{"gene":"WWC1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2003,"finding":"KIBRA was identified as a novel WW domain-containing protein with two N-terminal WW domains, an internal C2-like domain, and a C-terminal glutamic acid-rich stretch. The first WW domain specifically binds PPxY motifs in vitro. Transient transfection showed cytoplasmic localization with perinuclear enrichment.","method":"Yeast two-hybrid screen, in vitro interaction studies, transient transfection with Myc-tagged constructs","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay + localization, single lab, two orthogonal methods","pmids":["12559952"],"is_preprint":false},{"year":2004,"finding":"Protein kinase C zeta (PKCzeta) was identified as a KIBRA-interacting protein, and KIBRA is a novel substrate for PKCzeta phosphorylation.","method":"Co-immunoprecipitation, in vitro kinase assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro kinase assay, single lab","pmids":["15081397"],"is_preprint":false},{"year":2006,"finding":"KIBRA interacts with dynein light chain 1 (DLC1) both in vitro and in vivo, and the KIBRA-DLC1 complex is recruited to ER-responsive promoters. KIBRA-DLC1 interaction is required for estrogen receptor transactivation. KIBRA interacts with histone H3 via its glutamic acid-rich region, facilitating optimal ER transactivation.","method":"Co-immunoprecipitation, in vitro pulldown, chromatin immunoprecipitation (ChIP)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, in vitro binding, single lab with multiple orthogonal methods","pmids":["16684779"],"is_preprint":false},{"year":2008,"finding":"KIBRA was identified as an interaction partner of the polarity protein PATJ via yeast two-hybrid screen; the last four amino acids of KIBRA mediate binding to the eighth PDZ domain of PATJ. KIBRA also directly binds to synaptopodin. Stable knockdown of KIBRA in podocytes impaired directed cell migration.","method":"Yeast two-hybrid screen, co-immunoprecipitation, stable knockdown, directed migration assay","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid, Co-IP, functional KD phenotype, single lab, multiple orthogonal methods","pmids":["18596123"],"is_preprint":false},{"year":2008,"finding":"KIBRA binds via its WW domains to a PPxY motif in the tyrosine kinase receptor DDR1, and this interaction is disrupted by DDR1 ligands collagen type I or IV. KIBRA, DDR1, and PKCzeta form a trimeric complex. Overexpression and knockdown studies showed KIBRA promotes collagen-stimulated MAPK cascade activation.","method":"Co-immunoprecipitation, overexpression/knockdown, MAPK activation assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional gain/loss-of-function, single lab, multiple methods","pmids":["18190796"],"is_preprint":false},{"year":2008,"finding":"KIBRA can form head-to-tail homodimers, and dimerization is mediated by the internal C2-like domain. KIBRA is enriched at the postsynaptic density in hippocampal neurons with somatodendritic distribution.","method":"Binding studies (in vitro), immunohistochemistry, subcellular fractionation","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus localization experiments, single lab","pmids":["18672031"],"is_preprint":false},{"year":2009,"finding":"KIBRA co-immunoprecipitates with PKMzeta (the brain-specific variant of PKCzeta) in adult mouse brain, and co-localizes with PKMzeta in hippocampal CA1, CA3, and dentate gyrus neurons.","method":"Co-immunoprecipitation using anti-KIBRA antibody, immunohistochemistry, in situ hybridization","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from native brain tissue plus co-localization, single lab","pmids":["19129633"],"is_preprint":false},{"year":2010,"finding":"Drosophila Kibra functions as an upstream component of the Hippo signaling pathway together with Merlin and Expanded, forming a protein complex localized to the apical domain of epithelial cells. This complex regulates the Hippo kinase cascade via direct binding to Hpo and Sav. Kibra loss phenocopies hippo pathway mutants.","method":"Genetic epistasis in Drosophila, co-immunoprecipitation, immunofluorescence localization, loss-of-function analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across three concurrent independent papers, genetic epistasis plus Co-IP plus localization","pmids":["20159598"],"is_preprint":false},{"year":2010,"finding":"Drosophila Kibra colocalizes and associates with Merlin (Mer) and Expanded (Ex), promotes the Mer/Ex association, and this association is conserved in human cells. Kibra complexes with Warts and Kibra depletion in tissue culture cells induces marked reduction in Yki phosphorylation without affecting the Yki/Wts interaction.","method":"Co-immunoprecipitation, RNAi knockdown, phosphorylation