{"gene":"MPDZ","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1998,"finding":"MPDZ/MUPP1 was identified as a novel protein containing 13 PDZ domains that interacts with the C-terminal domain of the 5-HT2C serotonin receptor, identified via yeast two-hybrid screening. It has no obvious catalytic domain, suggesting a scaffolding/adaptor role.","method":"Yeast two-hybrid system","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — original discovery by single lab, yeast two-hybrid only","pmids":["9537516"],"is_preprint":false},{"year":2001,"finding":"MUPP1 is concentrated at tight junctions in polarized epithelial cells through direct binding to claudin-1 (via PDZ10 domain) and junctional adhesion molecule (JAM, via PDZ9 domain), functioning as a multivalent scaffold protein at TJs.","method":"Yeast two-hybrid, in vitro binding assays with recombinant MUPP1, immunofluorescence confocal microscopy, immunoelectron microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro binding, domain mapping, and localization in polarized epithelial cells","pmids":["11689568"],"is_preprint":false},{"year":2001,"finding":"The C-terminus of the 5-HT2C receptor selectively interacts with PDZ10 of MUPP1 via its SXV motif; 5-HT2A and 5-HT2B receptors also bind MUPP1 PDZ domains in vitro. The interaction triggers a conformational change within MUPP1.","method":"Yeast two-hybrid, co-immunoprecipitation from transfected COS-7 cells and rat choroid plexus, immunocytochemistry, in vitro binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP in native tissue plus domain mapping and conformational change evidence","pmids":["11150294"],"is_preprint":false},{"year":2000,"finding":"Ad9 E4-ORF1 oncoprotein aberrantly sequesters MUPP1 within the cytoplasm, while HPV-18 E6 oncoprotein targets MUPP1 for degradation; both interactions are mediated by the viral PDZ domain-binding motifs. This implicates MUPP1 in negative regulation of cellular proliferation.","method":"Co-immunoprecipitation, subcellular localization studies with wild-type and mutant viral proteins","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — functional consequence shown with mutant controls in cell-based assays","pmids":["11000240"],"is_preprint":false},{"year":2000,"finding":"MUPP1 binds to the cytoplasmic C-terminus of the NG2 chondroitin sulfate proteoglycan via its PDZ1 region; interaction demonstrated in cell lysates and requires the C-terminal half of the NG2 cytoplasmic domain.","method":"Yeast two-hybrid, GST pull-down assay, co-immunoprecipitation from cell extracts","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid confirmed by GST pull-down and co-IP in native cells","pmids":["10967549"],"is_preprint":false},{"year":2000,"finding":"MUPP1 binds to c-Kit via its PDZ10 domain through the c-Kit C-terminal sequence; kinase-negative c-Kit interacts more strongly with MUPP1 than wild-type, while constitutively activated D816V-Kit does not bind MUPP1. Deletion of the PDZ-binding motif drastically reduces c-Kit tyrosine kinase activity.","method":"Co-immunoprecipitation, yeast two-hybrid, domain mapping with mutants","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction demonstrated with functional mutant analysis linking PDZ binding to kinase regulation","pmids":["11018522"],"is_preprint":false},{"year":2002,"finding":"TAPP1 and TAPP2 interact with MUPP1 PDZ domains 10 and 13 through their C-terminal amino acids; endogenous TAPP1 co-immunoprecipitates endogenous MUPP1 from 293 cells. TAPP1 translocates to the plasma membrane upon PtdIns(3,4)P2 generation, potentially recruiting MUPP1 to the membrane.","method":"Co-immunoprecipitation of endogenous proteins, domain mapping, membrane translocation assay with wortmannin inhibition","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous protein co-IP confirmed interaction with functional implications for membrane recruitment","pmids":["11802782"],"is_preprint":false},{"year":2003,"finding":"Claudin-8 binds MUPP1 through its PDZ9 domain; both co-localize and co-immunoprecipitate at tight junctions in MDCK cells. Over-expression of MUPP1 reduces epithelial paracellular conductance.","method":"Yeast two-hybrid, co-immunoprecipitation, immunolocalization, transepithelial electrical resistance measurement","journal":"Cellular and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — interaction confirmed by multiple methods with functional TJ barrier readout","pmids":["12839333"],"is_preprint":false},{"year":2004,"finding":"MUPP1 forms a synaptic complex with SynGAP and CaMKII in hippocampal neurons; SynGAP and CaMKII are brought together by direct physical interaction with MUPP1 PDZ domains. Ca2+/CaM binding to CaMKII dissociates it from the MUPP1 complex, and Ca2+ via NMDAR drives SynGAP dephosphorylation, leading to p38 MAPK inactivation and potentiation of synaptic AMPA responses.","method":"Co-immunoprecipitation, peptide disruption of complex, siRNA knockdown, electrophysiology, AMPAR cluster counting","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including peptide disruption, siRNA, and electrophysiological readout; replicated with two complementary approaches","pmids":["15312654"],"is_preprint":false},{"year":2004,"finding":"CAR (coxsackievirus and adenovirus receptor) interacts with MUPP1 PDZ domain 13 via its C-terminal PDZ-binding motif within the tight junction; CAR expression is required for proper MUPP1 localization at tight junctions.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, in vitro binding, siRNA knockdown of CAR","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including siRNA functional test establishing the direction of the interaction","pmids":["15364909"],"is_preprint":false},{"year":2004,"finding":"Mpdz is identified as a quantitative trait gene for drug (alcohol and pentobarbital) withdrawal seizures in mice via positional cloning within a <1 cM interval on mouse chromosome 4.","method":"Positional cloning, congenic strain analysis, sequence analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — positional cloning with congenic strain genetic evidence establishes causal gene identity","pmids":["15208631"],"is_preprint":false},{"year":2006,"finding":"MUPP1 functions as a lipid raft-associated scaffolding protein in the acrosomal region of mammalian spermatozoa, controlling initial tethering and docking of the acrosomal vesicle during exocytosis; syntaxin 2 participates in the final acrosomal fusion step.","method":"Inhibitory antibody loading in permeabilized sperm, photosensitive Ca2+ chelator, immunogold electron microscopy, detergent-insoluble membrane fractionation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — function-blocking antibody experiment with controlled Ca2+ release, supported by ultrastructural localization","pmids":["17894389"],"is_preprint":false},{"year":2006,"finding":"MUPP1 and Patj share binding partners including JAM1, ZO-3, Pals1, Par6, and nectins; both localize to tight junctions, but only Patj (not MUPP1) is indispensable for TJ establishment and epithelial polarization. Pals1 has higher affinity for Patj than MUPP1 and is key for Patj's function in activating the Par6-aPKC complex.","method":"Co-immunoprecipitation, RNAi knockdown, transepithelial resistance measurement, immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple binding partners confirmed, functional distinction established by KO/KD with specific cellular readouts","pmids":["19255144"],"is_preprint":false},{"year":2006,"finding":"GABA(B)R2 C-terminus interacts with Mupp1 PDZ13; disruption of this interaction by point mutation or siRNA knockdown of Mupp1 decreases GABA(B) receptor stability and attenuates the duration of GABA(B) receptor signaling.","method":"PDZ domain array screen, biochemical co-immunoprecipitation, siRNA knockdown, receptor stability and signaling assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — PDZ array identified interaction, confirmed biochemically, and functionally validated by two complementary disruption approaches","pmids":["17145756"],"is_preprint":false},{"year":2007,"finding":"MUPP1 interacts with angiomotin (Amot), JEAP/Amot-like 1, and MASCOT/Amot-like 2 (Amot/JEAP family) via PDZ2/3 domains at tight junctions and apical membranes; however, PDZ-binding motifs of Amot/JEAP family are not required for their TJ localization, and dominant-negative MUPP1 does not affect their distribution.