MAP17 as its apical anchor and D-AKAP2/PKA as a recruited kinase, framing PDZK1 as both organizer and signaling platform.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down, blot overlay, co-IP and immunohistochemistry in renal/OK cell systems\",\n      \"pmids\": [\"14531806\", \"12837682\", \"14531807\", \"12754212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many interactions defined only in vitro or by colocalization\", \"Functional consequences for individual transporters not yet measured\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Quantitative binding and transport reconstitution showed PDZK1 directly enhances transporter activity, not merely localization, establishing a causal scaffold-to-function link for URAT1 and OCTN2.\",\n      \"evidence\": \"Surface plasmon resonance KD measurement, co-IP, surface biotinylation, transport assays in HEK293 cells\",\n      \"pmids\": [\"15304510\", \"15523054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How surface stabilization vs intrinsic activity contributes differs between partners and was not fully separated\", \"In vivo relevance to urate/carnitine handling not yet tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"In vivo KO studies extended the scaffold role to NaPi-IIa, CFEX, and basolateral Oatp1a1, revealing partner-specific outcomes from abundance loss to mistrafficking.\",\n      \"evidence\": \"Pdzk1 KO mice, brush-border membrane vesicle transport assays, microperfusion, peptide-affinity isolation with mass spectrometry, immunofluorescence\",\n      \"pmids\": [\"15517343\", \"16141316\", \"15994332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinct fates of partners (degradation vs intracellular retention) mechanistically unexplained\", \"NHE3 found unaffected, raising selectivity questions\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified PKA phosphorylation at Ser-509 as a regulatory switch coupling hormonal (glucagon) signaling to PDZK1-dependent SR-BI expression.\",\n      \"evidence\": \"Metabolic labeling, phosphoamino acid analysis, S509A mutagenesis, in vitro PKA assay, phospho-specific antibody, in vivo glucagon treatment\",\n      \"pmids\": [\"16174736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which Ser-509 phosphorylation alters scaffold function not defined\", \"Generality to other partners untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed PDZK1 controls receptor recycling and enzyme activity, broadening it from transporter scaffold to a regulator of GPCR trafficking (SSTR5) and NOS2 catalysis.\",\n      \"evidence\": \"Yeast two-hybrid, colocalization/trafficking assays with PDZ-motif deletions, co-IP, in vitro enzymatic and dimer assays\",\n      \"pmids\": [\"16012170\", \"17507652\", \"15766278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NOS2 enzymatic enhancement not confirmed in vivo\", \"DRA/CFTR domain assignments not functionally tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"KO physiology established that PDZK1 is required specifically for agonist-mediated (cAMP/Ca2+) regulation of NHE3 rather than its basal expression, refining its role to dynamic signaling control of ion transport.\",\n      \"evidence\": \"Pdzk1 KO mice, fluorometric NHE3 activity in colonic crypts, short-circuit current and ion flux measurements\",\n      \"pmids\": [\"17395628\", \"17347851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between PDZK1 and the second-messenger machinery not defined\", \"Whether NHE3 directly or indirectly engaged in vivo unresolved at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Domain-dissection and dominant-negative experiments in vivo established that all four PDZ domains contribute to SR-BI regulation and that an isolated PDZ1 acts dominant-negatively, defining the multivalent logic of the scaffold.\",\n      \"evidence\": \"Nested truncation and PDZ1-only transgenes in WT and Pdzk1 KO mice, Western blot, immunohistochemistry, plasma lipoprotein analysis\",\n      \"pmids\": [\"19116202\", \"18544532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why surface localization needs more than abundance restoration not mechanistically explained\", \"Role of individual domains in other partners not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended in vivo scaffold function to intestinal transport (PEPT1, OCTN2, MUC17) and CFTR-related secretion and to endothelial HDL/SR-BI signaling, separating a signaling role (eNOS/Src activation) from abundance control.\",\n      \"evidence\": \"Pdzk1 KO mice, oral pharmacokinetics, immunohistochemistry/EM, co-IP, carotid injury model, eNOS and migration assays\",\n      \"pmids\": [\"18322073\", \"17990980\", \"18174467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PDZK1 enables Src/eNOS signaling without affecting SR-BI abundance in endothelium unresolved\", \"Src-SR-BI association shown PDZK1-independent, leaving the coupling step unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined autoregulation by intramolecular head-to-tail self-association and direct NHE3 binding that reconstitutes Ca2+-mediated inhibition, providing a molecular basis for the dynamic NHE3 control seen in KO mice.\",\n      \"evidence\": \"In vitro and in vivo binding/conformational assays; direct NHE3 binding, FRET, shRNA knockdown and NHE3 transport reconstitution in Caco-2BBe\",\n      \"pmids\": [\"19173579\", \"19535329\", \"19221439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that relieves intramolecular self-association in vivo unknown\", \"Differential NHERF-family roles in CFTR/HCO3- secretion not fully mechanistic\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Crystal structure of PDZ1 bound to the SR-BI peptide plus mutagenesis revealed the binding chemistry and hinted at a second binding site, and PDZK1 was found necessary for SR-BI-dependent HCV entry.\",\n      \"evidence\": \"X-ray crystallography of PDZ1-peptide, carboxylate-loop mutagenesis with in vivo KO complementation, ternary complex reconstitution with EBP50/ezrin, HCV infection assays\",\n      \"pmids\": [\"20739281\", \"20237154\", \"20949066\", \"21183661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Y20A still partially functional in vivo implied an additional binding site not yet localized\", \"Microvillar shuttling and nuclear localization of PDZK1 not mechanistically explained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified PDZ3 as the second functional SR-BI binding site and showed differential transporter selectivity (NaPi-2c vs NaPi-2a), resolving the redundancy implied by earlier mutagenesis.