assays, immunofluorescence","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — independently replicated, multiple orthogonal methods, conserved in human cells","pmids":["20159599"],"is_preprint":false},{"year":2010,"finding":"Drosophila Kibra acts upstream of Hippo and Merlin in the Hippo signaling pathway, acts synergistically with Expanded, and physically interacts with Merlin. Kibra predominantly acts in the Merlin branch upstream of the core kinase cascade.","method":"Genetic epistasis in Drosophila, co-immunoprecipitation, loss-of-function analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent labs simultaneously published, genetic epistasis plus Co-IP","pmids":["20159600"],"is_preprint":false},{"year":2011,"finding":"Human KIBRA associates with and activates LATS1 and LATS2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates YAP phosphorylation; depletion reduces YAP phosphorylation. KIBRA stabilizes LATS2 by inhibiting its ubiquitination.","method":"Co-immunoprecipitation, phosphorylation assays, RNAi knockdown, overexpression, ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, kinase assay, ubiquitination assay, KD/OE), single rigorous study","pmids":["21233212"],"is_preprint":false},{"year":2011,"finding":"KIBRA directly binds to PICK1 and forms a complex with AMPA receptors (AMPARs) in neurons. KIBRA knockdown accelerates the rate of AMPAR recycling following NMDA receptor-induced internalization. Genetic deletion of KIBRA in mice impairs both LTD and LTP at hippocampal Schaffer collateral-CA1 synapses and causes severe deficits in contextual fear learning and memory.","method":"Co-immunoprecipitation, AMPAR recycling assay, electrophysiology in KIBRA knockout mice, behavioral memory tests","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knockout mouse with electrophysiology + behavioral phenotype + molecular binding assays, multiple orthogonal methods","pmids":["21943600"],"is_preprint":false},{"year":2011,"finding":"KIBRA binds to the PAR3-aPKC-PAR6 complex and localizes at tight junctions and apical domains in epithelial cells. KIBRA knockdown causes expansion of the apical domain and suppresses apical-containing vacuole formation through enhanced de novo apical exocytosis. KIBRA directly inhibits the kinase activity of aPKC in vitro.","method":"Co-immunoprecipitation, shRNA knockdown in MDCK 3D cysts, aPKC in vitro kinase assay, immunofluorescence","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay demonstrating direct inhibition plus Co-IP plus functional 3D cyst assay, single lab with multiple rigorous methods","pmids":["21497093"],"is_preprint":false},{"year":2011,"finding":"KIBRA is phosphorylated in a cell cycle-dependent manner with highest phosphorylation in mitosis. Aurora-A and Aurora-B kinases phosphorylate KIBRA both in vitro and in vivo, with Ser539 as the primary phosphorylation site. Wild-type (but not catalytically inactive) protein phosphatase 1 (PP1) associates with KIBRA and dephosphorylates Aurora-phosphorylated KIBRA. KIBRA associates with NF2/Merlin in a Ser539 phosphorylation-dependent manner. KIBRA depletion impairs Aurora-A/PP1 interaction.","method":"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, phospho-specific antibodies, cell cycle synchronization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + Co-IP, single lab with multiple orthogonal methods","pmids":["21878642"],"is_preprint":false},{"year":2011,"finding":"In Drosophila R8 photoreceptors, Kibra (together with Merlin and Lgl, but not Expanded or Fat) is required for Warts expression and activity to specify Rh6 fate, demonstrating a cell-type-specific subset of the Hippo pathway operating in postmitotic neuronal fate specification.","method":"Drosophila genetic loss-of-function, epistasis analysis, immunostaining","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis in Drosophila, single lab","pmids":["22055343"],"is_preprint":false},{"year":2012,"finding":"KIBRA activates Aurora kinases and is required for full Aurora kinase activation during mitosis. KIBRA promotes phosphorylation of LATS2 on Ser83 by activating Aurora-A, controlling LATS2 centrosome localization. Aurora-A is not required for KIBRA to associate with LATS2. KIBRA knockdown causes mitotic abnormalities including spindle/centrosome defects and chromosome misalignment.","method":"In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, immunofluorescence, mitotic phenotype analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + kinase assay + siRNA KD phenotype, single lab","pmids":["22904328"],"is_preprint":false},{"year":2012,"finding":"KIBRA is phosphorylated by CDK1 at Ser542 and Ser931 in response to spindle damage stress. CDC14A/B phosphatases associate with KIBRA and dephosphorylate CDK1-phosphorylated