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, biochemical fractionation","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction mapped to specific PDZ domains with functional epistasis tested by dominant-negative approach","pmids":["17397395"],"is_preprint":false},{"year":2007,"finding":"MUPP1 is upregulated by hypertonicity in kidney IMCD3 cells and is required for maintenance of tight epithelial barrier function; silencing of MUPP1 reduces transepithelial resistance by 24%.","method":"Antibody array proteomics, qPCR, Western blot, stable RNAi silencing, transepithelial resistance measurement","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — stable knockdown with quantitative barrier function readout","pmids":["17690246"],"is_preprint":false},{"year":2008,"finding":"MUPP1 binds the MT1 melatonin receptor via PDZ10 and the receptor's C-terminal DSV motif (Kd ~4 nM); this interaction is independent of receptor activation but is required for MT1-Gi coupling and Gi-mediated signaling, without affecting receptor localization or trafficking.","method":"Co-immunoprecipitation, isothermal titration calorimetry, PDZ domain mapping, peptide disruption, signaling assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding constant measured by ITC, interaction confirmed in native ovine tissue, functional consequence on G-protein coupling demonstrated by disruption","pmids":["18378672"],"is_preprint":false},{"year":2008,"finding":"MUPP1 interacts with hSSTR3 (human somatostatin receptor 3) via its PDZ domains; this interaction targets hSSTR3 to tight junctions, enabling somatostatin to regulate transepithelial permeability in a pertussis toxin-sensitive (Gi-dependent) manner.","method":"Co-immunoprecipitation, immunolocalization, transepithelial resistance/permeability assay, pertussis toxin treatment","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction linked to receptor targeting and functional signaling at TJs","pmids":["19071123"],"is_preprint":false},{"year":2008,"finding":"MUPP1 is upregulated by hypertonicity in kidney IMCD3 cells and correctly localizes claudin-4 to tight junctions; in MUPP1-silenced cells, claudin-4 is mistargeted to lysosomes, reducing TER equivalently to claudin-4 silencing.","method":"Co-immunoprecipitation, RNAi silencing, immunofluorescence, lysosome inhibitor rescue, transepithelial resistance measurement","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — mechanistic chain established: MUPP1 controls claudin-4 localization, confirmed by Co-IP, mislocalization phenotype, and rescue experiment","pmids":["18840681"],"is_preprint":false},{"year":2008,"finding":"MUPP1 localizes at oligodendrocyte-astrocyte gap junctions with Cx47; ablation of Cx47 leads to loss of MUPP1 (and ZONAB) at these junctions, while Cx32 ablation does not affect MUPP1, demonstrating Cx47-dependent targeting of MUPP1 to O/A gap junctions.","method":"Immunofluorescence, knockout mouse analysis (Cx47-KO and Cx32-KO)","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — localization dependency established using two complementary KO models","pmids":["18973575"],"is_preprint":false},{"year":2008,"finding":"Tech (neuronal RhoA GEF) binds MUPP1 PDZ10 and PDZ13 via its C-terminal PDZ ligand; endogenous Tech co-precipitates with MUPP1 from hippocampal and cortical brain extracts, and both co-localize near synapses in cortical neurons.","method":"Yeast two-hybrid, co-transfection in HEK293 cells, co-immunoprecipitation from brain extracts, immunostaining","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — endogenous interaction confirmed in brain tissue with PDZ domain specificity mapped","pmids":["18537874"],"is_preprint":false},{"year":2009,"finding":"CaMKIIα co-localizes with MUPP1 in the acrosomal region of spermatozoa and selectively binds to MUPP1 PDZ domains 10-11. CaMKII inhibition or competitive displacement of CaMKIIα from PDZ10-11 increases spontaneous acrosomal exocytosis; Ca2+/calmodulin releases CaMKIIα from MUPP1, dynamically regulating acrosomal secretion.","method":"Co-immunoprecipitation, CaMKII inhibitor treatment, competitive peptide displacement, acrosome reaction assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — domain-specific interaction with functional consequence demonstrated by two complementary disruption strategies","pmids":["19934217"],"is_preprint":false},{"year":2009,"finding":"MUPP1 interacts with renal K+ channel Kir4.2 via its C-terminal PDZ motif; co-expression of MUPP1 reduces cell surface expression of Kir4.2 and decreases whole-cell K+ currents in Xenopus oocytes.","method":"Yeast two-hybrid, reciprocal co-immunoprecipitation from rat kidney cortex, cell surface biotinylation, Xenopus oocyte electrophysiology, immunofluorescence","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 1-2 — interaction confirmed in native kidney tissue, functional consequence shown by electrophysiology and surface expression assay","pmids":["19420109"],"is_preprint":false},{"year":2011,"finding":"AF6 and MUPP1 are components of neuronal gap junctions in rodent brain, co-localizing with Cx36; MUPP1 interacts with Cx36 via the 10th PDZ domain of MUPP1 recognizing the C-terminus PDZ interaction motif of Cx36. This positions MUPP1 to potentially anchor CaMKII at electrical synapses.","method":"Co-immunoprecipitation, GST pull-down, immunofluorescence colocalization","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and pull-down confirmed domain-specific interaction in brain tissue","pmids":["22211808"],"is_preprint":false},{"year":2012,"finding":"CADM1/SynCAM1 C-terminal peptide associates with MUPP1 PDZ1-5 in the cerebellum; MUPP1 also interacts with GABBR2 at PDZ13. Loss of CADM1 in KO mice increases GABBR2 protein (but not mRNA) levels, suggesting that the CADM1-MUPP1-GABBR2 complex stabilizes GABBR2.","method":"Co-immunoprecipitation, pull-down assay, immunofluorescence, knockout mouse analysis","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — complex formation shown by multiple methods; functional consequence tested in KO model","pmids":["22994563"],"is_preprint":false},{"year":2013,"finding":"MUPP1 expression inversely correlates with PATJ protein levels by acting on stabilization of the PATJ/PALS1 complex; MUPP1 depletion leads to increased PATJ localized at the migrating front with increased PAR3 recruitment, indicating MUPP1 regulates polarity complex balance.","method":"RNAi depletion, co-immunoprecipitation, immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional consequence of MUPP1 depletion on complex stability and localization established","pmids":["23880463"],"is_preprint":false},{"year":2013,"finding":"Loss-of-function mutation in MPDZ causes severe congenital hydrocephalus (communicating type) following autosomal recessive inheritance, establishing MPDZ as a congenital hydrocephalus disease gene.","method":"Autozygosity mapping, linkage analysis, direct sequencing of candidate genes","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mapping with truncating mutation identified in affected families; founder mutation found in second family","pmids":["23240096"],"is_preprint":false},{"year":2014,"finding":"MUPP1 organizes a macromolecular signaling complex in mouse olfactory sensory neurons; disruption of the PDZ signaling complex by inhibitory peptide strongly impairs odor responses and alters activation and termination kinetics.","method":"Co-immunoprecipitation, inhibitory peptide disruption, electrophysiological recording of olfactory sensory neurons","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — functional complex established by Co-IP, with peptide disruption causing specific electrophysiological phenotype","pmids":["24652834"],"is_preprint":false},{"year":2014,"finding":"Neurexin 1 (and neurexins 2 and 3) interact with MUPP1 through its PDZ domain; MUPP1 and neurexin 1 co-localize in cultured cells.","method":"Yeast two-hybrid, co-localization in cultured cells","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — yeast two-hybrid and colocalization without biochemical confirmation of endogenous interaction","pmids":["25036961"],"is_preprint":false},{"year":2015,"finding":"CASPR2 interacts with GPR37 via MUPP1 as a bridge; CASPR2 binds MUPP1 PDZ3, GPR37 binds MUPP1 PDZ11. The ASD-associated GPR37(R558Q) mutant shows reduced MUPP1 interaction and is not transported to the cell surface, while wild-type GPR37 is transported to dendrites and synapses by MUPP1.","method":"Co-immunoprecipitation from mouse brain, transfection experiments, immunofluorescence in hippocampal neurons, PDZ domain mapping","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — complex confirmed in native brain tissue, PDZ domains mapped, functional surface trafficking consequence shown with ASD mutant","pmids":["25977097"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of MUPP1 PDZ4 domain resolved at 1.6 Å; the domain contains three α-helices and six β-strands, with a binding pocket formed by GLGI motif, L562/A564 on β-strand B, and H605/V608/L612 on α-helix B.","method":"X-ray crystallography, size-exclusion chromatography","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure determined at high resolution; limited functional validation","pmids":["25662616"],"is_preprint":false},{"year":2016,"finding":"CaMKIIα C-terminal tail binds MUPP1 PDZ11 with moderate affinity (Kd = 0.47 µM) and PDZ5 with lower affinity (Kd = 25.2 µM); rationally designed peptide mutants can achieve ~10-fold improved affinity for PDZ11, establishing structure-activity relationships for CaMKIIα-MUPP1 interaction.","method":"Fluorescence titration, computational structure-based modeling, mutagenesis of peptide ligands","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro binding affinity measured with fluorescence spectroscopy and validated by rational design","pmids":["26984442"],"is_preprint":false},{"year":2017,"finding":"Global or conditional (Nestin-positive cell) deletion of Mpdz in mice causes supratentorial hydrocephalus due to progressive loss of ependymal cell barrier integrity (without morphological defects in cilia or tight junctions), accompanied by diminished Pals1 expression and increased RhoA activity in astrocytes, followed by reactive astrogliosis and aqueductal stenosis.","method":"Conditional knockout mouse, MRI, immunofluorescence, in vitro barrier integrity assay, RhoA activity assay","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple KO models with mechanistic pathway identification (Pals1, RhoA), supported by in vitro