\",\n      \"evidence\": \"ITC, X-ray crystallography of PDZ3-peptide, double-mutant transgene complementation in KO mice, FRET interaction measurements\",\n      \"pmids\": [\"21602281\", \"21388960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why two binding sites of unequal affinity are needed in vivo not defined\", \"Basis of transporter selectivity between near-identical partners unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established PDZK1 as a signaling-complex organizer assembling PLC-\\u03b23 with somatostatin receptors to drive Ca2+ and ERK signaling, and linked it to pigmentation biology.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, siRNA knockdown, Ca2+ mobilization and ERK1/2 assays; melanocyte/keratinocyte coculture studies\",\n      \"pmids\": [\"22528496\", \"22696060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pigmentation findings (idx 36) low-confidence and largely correlative\", \"Direct vs indirect engagement of PLC-\\u03b23 within the SSTR complex not fully separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved a noncanonical, lipid-binding role for PDZ4 in anchoring PDZK1 itself to the membrane and defined kinesin-1 recruitment as the mechanism of partner trafficking.\",\n      \"evidence\": \"Domain replacement transgenic mice, HDX-MS and SPR with lipid vesicles; vesicle isolation from KO liver, motor-protein immunofluorescence, in vitro microtubule motility assays\",\n      \"pmids\": [\"23720744\", \"24115750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PDZK1 biases the kinesin-vs-dynein choice molecularly is unknown\", \"Whether PDZ4 lipid binding is regulated dynamically untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Determined the D-AKAP2:PKA RII:PDZK1 ternary structure showing ordered, polyvalent assembly, and mapped further transporter/receptor partners and NHERF2 heterodimerization that build macrocomplexes.\",\n      \"evidence\": \"X-ray crystallography of ternary complex with SPR; co-IP, FRET/FRAP, yeast three-hybrid, transport and signaling assays for hIP, OATP1A2, CRFR1/5-HT2AR, NHERF2\",\n      \"pmids\": [\"25348485\", \"21653824\", \"24728453\", \"24867958\", \"25562428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of higher-order macrocomplexes in vivo unclear\", \"Receptor-specific PDZ-dependent vs -independent modes (e.g., 5-HT2AR) not structurally explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended PDZK1 to tumor-suppressive signaling by showing it disrupts SHP-1/PLC\\u03b23 association to alter Akt/STAT5 signaling and restrain renal carcinoma growth.\",\n      \"evidence\": \"Overexpression/knockdown in ccRCC lines, co-IP, phospho-protein Western blots, proliferation/migration assays, xenografts\",\n      \"pmids\": [\"28692056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffold-mediated effect on SHP-1 phosphorylation not separated\", \"Single-lab xenograft model\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined PDZK1 as a stabilizer of PTEN that suppresses PI3K/AKT and as a renal scaffold for SMCT1/2-URAT1 complexes, broadening both its oncologic and transport-organizing roles.\",\n      \"evidence\": \"Co-IP and PTEN phospho-Western with proliferation assays and xenografts; yeast two-hybrid, transport assay, in vitro complex assembly, immunohistochemistry for SMCT/URAT1\",\n      \"pmids\": [\"30930234\", \"30604288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PDZK1 binding blocks PTEN C-terminal phosphorylation mechanistically unknown\", \"SMCT/URAT1 tri-complex function in vivo untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated PDZK1 is required for basolateral trafficking of human OATP1B1 (but not OATP1B3) via PDZ1, confirming human-relevant partner selectivity in hepatic drug uptake.\",\n      \"evidence\": \"Co-IP from cotransfected 293T cells and human liver, domain-selective co-IP, immunofluorescence with PDZ-motif truncation in HeLa\",\n      \"pmids\": [\"37442606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis for OATP1B1 vs OATP1B3 discrimination not defined\", \"In vivo consequence for drug disposition not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified non-epithelial roles in mitochondrial homeostasis: PDZK1 limits Hmgcs2 ubiquitination to preserve chondrocyte mitochondrial function and promotes c-Cbl-mediated EGFR degradation to restrain breast cancer.\",\n      \"evidence\": \"Chondrocyte-specific KO mice with mRNA-seq, ubiquitination and mitochondrial assays and AAV rescue; co-IP, EGFR phospho/ubiquitination assays, xenografts and erlotinib sensitivity\",\n      \"pmids\": [\"39019845\", \"38604999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a brush-border scaffold influences Hmgcs2 ubiquitination mechanistically unresolved\", \"Whether EGFR/Hmgcs2 effects involve canonical PDZ binding not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PDZK1 integrates its multivalent, conformationally regulated architecture to dynamically select among dozens of partners and bias trafficking, signaling, or degradation outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking intramolecular self-association and Ser-509 phosphorylation to partner-specific outcomes\", \"Trigger relieving autoinhibition in vivo unknown\", \"Mechanism of kinesin-vs-dynein motor selection undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 7, 16, 42]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8, 16, 14, 51]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 10, 11, 26, 49]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [28, 38]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [11, 24, 38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009609\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [7, 8, 16, 24, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [20, 35, 39, 47]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [11, 38, 49]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"PDZK1/SR-BI complex\",\n      \"D-AKAP2:PKA RII:PDZK1 ternary complex\",\n      \"PLC-\\u03b23/SSTR/PDZK1 signaling complex\",\n      \"PDZK1/EBP50/ezrin ternary complex\"\n    ],\n    \"partners\": [\n      \"SCARB1\",\n      \"URAT1\",\n      \"SLC22A5\",\n      \"MAP17\",\n      \"SLCO1A1\",\n      \"NHE3\",\n      \"AKAP10\",\n      \"NHERF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}