KIBRA in vitro and in cells. CDK1-non-phosphorylatable KIBRA shows reduced interaction with CDC14B. Phospho-regulation of KIBRA by CDK1 and CDC14 is involved in mitotic exit under spindle stress.","method":"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, inducible expression cell lines, phospho-specific antibodies","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase/phosphatase assay + mutagenesis + Co-IP, single lab","pmids":["22784093"],"is_preprint":false},{"year":2012,"finding":"Loss of KIBRA in MCF10A cells produces epithelial-to-mesenchymal transition (EMT) features with decreased LATS and YAP phosphorylation but not MST1/2, demonstrating MST-independent regulation of Hippo signaling. Ectopic KIBRA expression antagonizes YAP via serine 127 phosphorylation.","method":"shRNA knockdown, phosphorylation assays by Western blot, 3D morphogenesis assay, gene expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined molecular phenotype plus phosphorylation assays, single lab","pmids":["22614006"],"is_preprint":false},{"year":2013,"finding":"KIBRA is phosphorylated by ERK1/2 at Ser548 and by RSK1/2 at Thr929 and Ser947 in vitro and in cells. RSK-mediated phosphorylation is required for KIBRA binding to RSK1 but not RSK2. KIBRA knockdown impaired cell migration and proliferation in breast cancer cells; phospho-regulation by ERK1/2 and RSK1/2 is required for proper cell proliferation and migration.","method":"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, inducible expression cell lines, migration/proliferation assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + functional assays, single lab","pmids":["24269383"],"is_preprint":false},{"year":2013,"finding":"KIBRA is necessary and sufficient to stabilize PKMzeta against proteasomal degradation. A short amino acid motif near the C-terminus of KIBRA mediates binding to PKMzeta. Hippocampal knockdown of KIBRA in rats and KIBRA knockout in mice both result in decreased spatial memory performance and decreased PKMzeta protein levels.","method":"Co-immunoprecipitation, proteasome inhibitor experiments, KIBRA knockdown/knockout, behavioral memory assays, Western blot","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KD in rats, KO in mice, behavioral + molecular phenotypes), single rigorous study","pmids":["24117625"],"is_preprint":false},{"year":2013,"finding":"Two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in the C2 domain of KIBRA produce variants with distinct Ca2+-dependent binding preferences for monophosphorylated phosphatidylinositols, likely due to differences in dynamics and folding of the lipid-binding pocket.","method":"Lipid binding assays, structural modeling/dynamics analysis, genetic association","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional lipid binding assays with structural analysis, single lab","pmids":["23778582"],"is_preprint":false},{"year":2014,"finding":"PTPN14 interacts with KIBRA through the PPXY domain of PTPN14 and WW domain of KIBRA. PTPN14 and KIBRA can activate LATS1 independently and cooperatively. PTPN14 increases LATS1 protein stability. KIBRA re-expression rescues PTPN14-knockdown-induced cell migration defects and aberrant 3D morphogenesis through LATS1 activation and cytoplasmic YAP sequestration.","method":"Co-immunoprecipitation, LATS1 kinase assay, shRNA knockdown, 3D morphogenesis assay, rescue experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional KD/rescue, kinase assays, single lab with multiple methods","pmids":["25023289"],"is_preprint":false},{"year":2015,"finding":"Deletion of KIBRA in mice increases filopodial-like long dendritic spines in neocortical and hippocampal neurons both in vivo (Golgi staining) and in vitro. Electron microscopy revealed fewer perforated synapses and spinules in KIBRA knockout neurons.","method":"Constitutive KIBRA knockout mice, Golgi impregnation, immunofluorescence, electron microscopy","journal":"Frontiers in neuroanatomy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with multiple morphological readouts, single lab","pmids":["25750616"],"is_preprint":false},{"year":2016,"finding":"Acetylation of tau at K274 and K281 (mimicked by tauKQ mutation) reduces postsynaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. LTP deficits from tauKQ were rescued by promoting actin polymerization or by KIBRA expression.","method":"Transgenic mouse model, electrophysiology (LTP), AMPAR insertion assay, actin polymerization assay, KIBRA rescue expression","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse + electrophysiology + rescue experiments + molecular mechanism defined, single rigorous study with multiple orthogonal methods","pmids":["27041503"],"is_preprint":false},{"year":2016,"finding":"KIBRA overexpression