validation","pmids":["28500065"],"is_preprint":false},{"year":2018,"finding":"MPDZ physically interacts with the intracellular C-terminus of DLL1 and DLL4 Notch ligands and enables their interaction with the adherens junction protein Nectin-2; inactivation of MPDZ impairs Notch signaling and increases blood vessel sprouting in endothelial cells and embryonic mouse hindbrain.","method":"Co-immunoprecipitation, MPDZ gene inactivation in cell models and conditional endothelial KO mice, vessel sprouting assay, Notch signaling assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — physical interaction demonstrated biochemically, functional consequence confirmed in multiple cellular models and in vivo mouse model","pmids":["29620522"],"is_preprint":false},{"year":2019,"finding":"In Mpdz loss-of-function mice, the permeability of the choroid plexus epithelial monolayer is abnormally high; MRI shows contrast medium penetrates brain ventricles of KO but not normal mice, and CSF protein concentration is up to 53-fold elevated, with ultrastructural evidence suggesting increased transcytosis.","method":"MRI with contrast medium, comparative proteomics of CSF, immunohistochemistry, ultrastructural analysis (electron microscopy)","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (MRI, proteomics, EM) in KO mouse model establishing choroid plexus hyperpermeability as the mechanism of MPDZ-linked hydrocephalus","pmids":["30518636"],"is_preprint":false},{"year":2019,"finding":"DAPLE directly binds the PDZ3 domain of MPDZ via its C-terminal PDZ-binding motif; both co-localize at apical cell junctions. MPDZ is required for DAPLE-mediated apical constriction of neuroepithelial cells, neural plate bending, and neural tube closure in Xenopus, showing cooperative function of two NSCH-linked proteins.","method":"Co-immunoprecipitation, direct binding assay, morpholino knockdown in Xenopus, apical constriction assay in cultured cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — direct interaction shown by biochemical assay, epistasis established in Xenopus developmental model and cultured cells","pmids":["31268831"],"is_preprint":false},{"year":2021,"finding":"MPDZ promotes tumor suppressor activity through the Hippo-YAP pathway: MPDZ activates YAP phosphorylation at Ser127 and inhibits YAP expression by stabilizing MST1 and physically interacting with LATS1.","method":"Co-immunoprecipitation, Western blot for pathway components, MPDZ knockout and overexpression in cell lines and mice","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 — interaction with LATS1 shown by Co-IP, pathway placement supported by KO/OE with phosphorylation readouts; single lab","pmids":["34108620"],"is_preprint":false},{"year":2023,"finding":"Loss of MPDZ (with PATJ) in mouse preimplantation embryos disrupts apical domain establishment, tight junctions, and actin filaments, leading to ectopic Hippo signaling activation in outer cells and suppression of Cdx2 expression and trophectoderm differentiation.","method":"Zygote microinjection of siRNA, immunofluorescence, blastocyst morphology assessment","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi in embryos with multiple molecular and cellular readouts linking MPDZ to polarity, tight junctions, Hippo signaling and lineage specification","pmids":["37318097"],"is_preprint":false}],"current_model":"MPDZ/MUPP1 is a large multi-PDZ domain scaffolding protein (13 PDZ domains) concentrated at tight junctions and apical junctions of epithelial and neuronal cells, where it functions as a multivalent scaffold assembling protein complexes: it directly binds claudins (via PDZ9/10), JAM, CAR, GPCR C-termini (5-HT2C, MT1, GABA(B)R2, hSSTR3, c-Kit, MT1 via PDZ10/13), CaMKIIα (via PDZ10-11), SynGAP, and Notch ligands DLL1/4, thereby organizing signaling cascades including NMDAR-CaMKII-SynGAP-p38 MAPK control of AMPAR plasticity, Gi-coupled receptor signaling, Notch/DLL4-mediated angiogenesis, and Hippo-YAP pathway tumor suppression; loss of MPDZ disrupts ependymal and choroid plexus barrier integrity (with increased RhoA activity and Pals1 loss), causing congenital hydrocephalus, and its expression in the substantia nigra pars reticulata regulates alcohol withdrawal severity."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of MPDZ as a 13-PDZ-domain protein interacting with the 5-HT2C receptor established its scaffolding architecture and first receptor partnership, answering whether cells possess multi-PDZ adaptors that could simultaneously bind multiple partners.","evidence":"Yeast two-hybrid screen with 5-HT2C C-terminus in human brain library","pmids":["9537516"],"confidence":"Medium","gaps":["Single interaction method (Y2H) without endogenous validation","No cellular function assigned"]},{"year":2001,"claim":"Localization of MUPP1 to tight junctions through direct binding of claudin-1 (PDZ10) and JAM (PDZ9) revealed MPDZ as a core TJ scaffold, redefining it from a receptor adaptor to a junctional organizer.","evidence":"Y2H, in vitro binding, immunofluorescence, and immunoelectron microscopy in polarized MDCK cells","pmids":["11689568","11150294"],"confidence":"High","gaps":["Functional consequence of MUPP1 loss on barrier integrity not yet tested","Redundancy with PATJ not addressed"]},{"year":2000,"claim":"Viral oncoproteins (Ad9 E4-ORF1, HPV-18 E6) targeting MUPP1 for sequestration or degradation implied a tumor-suppressive role, connecting MPDZ to proliferation control before direct evidence in cancer pathways existed.","evidence":"Co-IP and subcellular localization with wild-type and mutant viral proteins","pmids":["11000240"],"confidence":"Medium","gaps":["No direct measurement of MUPP1 effect on proliferation","Endogenous tumor suppressor mechanism not identified"]},{"year":2004,"claim":"Assembly of a SynGAP–CaMKIIα ternary complex on MUPP1 at synapses, with Ca²⁺/CaM-dependent disassembly driving p38 MAPK inactivation and AMPAR potentiation, established MPDZ as a critical scaffold for synaptic plasticity.","evidence":"Co-IP, competitive peptide disruption, siRNA knockdown, electrophysiology, and AMPAR cluster analysis in hippocampal neurons","pmids":["15312654"],"confidence":"High","gaps":["In vivo behavioral consequence of MPDZ loss at synapses not tested","Structural basis of ternary complex unknown"]},{"year":2004,"claim":"Positional cloning of Mpdz as the quantitative trait gene for alcohol and pentobarbital withdrawal seizures in mice linked MPDZ scaffolding to CNS excitability and pharmacogenetics.","evidence":"Congenic strain analysis and positional cloning within <1 cM interval on mouse chromosome 4","pmids":["15208631"],"confidence":"High","gaps":["Molecular mechanism connecting MPDZ variants to seizure threshold not identified","Human MPDZ variants in alcohol withdrawal not tested"]},{"year":2008,"claim":"Demonstration that MUPP1 controls claudin-4 targeting to TJs (preventing lysosomal mislocalization) and is required for epithelial barrier maintenance under hypertonic stress provided the first mechanistic link between MUPP1 and cargo sorting at junctions.","evidence":"RNAi silencing, Co-IP, immunofluorescence, lysosome inhibitor rescue, and TER measurement in IMCD3 cells","pmids":["18840681","17690246"],"confidence":"High","gaps":["Whether MUPP1 directly prevents claudin ubiquitination or acts through an intermediary unknown","In vivo renal phenotype of MPDZ loss not assessed"]},{"year":2008,"claim":"High-affinity binding of MUPP1 PDZ10 to the MT1 melatonin receptor (Kd ~4 nM), required for Gi coupling but not receptor trafficking, established MPDZ as an essential scaffold for GPCR–G-protein assembly rather than merely a localizing factor.","evidence":"ITC binding measurements, Co-IP from native ovine pars tuberalis, peptide disruption of Gi signaling","pmids":["18378672"],"confidence":"High","gaps":["Whether MUPP1 scaffolds a pre-coupled receptor–Gi complex or facilitates dynamic coupling unknown","Structural basis of PDZ10-mediated Gi coupling not resolved"]},{"year":2009,"claim":"Functional redundancy and distinction between MUPP1 and PATJ at tight junctions was clarified: both share binding partners (JAM1, Pals1, Par6), but only PATJ is indispensable for TJ establishment and epithelial polarization, positioning MUPP1 as a modulatory rather than essential TJ scaffold in standard culture.","evidence":"RNAi knockdown, Co-IP, TER measurement in MDCK cells","pmids":["19255144"],"confidence":"High","gaps":["In vivo tissue-specific contexts where MUPP1 becomes essential (e.g., ependyma) not yet examined","Whether MUPP1 and PATJ compete for the same binding sites on Pals1 not resolved"]},{"year":2013,"claim":"Identification of a loss-of-function MPDZ mutation in families with autosomal recessive congenital hydrocephalus established MPDZ as a human disease gene, linking its junctional scaffolding to brain barrier integrity.","evidence":"Autozygosity mapping and linkage analysis with truncating mutation in two consanguineous families","pmids":["23240096"],"confidence":"Medium","gaps":["Cellular mechanism of hydrocephalus not determined at this point","No functional rescue or animal model confirmation"]},{"year":2017,"claim":"Conditional Mpdz knockout mice recapitulated hydrocephalus through progressive ependymal barrier failure with diminished Pals1 and elevated RhoA activity, establishing a mechanistic pathway from MPDZ loss to barrier breakdown and aqueductal stenosis.","evidence":"Global and Nestin-Cre conditional KO mice, MRI, RhoA activity assay, in vitro barrier assays","pmids":["28500065"],"confidence":"High","gaps":["Whether Pals1 loss is cause or consequence of ependymal breakdown not resolved","Therapeutic potential of RhoA inhibition not tested"]},{"year":2018,"claim":"MPDZ was shown to scaffold Notch ligands DLL1/DLL4 with nectin-2 at endothelial junctions; its loss impaired Notch signaling and increased vessel sprouting, extending MPDZ function from epithelial barriers to vascular morphogenesis.","evidence":"Co-IP, conditional endothelial KO in mice, hindbrain vessel sprouting assay, Notch reporter","pmids":["29620522"],"confidence":"High","gaps":["Whether MPDZ regulates Notch signaling in non-endothelial contexts unknown","Which PDZ domains mediate DLL interactions not fully mapped"]},{"year":2019,"claim":"MRI-based demonstration that Mpdz-null choroid plexus is hyperpermeble, with 53-fold elevated CSF protein, pinpointed the choroid plexus as a primary site of MPDZ-dependent barrier failure in hydrocephalus.","evidence":"Contrast-enhanced MRI, CSF comparative proteomics, electron microscopy in KO mice","pmids":["30518636"],"confidence":"High","gaps":["Relative contributions of ependymal vs. choroid plexus permeability to hydrocephalus not dissected","Transcytosis mechanism suggested by EM not molecularly characterized"]},{"year":2021,"claim":"MPDZ was found to activate Hippo-YAP signaling by stabilizing MST1 and interacting with LATS1 to promote YAP phosphorylation, providing a molecular mechanism for the tumor-suppressive role first implied by viral oncoprotein targeting.","evidence":"Co-IP with LATS1, Western blot for phospho-YAP, MPDZ KO and overexpression in cell lines and xenograft mice","pmids":["34108620"],"confidence":"Medium","gaps":["Single-lab finding; independent replication needed","Direct binding interface between MPDZ and LATS1 not structurally resolved","Whether Hippo activation is relevant in ependymal/choroid plexus cells unknown"]},{"year":2023,"claim":"Loss of MPDZ (with PATJ) in preimplantation embryos disrupted apical polarity, tight junctions, and Hippo pathway activity in outer cells, suppressing trophectoderm specification — connecting MPDZ scaffolding to the earliest mammalian lineage decision.","evidence":"Zygote siRNA microinjection, immunofluorescence, blastocyst assessment","pmids":["37318097"],"confidence":"Medium","gaps":["Combined MPDZ+PATJ knockdown does not distinguish individual contributions","Whether MPDZ acts through Hippo directly or via polarity disruption in this context is unclear"]},{"year":null,"claim":"It remains unknown how the 13 PDZ domains of MPDZ are coordinately regulated to achieve context-specific complex assembly, what post-translational modifications control MPDZ activity, and whether MPDZ dysfunction contributes to human neuropsychiatric phenotypes beyond hydrocephalus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length MPDZ structure available","Post-translational regulation of MPDZ largely uncharacterized","Human genetic studies for neuropsychiatric or vascular phenotypes lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,8,16,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7,9,18,33]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,17,36]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[1,7,9,18,33]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,10,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[35,37]}],"complexes":["SynGAP-CaMKIIα-MUPP1 synaptic complex","Tight junction scaffold complex (claudin-JAM-CAR-MUPP1)","CRB3-Pals1-PATJ/MUPP1 apical polarity complex"],"partners":["CLDN1","F11R","SYNGAP1","CAMK2A","MTNR1A","GABBR2","DLL4","LATS1"],"other_free_text":[]},"mechanistic_narrative":"MPDZ (MUPP1) is a multivalent PDZ-domain scaffolding protein that organizes signaling complexes at tight junctions, synapses, and gap junctions to regulate epithelial barrier integrity, neuronal plasticity, receptor signaling, and developmental patterning. Its 13 PDZ domains simultaneously engage claudins, JAM, and CAR at tight junctions to maintain paracellular barrier function — loss of MPDZ mislocalizes claudin-4 to lysosomes and increases epithelial permeability — while in neurons it assembles a SynGAP–CaMKIIα complex whose Ca²⁺/calmodulin-dependent disassembly controls p38 MAPK inactivation and AMPAR potentiation [PMID:11689568, PMID:18840681, PMID:15312654]. MPDZ scaffolds GPCR signaling by coupling receptors (MT1, GABA_B R2, 5-HT2C, hSSTR3) to Gi proteins and stabilizing receptor expression, and it bridges Notch ligands DLL1/DLL4 with nectin-2 to enable Notch-dependent angiogenesis [PMID:18378672, PMID:17145756, PMID:29620522]. Loss-of-function mutations in MPDZ cause autosomal recessive congenital hydrocephalus through disrupted ependymal and choroid plexus barrier integrity, with diminished Pals1, elevated RhoA activity, and massively increased choroid plexus permeability [PMID:23240096, PMID:28500065, PMID:30518636]."},"prefetch_data":{"uniprot":{"accession":"O75970","full_name":"Multiple PDZ domain protein","aliases":["Multi-PDZ domain protein 1"],"length_aa":2070,"mass_kda":221.6,"function":"Member of the NMDAR signaling complex that may play a role in control of AMPAR potentiation and synaptic plasticity in excitatory synapses (PubMed:11150294, PubMed:15312654). 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FAAP100","url":"https://www.omim.org/entry/611301"},{"mim_id":"610438","title":"RESTLESS LEGS SYNDROME, SUSCEPTIBILITY TO, 3; RLS3","url":"https://www.omim.org/entry/610438"},{"mim_id":"603785","title":"MULTIPLE PDZ DOMAIN CRUMBS CELL POLARITY COMPLEX COMPONENT; MPDZ","url":"https://www.omim.org/entry/603785"},{"mim_id":"236600","title":"HYDROCEPHALUS, CONGENITAL, 1; HYC1","url":"https://www.omim.org/entry/236600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":80.1}],"url":"https://www.proteinatlas.org/search/MPDZ"},"hgnc":{"alias_symbol":["MUPP1"],"prev_symbol":[]},"alphafold":{"accession":"O75970","domains":[{"cath_id":"2.30.42.10","chopping":"123-223","consensus_level":"high","plddt":79.3729,"start":123,"end":223},{"cath_id":"2.30.42.10","chopping":"250-337","consensus_level":"medium","plddt":78.8058,"start":250,"end":337},{"cath_id":"2.30.42.10","chopping":"384-459","consensus_level":"high","plddt":81.547,"start":384,"end":459},{"cath_id":"2.30.42.10","chopping":"532-633","consensus_level":"medium","plddt":88.0011,"start":532,"end":633},{"cath_id":"2.30.42.10","chopping":"714-760_776-787","consensus_level":"medium","plddt":84.9207,"start":714,"end":787},{"cath_id":"2.30.42.10","chopping":"1019-1068","consensus_level":"medium","plddt":87.0716,"start":1019,"end":1068},{"cath_id":"2.30.42.10","chopping":"1147-1160_1177-1244","consensus_level":"high","plddt":83.1902,"start":1147,"end":1244},{"cath_id":"2.30.42.10","chopping":"1335-1439","consensus_level":"high","plddt":87.5415,"start":1335,"end":1439},{"cath_id":"2.30.42.10","chopping":"1616-1717","consensus_level":"medium","plddt":82.5454,"start":1616,"end":1717},{"cath_id":"2.30.42.10","chopping":"1722-1807","consensus_level":"medium","plddt":82.3687,"start":1722,"end":1807},{"cath_id":"2.30.42.10","chopping":"1861-1947","consensus_level":"high","plddt":82.2171,"start":1861,"end":1947},{"cath_id":"2.30.42.10","chopping":"1982-2070","consensus_level":"medium","plddt":82.4434,"start":1982,"end":2070},{"cath_id":"1.10.287","chopping":"10-42","consensus_level":"high","plddt":85.8718,"start":10,"end":42}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75970","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75970-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75970-F1-predicted_aligned_error_v6.png","plddt_mean":63.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MPDZ","jax_strain_url":"https://www.jax.org/strain/search?query=MPDZ"},"sequence":{"accession":"O75970","fasta_url":"https://rest.uniprot.org/uniprotkb/O75970.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75970/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75970"}},"corpus_meta":[{"pmid":"11689568","id":"PMC_11689568","title":"Multi-PDZ 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Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19420109","citation_count":8,"is_preprint":false},{"pmid":"36429029","id":"PMC_36429029","title":"Novel Compound Heterozygous Variations in MPDZ Gene Caused Isolated Bilateral Macular Coloboma in a Chinese Family.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36429029","citation_count":6,"is_preprint":false},{"pmid":"18417361","id":"PMC_18417361","title":"The MUPP1-SynGAPalpha protein complex does not mediate activity-induced LTP.","date":"2008","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/18417361","citation_count":6,"is_preprint":false},{"pmid":"22159006","id":"PMC_22159006","title":"Profiling retinal biochemistry in the MPDZ mutant retinal dysplasia and degeneration chick: a model of human RP and LCA.","date":"2012","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/22159006","citation_count":5,"is_preprint":false},{"pmid":"25036961","id":"PMC_25036961","title":"Neuronal cell-surface protein neurexin 1 interaction with multi-PDZ domain protein MUPP1.","date":"2014","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25036961","citation_count":5,"is_preprint":false},{"pmid":"38498110","id":"PMC_38498110","title":"Prenatal phenotype of a homozygous nonsense MPDZ variant in a fetus with severe congenital hydrocephalus.","date":"2024","source":"Prenatal diagnosis","url":"https://pubmed.ncbi.nlm.nih.gov/38498110","citation_count":4,"is_preprint":false},{"pmid":"36594712","id":"PMC_36594712","title":"Retinal manifestations in autosomal recessive MPDZ maculopathy: report of two cases and literature review.","date":"2023","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36594712","citation_count":3,"is_preprint":false},{"pmid":"32108449","id":"PMC_32108449","title":"Comparison of SynCAM1/CADM1 PDZ interactions with MUPP1 using mammalian and bacterial pull-down systems.","date":"2020","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/32108449","citation_count":3,"is_preprint":false},{"pmid":"38857973","id":"PMC_38857973","title":"Expanding the spectrum of phenotypes for MPDZ: Report of four unrelated families and review of the literature.