increases constitutive recycling of GluA1-containing AMPA receptors and favors their activity-dependent surface expression, increases LTP but prevents LTD induction, and causes dendritic rearrangements. KIBRA knockdown abolishes LTP, decreases GluA1-AMPAR recycling, and reduces dendritic arborization.","method":"Lentiviral KIBRA overexpression/knockdown in mice, electrophysiology (LTP/LTD), AMPAR surface expression assay, confocal microscopy of dendritic morphology","journal":"Neurobiology of learning and memory","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo manipulation with electrophysiology + AMPAR assay + morphology, multiple orthogonal methods","pmids":["27498008"],"is_preprint":false},{"year":2017,"finding":"In Drosophila, Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain (the medial apical cortex). Merlin and Kibra together recruit the adapter protein Salvador, which recruits Hippo kinase. Crumbs has a dual effect: promotes Expanded function but sequesters Kibra to downregulate Hippo signaling.","method":"Drosophila genetics (loss-of-function, epistasis), immunofluorescence localization, protein interaction assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus spatial localization analysis plus binding assays, single rigorous study","pmids":["28292426"],"is_preprint":false},{"year":2017,"finding":"KIBRA overexpression in murine podocytes promoted LATS kinase phosphorylation leading to YAP Ser-127 phosphorylation, YAP cytoplasmic sequestration, and reduction in YAP target gene expression. KIBRA overexpression induced actin cytoskeletal disruption and reduction of focal adhesions, rescued by YAP overexpression. Constitutive KIBRA knockout mice displayed reduced phospho-YAP and were protected from acute podocyte foot process effacement.","method":"KIBRA overexpression/knockout in podocytes and mice, phosphorylation assays, immunofluorescence, in vivo protamine sulfate injury model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse in vivo model plus in vitro gain/loss of function with rescue, multiple orthogonal methods","pmids":["28982981"],"is_preprint":false},{"year":2018,"finding":"KIBRA functions cooperatively with PTPN14 to trigger mechanotransduction-regulated signals that inhibit nuclear localization of YAP/TAZ. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro.","method":"In vivo metastasis assay, tumorsphere formation assay, co-immunoprecipitation, nuclear/cytoplasmic fractionation","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo metastasis assay plus Co-IP plus YAP localization, single lab","pmids":["29562176"],"is_preprint":false},{"year":2018,"finding":"The EZH2-H3K27me3-DNMT1 complex is enriched at the wwc1 promoter and mediates epigenetic silencing of KIBRA in triple-negative breast cancer cells. EZH2 knockdown leads to partial increase in KIBRA expression and reduction in H3K27me3 and DNMT1 at the promoter.","method":"Co-immunoprecipitation, ChIP, bisulfite sequencing, MeDIP, ChIP-qPCR, shRNA knockdown","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple epigenetic methods (ChIP, MeDIP, bisulfite sequencing, Co-IP), single lab","pmids":["30121333"],"is_preprint":false},{"year":2019,"finding":"KIBRA stabilizes Rab27a by preventing its ubiquitination and proteasomal degradation through direct protein interaction. KIBRA knockdown or overexpression in neuronal and podocyte cell lines decreases or increases exosome secretion respectively. KIBRA depletion increases MVB size and number. KIBRA knockout mouse brains show significantly decreased Rab27a.","method":"Co-immunoprecipitation, ubiquitination assay, KIBRA KO mouse, nanoparticle tracking analysis (exosome quantification), electron microscopy of MVBs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse plus in vitro binding plus ubiquitination assay plus functional exosome readout, multiple orthogonal methods in single study","pmids":["30967557"],"is_preprint":false},{"year":2019,"finding":"Kibra binds to postsynaptic density-enriched Dendrin via its N-terminal WW1-WW2 tandem domains with nanomolar affinity. Crystal structure of Kibra WW12 in complex with Dendrin PY motifs was determined. A peptide inhibitor blocking Kibra-Dendrin interaction attenuated excitatory synaptic transmission, blocked LTP induction, and impaired spatial learning and memory. A Tourette syndrome patient mutation in Kibra causes defects in Dendrin binding.","method":"Crystal structure determination, isothermal titration calorimetry (ITC), peptide inhibitor design, electrophysiology, behavioral memory assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + ITC + functional inhibitor + electrophysiology + behavioral assays, multiple rigorous orthogonal methods","pmids":["30784589"],"is_preprint":false},{"year":2019,"finding":"KIBRA