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38857973","citation_count":3,"is_preprint":false},{"pmid":"37318097","id":"PMC_37318097","title":"PATJ and MPDZ are required for trophectoderm lineage specification in early mouse embryos.","date":"2023","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/37318097","citation_count":2,"is_preprint":false},{"pmid":"25662616","id":"PMC_25662616","title":"Biochemical and structural characterization of MUPP1-PDZ4 domain from Mus musculus.","date":"2015","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/25662616","citation_count":2,"is_preprint":false},{"pmid":"28832060","id":"PMC_28832060","title":"Rational design of an orthogonal noncovalent interaction system at the MUPP1 PDZ11 complex interface with CaMKIIα-derived peptides in human fertilization.","date":"2017","source":"Molecular bioSystems","url":"https://pubmed.ncbi.nlm.nih.gov/28832060","citation_count":2,"is_preprint":false},{"pmid":"35305607","id":"PMC_35305607","title":"Evaluating the association between MPDZ-NF1B rs1324183 and keratoconus in an independent northwestern Chinese population.","date":"2022","source":"BMC ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/35305607","citation_count":1,"is_preprint":false},{"pmid":"38818866","id":"PMC_38818866","title":"Expanding the phenotypic spectrum of MPDZ gene variants: A case report with prenatally detected Dandy-Walker malformation and single ventricle heart.","date":"2024","source":"Prenatal diagnosis","url":"https://pubmed.ncbi.nlm.nih.gov/38818866","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.05.674388","title":"A steady state pool of calcium-dependent actin is maintained by Homer and controls epithelial mechanosensation","date":"2025-09-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.05.674388","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33861,"output_tokens":8437,"usd":0.114069},"stage2":{"model":"claude-opus-4-6","input_tokens":12298,"output_tokens":3585,"usd":0.226672},"total_usd":0.340741,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"MPDZ/MUPP1 was identified as a novel protein containing 13 PDZ domains that interacts with the C-terminal domain of the 5-HT2C serotonin receptor, identified via yeast two-hybrid screening. It has no obvious catalytic domain, suggesting a scaffolding/adaptor role.\",\n      \"method\": \"Yeast two-hybrid system\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — original discovery by single lab, yeast two-hybrid only\",\n      \"pmids\": [\"9537516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MUPP1 is concentrated at tight junctions in polarized epithelial cells through direct binding to claudin-1 (via PDZ10 domain) and junctional adhesion molecule (JAM, via PDZ9 domain), functioning as a multivalent scaffold protein at TJs.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays with recombinant MUPP1, immunofluorescence confocal microscopy, immunoelectron microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro binding, domain mapping, and localization in polarized epithelial cells\",\n      \"pmids\": [\"11689568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The C-terminus of the 5-HT2C receptor selectively interacts with PDZ10 of MUPP1 via its SXV motif; 5-HT2A and 5-HT2B receptors also bind MUPP1 PDZ domains in vitro. The interaction triggers a conformational change within MUPP1.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from transfected COS-7 cells and rat choroid plexus, immunocytochemistry, in vitro binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP in native tissue plus domain mapping and conformational change evidence\",\n      \"pmids\": [\"11150294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ad9 E4-ORF1 oncoprotein aberrantly sequesters MUPP1 within the cytoplasm, while HPV-18 E6 oncoprotein targets MUPP1 for degradation; both interactions are mediated by the viral PDZ domain-binding motifs. This implicates MUPP1 in negative regulation of cellular proliferation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization studies with wild-type and mutant viral proteins\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional consequence shown with mutant controls in cell-based assays\",\n      \"pmids\": [\"11000240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MUPP1 binds to the cytoplasmic C-terminus of the NG2 chondroitin sulfate proteoglycan via its PDZ1 region; interaction demonstrated in cell lysates and requires the C-terminal half of the NG2 cytoplasmic domain.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down assay, co-immunoprecipitation from cell extracts\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid confirmed by GST pull-down and co-IP in native cells\",\n      \"pmids\": [\"10967549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MUPP1 binds to c-Kit via its PDZ10 domain through the c-Kit C-terminal sequence; kinase-negative c-Kit interacts more strongly with MUPP1 than wild-type, while constitutively activated D816V-Kit does not bind MUPP1. Deletion of the PDZ-binding motif drastically reduces c-Kit tyrosine kinase activity.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, domain mapping with mutants\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction demonstrated with functional mutant analysis linking PDZ binding to kinase regulation\",\n      \"pmids\": [\"11018522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TAPP1 and TAPP2 interact with MUPP1 PDZ domains 10 and 13 through their C-terminal amino acids; endogenous TAPP1 co-immunoprecipitates endogenous MUPP1 from 293 cells. TAPP1 translocates to the plasma membrane upon PtdIns(3,4)P2 generation, potentially recruiting MUPP1 to the membrane.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, domain mapping, membrane translocation assay with wortmannin inhibition\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous protein co-IP confirmed interaction with functional implications for membrane recruitment\",\n      \"pmids\": [\"11802782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Claudin-8 binds MUPP1 through its PDZ9 domain; both co-localize and co-immunoprecipitate at tight junctions in MDCK cells. Over-expression of MUPP1 reduces epithelial paracellular conductance.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunolocalization, transepithelial electrical resistance measurement\",\n      \"journal\": \"Cellular and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by multiple methods with functional TJ barrier readout\",\n      \"pmids\": [\"12839333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MUPP1 forms a synaptic complex with SynGAP and CaMKII in hippocampal neurons; SynGAP and CaMKII are brought together by direct physical interaction with MUPP1 PDZ domains. Ca2+/CaM binding to CaMKII dissociates it from the MUPP1 complex, and Ca2+ via NMDAR drives SynGAP dephosphorylation, leading to p38 MAPK inactivation and potentiation of synaptic AMPA responses.\",\n      \"method\": \"Co-immunoprecipitation, peptide disruption of complex, siRNA knockdown, electrophysiology, AMPAR cluster counting\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including peptide disruption, siRNA, and electrophysiological readout; replicated with two complementary approaches\",\n      \"pmids\": [\"15312654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CAR (coxsackievirus and adenovirus receptor) interacts with MUPP1 PDZ domain 13 via its C-terminal PDZ-binding motif within the tight junction; CAR expression is required for proper MUPP1 localization at tight junctions.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, in vitro binding, siRNA knockdown of CAR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including siRNA functional test establishing the direction of the interaction\",\n      \"pmids\": [\"15364909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mpdz is identified as a quantitative trait gene for drug (alcohol and pentobarbital) withdrawal seizures in mice via positional cloning within a <1 cM interval on mouse chromosome 4.\",\n      \"method\": \"Positional cloning, congenic strain analysis, sequence analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — positional cloning with congenic strain genetic evidence establishes causal gene identity\",\n      \"pmids\": [\"15208631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MUPP1 functions as a lipid raft-associated scaffolding protein in the acrosomal region of mammalian spermatozoa, controlling initial tethering and docking of the acrosomal vesicle during exocytosis; syntaxin 2 participates in the final acrosomal fusion step.\",\n      \"method\": \"Inhibitory antibody loading in permeabilized sperm, photosensitive Ca2+ chelator, immunogold electron microscopy, detergent-insoluble membrane fractionation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — function-blocking antibody experiment with controlled Ca2+ release, supported by ultrastructural localization\",\n      \"pmids\": [\"17894389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MUPP1 and Patj share binding partners including JAM1, ZO-3, Pals1, Par6, and nectins; both localize to tight junctions, but only Patj (not MUPP1) is indispensable for TJ establishment and epithelial polarization. Pals1 has higher affinity for Patj than MUPP1 and is key for Patj's function in activating the Par6-aPKC complex.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, transepithelial resistance measurement, immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple binding partners confirmed, functional distinction established by KO/KD with specific cellular readouts\",\n      \"pmids\": [\"19255144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GABA(B)R2 C-terminus interacts with Mupp1 PDZ13; disruption of this interaction by point mutation or siRNA knockdown of Mupp1 decreases GABA(B) receptor stability and attenuates the duration of GABA(B) receptor signaling.\",\n      \"method\": \"PDZ domain array screen, biochemical co-immunoprecipitation, siRNA knockdown, receptor stability and signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — PDZ array identified interaction, confirmed biochemically, and functionally validated by two complementary disruption approaches\",\n      \"pmids\": [\"17145756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MUPP1 interacts with angiomotin (Amot), JEAP/Amot-like 1, and MASCOT/Amot-like 2 (Amot/JEAP family) via PDZ2/3 domains at tight junctions and apical membranes; however, PDZ-binding motifs of Amot/JEAP family are not required for their TJ localization, and dominant-negative MUPP1 does not affect their distribution.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence, biochemical fractionation\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction mapped to specific PDZ domains with functional epistasis tested by dominant-negative approach\",\n      \"pmids\": [\"17397395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MUPP1 is upregulated by hypertonicity in kidney IMCD3 cells and is required for maintenance of tight epithelial barrier function; silencing of MUPP1 reduces transepithelial resistance by 24%.\",\n      \"method\": \"Antibody array proteomics, qPCR, Western blot, stable RNAi silencing, transepithelial resistance measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — stable knockdown with quantitative barrier function readout\",\n      \"pmids\": [\"17690246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MUPP1 binds the MT1 melatonin receptor via PDZ10 and the receptor's C-terminal DSV motif (Kd ~4 nM); this interaction is independent of receptor activation but is required for MT1-Gi coupling and Gi-mediated signaling, without affecting receptor localization or trafficking.\",\n      \"method\": \"Co-immunoprecipitation, isothermal titration calorimetry, PDZ domain mapping, peptide disruption, signaling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding constant measured by ITC, interaction confirmed in native ovine tissue, functional consequence on G-protein coupling demonstrated by disruption\",\n      \"pmids\": [\"18378672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MUPP1 interacts with hSSTR3 (human somatostatin receptor 3) via its PDZ domains; this interaction targets hSSTR3 to tight junctions, enabling somatostatin to regulate transepithelial permeability in a pertussis toxin-sensitive (Gi-dependent) manner.\",\n      \"method\": \"Co-immunoprecipitation, immunolocalization, transepithelial resistance/permeability assay, pertussis toxin treatment\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction linked to receptor targeting and functional signaling at TJs\",\n      \"pmids\": [\"19071123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MUPP1 is upregulated by hypertonicity in kidney IMCD3 cells and correctly localizes claudin-4 to tight junctions; in MUPP1-silenced cells, claudin-4 is mistargeted to lysosomes, reducing TER equivalently to claudin-4 silencing.\",\n      \"method\": \"Co-immunoprecipitation, RNAi silencing, immunofluorescence, lysosome inhibitor rescue, transepithelial resistance measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic chain established: MUPP1 controls claudin-4 localization, confirmed by Co-IP, mislocalization phenotype, and rescue experiment\",\n      \"pmids\": [\"18840681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MUPP1 localizes at oligodendrocyte-astrocyte gap junctions with Cx47; ablation of Cx47 leads to loss of MUPP1 (and ZONAB) at these junctions, while Cx32 ablation does not affect MUPP1, demonstrating Cx47-dependent targeting of MUPP1 to O/A gap junctions.\",\n      \"method\": \"Immunofluorescence, knockout mouse analysis (Cx47-KO and Cx32-KO)\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — localization dependency established using two complementary KO models\",\n      \"pmids\": [\"18973575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Tech (neuronal RhoA GEF) binds MUPP1 PDZ10 and PDZ13 via its C-terminal PDZ ligand; endogenous Tech co-precipitates with MUPP1 from hippocampal and cortical brain extracts, and both co-localize near synapses in cortical neurons.\",\n      \"method\": \"Yeast two-hybrid, co-transfection in HEK293 cells, co-immunoprecipitation from brain extracts, immunostaining\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — endogenous interaction confirmed in brain tissue with PDZ domain specificity mapped\",\n      \"pmids\": [\"18537874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CaMKIIα co-localizes with MUPP1 in the acrosomal region of spermatozoa and selectively binds to MUPP1 PDZ domains 10-11. CaMKII inhibition or competitive displacement of CaMKIIα from PDZ10-11 increases spontaneous acrosomal exocytosis; Ca2+/calmodulin releases CaMKIIα from MUPP1, dynamically regulating acrosomal secretion.\",\n      \"method\": \"Co-immunoprecipitation, CaMKII inhibitor treatment, competitive peptide displacement, acrosome reaction assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific interaction with functional consequence demonstrated by two complementary disruption strategies\",\n      \"pmids\": [\"19934217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MUPP1 interacts with renal K+ channel Kir4.2 via its C-terminal PDZ motif; co-expression of MUPP1 reduces cell surface expression of Kir4.2 and decreases whole-cell K+ currents in Xenopus oocytes.\",\n      \"method\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation from rat kidney cortex, cell surface biotinylation, Xenopus oocyte electrophysiology, immunofluorescence\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — interaction confirmed in native kidney tissue, functional consequence shown by electrophysiology and surface expression assay\",\n      \"pmids\": [\"19420109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AF6 and MUPP1 are components of neuronal gap junctions in rodent brain, co-localizing with Cx36; MUPP1 interacts with Cx36 via the 10th PDZ domain of MUPP1 recognizing the C-terminus PDZ interaction motif of Cx36. This positions MUPP1 to potentially anchor CaMKII at electrical synapses.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, immunofluorescence colocalization\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and pull-down confirmed domain-specific interaction in brain tissue\",\n      \"pmids\": [\"22211808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CADM1/SynCAM1 C-terminal peptide associates with MUPP1 PDZ1-5 in the cerebellum; MUPP1 also interacts with GABBR2 at PDZ13. Loss of CADM1 in KO mice increases GABBR2 protein (but not mRNA) levels, suggesting that the CADM1-MUPP1-GABBR2 complex stabilizes GABBR2.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assay, immunofluorescence, knockout mouse analysis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — complex formation shown by multiple methods; functional consequence tested in KO model\",\n      \"pmids\": [\"22994563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MUPP1 expression inversely correlates with PATJ protein levels by acting on stabilization of the PATJ/PALS1 complex; MUPP1 depletion leads to increased PATJ localized at the migrating front with increased PAR3 recruitment, indicating MUPP1 regulates polarity complex balance.\",\n      \"method\": \"RNAi depletion, co-immunoprecipitation, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional consequence of MUPP1 depletion on complex stability and localization established\",\n      \"pmids\": [\"23880463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss-of-function mutation in MPDZ causes severe congenital hydrocephalus (communicating type) following autosomal recessive inheritance, establishing MPDZ as a congenital hydrocephalus disease gene.\",\n      \"method\": \"Autozygosity mapping, linkage analysis, direct sequencing of candidate genes\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mapping with truncating mutation identified in affected families; founder mutation found in second family\",\n      \"pmids\": [\"23240096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MUPP1 organizes a macromolecular signaling complex in mouse olfactory sensory neurons; disruption of the PDZ signaling complex by inhibitory peptide strongly impairs odor responses and alters activation and termination kinetics.\",\n      \"method\": \"Co-immunoprecipitation, inhibitory peptide disruption, electrophysiological recording of olfactory sensory neurons\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional complex established by Co-IP, with peptide disruption causing specific electrophysiological phenotype\",\n      \"pmids\": [\"24652834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Neurexin 1 (and neurexins 2 and 3) interact with MUPP1 through its PDZ domain; MUPP1 and neurexin 1 co-localize in cultured cells.\",\n      \"method\": \"Yeast two-hybrid, co-localization in cultured cells\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and colocalization without biochemical confirmation of endogenous interaction\",\n      \"pmids\": [\"25036961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CASPR2 interacts with GPR37 via MUPP1 as a bridge; CASPR2 binds MUPP1 PDZ3, GPR37 binds MUPP1 PDZ11. The ASD-associated GPR37(R558Q) mutant shows reduced MUPP1 interaction and is not transported to the cell surface, while wild-type GPR37 is transported to dendrites and synapses by MUPP1.\",\n      \"method\": \"Co-immunoprecipitation from mouse brain, transfection experiments, immunofluorescence in hippocampal neurons, PDZ domain mapping\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — complex confirmed in native brain tissue, PDZ domains mapped, functional surface trafficking consequence shown with ASD mutant\",\n      \"pmids\": [\"25977097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of MUPP1 PDZ4 domain resolved at 1.6 Å; the domain contains three α-helices and six β-strands, with a binding pocket formed by GLGI motif, L562/A564 on β-strand B, and H605/V608/L612 on α-helix B.\",\n      \"method\": \"X-ray crystallography, size-exclusion chromatography\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure determined at high resolution; limited functional validation\",\n      \"pmids\": [\"25662616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CaMKIIα C-terminal tail binds MUPP1 PDZ11 with moderate affinity (Kd = 0.47 µM) and PDZ5 with lower affinity (Kd = 25.2 µM); rationally designed peptide mutants can achieve ~10-fold improved affinity for PDZ11, establishing structure-activity relationships for CaMKIIα-MUPP1 interaction.\",\n      \"method\": \"Fluorescence titration, computational structure-based modeling, mutagenesis of peptide ligands\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding affinity measured with fluorescence spectroscopy and validated by rational design\",\n      \"pmids\": [\"26984442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Global or conditional (Nestin-positive cell) deletion of Mpdz in mice causes supratentorial hydrocephalus due to progressive loss of ependymal cell barrier integrity (without morphological defects in cilia or tight junctions), accompanied by diminished Pals1 expression and increased RhoA activity in astrocytes, followed by reactive astrogliosis and aqueductal stenosis.\",\n      \"method\": \"Conditional knockout mouse, MRI, immunofluorescence, in vitro barrier integrity assay, RhoA activity assay\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple KO models with mechanistic pathway identification (Pals1, RhoA), supported by in vitro validation\",\n      \"pmids\": [\"28500065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MPDZ physically interacts with the intracellular C-terminus of DLL1 and DLL4 Notch ligands and enables their interaction with the adherens junction protein Nectin-2; inactivation of MPDZ impairs Notch signaling and increases blood vessel sprouting in endothelial cells and embryonic mouse hindbrain.\",\n      \"method\": \"Co-immunoprecipitation, MPDZ gene inactivation in cell models and conditional endothelial KO mice, vessel sprouting assay, Notch signaling assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction demonstrated biochemically, functional consequence confirmed in multiple cellular models and in vivo mouse model\",\n      \"pmids\": [\"29620522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Mpdz loss-of-function mice, the permeability of the choroid plexus epithelial monolayer is abnormally high; MRI shows contrast medium penetrates brain ventricles of KO but not normal mice, and CSF protein concentration is up to 53-fold elevated, with ultrastructural evidence suggesting increased transcytosis.\",\n      \"method\": \"MRI with contrast medium, comparative proteomics of CSF, immunohistochemistry, ultrastructural analysis (electron microscopy)\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MRI, proteomics, EM) in KO mouse model establishing choroid plexus hyperpermeability as the mechanism of MPDZ-linked hydrocephalus\",\n      \"pmids\": [\"30518636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DAPLE directly binds the PDZ3 domain of MPDZ via its C-terminal PDZ-binding motif; both co-localize at apical cell junctions. MPDZ is required for DAPLE-mediated apical constriction of neuroepithelial cells, neural plate bending, and neural tube closure in Xenopus, showing cooperative function of two NSCH-linked proteins.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assay, morpholino knockdown in Xenopus, apical constriction assay in cultured cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction shown by biochemical assay, epistasis established in Xenopus developmental model and cultured cells\",\n      \"pmids\": [\"31268831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MPDZ promotes tumor suppressor activity through the Hippo-YAP pathway: MPDZ activates YAP phosphorylation at Ser127 and inhibits YAP expression by stabilizing MST1 and physically interacting with LATS1.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for pathway components, MPDZ knockout and overexpression in cell lines and mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — interaction with LATS1 shown by Co-IP, pathway placement supported by KO/OE with phosphorylation readouts; single lab\",\n      \"pmids\": [\"34108620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of MPDZ (with PATJ) in mouse preimplantation embryos disrupts apical domain establishment, tight junctions, and actin filaments, leading to ectopic Hippo signaling activation in outer cells and suppression of Cdx2 expression and trophectoderm differentiation.\",\n      \"method\": \"Zygote microinjection of siRNA, immunofluorescence, blastocyst morphology assessment\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi in embryos with multiple molecular and cellular readouts linking MPDZ to polarity, tight junctions, Hippo signaling and lineage specification\",\n      \"pmids\": [\"37318097\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MPDZ/MUPP1 is a large multi-PDZ domain scaffolding protein (13 PDZ domains) concentrated at tight junctions and apical junctions of epithelial and neuronal cells, where it functions as a multivalent scaffold assembling protein complexes: it directly binds claudins (via PDZ9/10), JAM, CAR, GPCR C-termini (5-HT2C, MT1, GABA(B)R2, hSSTR3, c-Kit, MT1 via PDZ10/13), CaMKIIα (via PDZ10-11), SynGAP, and Notch ligands DLL1/4, thereby organizing signaling cascades including NMDAR-CaMKII-SynGAP-p38 MAPK control of AMPAR plasticity, Gi-coupled receptor signaling, Notch/DLL4-mediated angiogenesis, and Hippo-YAP pathway tumor suppression; loss of MPDZ disrupts ependymal and choroid plexus barrier integrity (with increased RhoA activity and Pals1 loss), causing congenital hydrocephalus, and its expression in the substantia nigra pars reticulata regulates alcohol withdrawal severity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MPDZ (MUPP1) is a multivalent PDZ-domain scaffolding protein that organizes signaling complexes at tight junctions, synapses, and gap junctions to regulate epithelial barrier integrity, neuronal plasticity, receptor signaling, and developmental patterning. Its 13 PDZ domains simultaneously engage claudins, JAM, and CAR at tight junctions to maintain paracellular barrier function — loss of MPDZ mislocalizes claudin-4 to lysosomes and increases epithelial permeability — while in neurons it assembles a SynGAP–CaMKIIα complex whose Ca²⁺/calmodulin-dependent disassembly controls p38 MAPK inactivation and AMPAR potentiation [PMID:11689568, PMID:18840681, PMID:15312654]. MPDZ scaffolds GPCR signaling by coupling receptors (MT1, GABA_B R2, 5-HT2C, hSSTR3) to Gi proteins and stabilizing receptor expression, and it bridges Notch ligands DLL1/DLL4 with nectin-2 to enable Notch-dependent angiogenesis [PMID:18378672, PMID:17145756, PMID:29620522]. Loss-of-function mutations in MPDZ cause autosomal recessive congenital hydrocephalus through disrupted ependymal and choroid plexus barrier integrity, with diminished Pals1, elevated RhoA activity, and massively increased choroid plexus permeability [PMID:23240096, PMID:28500065, PMID:30518636].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of MPDZ as a 13-PDZ-domain protein interacting with the 5-HT2C receptor established its scaffolding architecture and first receptor partnership, answering whether cells possess multi-PDZ adaptors that could simultaneously bind multiple partners.\",\n      \"evidence\": \"Yeast two-hybrid screen with 5-HT2C C-terminus in human brain library\",\n      \"pmids\": [\"9537516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single interaction method (Y2H) without endogenous validation\", \"No cellular function assigned\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Localization of MUPP1 to tight junctions through direct binding of claudin-1 (PDZ10) and JAM (PDZ9) revealed MPDZ as a core TJ scaffold, redefining it from a receptor adaptor to a junctional organizer.\",\n      \"evidence\": \"Y2H, in vitro binding, immunofluorescence, and immunoelectron microscopy in polarized MDCK cells\",\n      \"pmids\": [\"11689568\", \"11150294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MUPP1 loss on barrier integrity not yet tested\", \"Redundancy with PATJ not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Viral oncoproteins (Ad9 E4-ORF1, HPV-18 E6) targeting MUPP1 for sequestration or degradation implied a tumor-suppressive role, connecting MPDZ to proliferation control before direct evidence in cancer pathways existed.\",\n      \"evidence\": \"Co-IP and subcellular localization with wild-type and mutant viral proteins\",\n      \"pmids\": [\"11000240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct measurement of MUPP1 effect on proliferation\", \"Endogenous tumor suppressor mechanism not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Assembly of a SynGAP–CaMKIIα ternary complex on MUPP1 at synapses, with Ca²⁺/CaM-dependent disassembly driving p38 MAPK inactivation and AMPAR potentiation, established MPDZ as a critical scaffold for synaptic plasticity.\",\n      \"evidence\": \"Co-IP, competitive peptide disruption, siRNA knockdown, electrophysiology, and AMPAR cluster analysis in hippocampal neurons\",\n      \"pmids\": [\"15312654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo behavioral consequence of MPDZ loss at synapses not tested\", \"Structural basis of ternary complex unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Positional cloning of Mpdz as the quantitative trait gene for alcohol and pentobarbital withdrawal seizures in mice linked MPDZ scaffolding to CNS excitability and pharmacogenetics.\",\n      \"evidence\": \"Congenic strain analysis and positional cloning within <1 cM interval on mouse chromosome 4\",\n      \"pmids\": [\"15208631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting MPDZ variants to seizure threshold not identified\", \"Human MPDZ variants in alcohol withdrawal not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that MUPP1 controls claudin-4 targeting to TJs (preventing lysosomal mislocalization) and is required for epithelial barrier maintenance under hypertonic stress provided the first mechanistic link between MUPP1 and cargo sorting at junctions.\",\n      \"evidence\": \"RNAi silencing, Co-IP, immunofluorescence, lysosome inhibitor rescue, and TER measurement in IMCD3 cells\",\n      \"pmids\": [\"18840681\", \"17690246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MUPP1 directly prevents claudin ubiquitination or acts through an intermediary unknown\", \"In vivo renal phenotype of MPDZ loss not assessed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"High-affinity binding of MUPP1 PDZ10 to the MT1 melatonin receptor (Kd ~4 nM), required for Gi coupling but not receptor trafficking, established MPDZ as an essential scaffold for GPCR–G-protein assembly rather than merely a localizing factor.\",\n      \"evidence\": \"ITC binding measurements, Co-IP from native ovine pars tuberalis, peptide disruption of Gi signaling\",\n      \"pmids\": [\"18378672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MUPP1 scaffolds a pre-coupled receptor–Gi complex or facilitates dynamic coupling unknown\", \"Structural basis of PDZ10-mediated Gi coupling not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Functional redundancy and distinction between MUPP1 and PATJ at tight junctions was clarified: both share binding partners (JAM1, Pals1, Par6), but only PATJ is indispensable for TJ establishment and epithelial polarization, positioning MUPP1 as a modulatory rather than essential TJ scaffold in standard culture.\",\n      \"evidence\": \"RNAi knockdown, Co-IP, TER measurement in MDCK cells\",\n      \"pmids\": [\"19255144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo tissue-specific contexts where MUPP1 becomes essential (e.g., ependyma) not yet examined\", \"Whether MUPP1 and PATJ compete for the same binding sites on Pals1 not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of a loss-of-function MPDZ mutation in families with autosomal recessive congenital hydrocephalus established MPDZ as a human disease gene, linking its junctional scaffolding to brain barrier integrity.\",\n      \"evidence\": \"Autozygosity mapping and linkage analysis with truncating mutation in two consanguineous families\",\n      \"pmids\": [\"23240096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mechanism of hydrocephalus not determined at this point\", \"No functional rescue or animal model confirmation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional Mpdz knockout mice recapitulated hydrocephalus through progressive ependymal barrier failure with diminished Pals1 and elevated RhoA activity, establishing a mechanistic pathway from MPDZ loss to barrier breakdown and aqueductal stenosis.\",\n      \"evidence\": \"Global and Nestin-Cre conditional KO mice, MRI, RhoA activity assay, in vitro barrier assays\",\n      \"pmids\": [\"28500065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Pals1 loss is cause or consequence of ependymal breakdown not resolved\", \"Therapeutic potential of RhoA inhibition not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"MPDZ was shown to scaffold Notch ligands DLL1/DLL4 with nectin-2 at endothelial junctions; its loss impaired Notch signaling and increased vessel sprouting, extending MPDZ function from epithelial barriers to vascular morphogenesis.\",\n      \"evidence\": \"Co-IP, conditional endothelial KO in mice, hindbrain vessel sprouting assay, Notch reporter\",\n      \"pmids\": [\"29620522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MPDZ regulates Notch signaling in non-endothelial contexts unknown\", \"Which PDZ domains mediate DLL interactions not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"MRI-based demonstration that Mpdz-null choroid plexus is hyperpermeble, with 53-fold elevated CSF protein, pinpointed the choroid plexus as a primary site of MPDZ-dependent barrier failure in hydrocephalus.\",\n      \"evidence\": \"Contrast-enhanced MRI, CSF comparative proteomics, electron microscopy in KO mice\",\n      \"pmids\": [\"30518636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of ependymal vs. choroid plexus permeability to hydrocephalus not dissected\", \"Transcytosis mechanism suggested by EM not molecularly characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MPDZ was found to activate Hippo-YAP signaling by stabilizing MST1 and interacting with LATS1 to promote YAP phosphorylation, providing a molecular mechanism for the tumor-suppressive role first implied by viral oncoprotein targeting.\",\n      \"evidence\": \"Co-IP with LATS1, Western blot for phospho-YAP, MPDZ KO and overexpression in cell lines and xenograft mice\",\n      \"pmids\": [\"34108620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding; independent replication needed\", \"Direct binding interface between MPDZ and LATS1 not structurally resolved\", \"Whether Hippo activation is relevant in ependymal/choroid plexus cells unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Loss of MPDZ (with PATJ) in preimplantation embryos disrupted apical polarity, tight junctions, and Hippo pathway activity in outer cells, suppressing trophectoderm specification — connecting MPDZ scaffolding to the earliest mammalian lineage decision.\",\n      \"evidence\": \"Zygote siRNA microinjection, immunofluorescence, blastocyst assessment\",\n      \"pmids\": [\"37318097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Combined MPDZ+PATJ knockdown does not distinguish individual contributions\", \"Whether MPDZ acts through Hippo directly or via polarity disruption in this context is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the 13 PDZ domains of MPDZ are coordinately regulated to achieve context-specific complex assembly, what post-translational modifications control MPDZ activity, and whether MPDZ dysfunction contributes to human neuropsychiatric phenotypes beyond hydrocephalus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length MPDZ structure available\", \"Post-translational regulation of MPDZ largely uncharacterized\", \"Human genetic studies for neuropsychiatric or vascular phenotypes lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 8, 16, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7, 9, 18, 33]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [16, 17, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 17, 36]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [1, 7, 9, 18, 33]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 10, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [35, 37]}\n    ],\n    \"complexes\": [\n      \"SynGAP-CaMKIIα-MUPP1 synaptic complex\",\n      \"Tight junction scaffold complex (claudin-JAM-CAR-MUPP1)\",\n      \"CRB3-Pals1-PATJ/MUPP1 apical polarity complex\"\n    ],\n    \"partners\": [\n      \"CLDN1\",\n      \"F11R\",\n      \"SYNGAP1\",\n      \"CAMK2A\",\n      \"MTNR1A\",\n      \"GABBR2\",\n      \"DLL4\",\n      \"LATS1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}