stabilization of PKMzeta is isoform-specific in Aplysia: different splice isoforms of KIBRA in a conserved C-terminal region stabilize different PKM isoforms based on an isoform-specific α-helix 'handle' in PKMs. Isoform-specific competition for KIBRA stabilization determines the selectivity of dominant-negative PKMs in erasing long-term facilitation.","method":"Overexpression in Aplysia sensorimotor neurons, dominant-negative PKM isoform competition, synaptic facilitation assays","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional isoform-specific rescue/competition assays in Aplysia, single lab","pmids":["31537706"],"is_preprint":false},{"year":2021,"finding":"In Drosophila, Hippo pathway activation promotes Kibra degradation via SCFSlimb-mediated ubiquitination independently of Yorkie-mediated transcription. This mechanism requires Merlin, Salvador, Hpo, and Warts, and functions independently of other upstream Hippo pathway activators. Kibra degradation is patterned by differences in mechanical tension across the wing.","method":"Drosophila genetics, ubiquitination assays, epistasis analysis, live imaging","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus ubiquitination assays, single lab","pmids":["33555257"],"is_preprint":false},{"year":2022,"finding":"Under basal conditions, WWC1 and LATS kinases are associated, sequestering WWC1 from synaptic AMPAR complexes. A point mutation disrupting WWC1/LATS binding elevates WWC1 abundance in AMPAR complexes and improves hippocampal-dependent learning and memory in mice.","method":"Cell-surface proteomics in hippocampal tissue of Wwc1-deficient mice, hippocampus-specific interactome, point mutation knock-in, behavioral memory tests","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics + knock-in mutation + behavioral assays, single rigorous study with multiple orthogonal methods","pmids":["36476872"],"is_preprint":false},{"year":2022,"finding":"Adult-onset (but not juvenile-onset) deletion of KIBRA in forebrain neurons impairs LTP and long-term spatial memory. Adult KIBRA deletion decreases extrasynaptic AMPAR levels under basal conditions and impairs LTP-induced AMPAR upregulation.","method":"Inducible KIBRA knockout mouse, electrophysiology (LTP), AMPAR surface expression assay, behavioral memory tests","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible KO mouse with electrophysiology and AMPAR assay, single lab","pmids":["36465112"],"is_preprint":false},{"year":2023,"finding":"In Drosophila epithelial cells, apical polarity network (via aPKC) tethers Kibra at the junctional cortex to silence its activity, while medial actomyosin flows promote Kibra-mediated Hippo complex formation at the medial cortex to activate the pathway.","method":"Drosophila genetics, live imaging, immunofluorescence, actomyosin perturbation experiments","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with genetic perturbations, single lab","pmids":["37729921"],"is_preprint":false},{"year":2023,"finding":"WWC1 and its paralogs (WWC2/3) bind directly to angiomotin (AMOT) family proteins and recruit USP9X to deubiquitinate and stabilize Motins. Neuron-specific deletion of Wwc1 and Wwc2 reduces Molin levels, decreases dendritic spine density, and impairs memory and learning. Ectopic AMOT expression partially rescues these neuronal phenotypes.","method":"Co-immunoprecipitation, deubiquitination assays, neuron-specific conditional knockout mice, dendritic spine quantification, behavioral memory tests, rescue expression","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP + deubiquitination assay + conditional KO mouse + rescue, multiple orthogonal methods in single study","pmids":["37528078"],"is_preprint":false},{"year":2024,"finding":"KIBRA complexes with PKMzeta at activated synapses, anchoring the kinase's potentiating action to maintain late-phase LTP and long-term spatial memory. Two structurally distinct KIBRA-PKMzeta dimerization antagonists disrupt established late-LTP and long-term memory without affecting basal synaptic transmission. The effect of both antagonists requires PKMzeta (no effect in PKMzeta knockout mice).","method":"Peptide antagonists of KIBRA-PKMzeta interaction, electrophysiology (late-LTP), PKMzeta knockout mouse epistasis, behavioral memory assays, co-immunoprecipitation","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — two structurally distinct antagonists + KO epistasis + electrophysiology + behavioral assays, rigorous multi-method study","pmids":["38924398"],"is_preprint":false},{"year":2024,"finding":"The C-terminus of KIBRA (CT-KIBRA) restores synaptic plasticity and memory in transgenic mice expressing pathogenic human tau by stabilizing PKMzeta, without altering tau levels or preventing tau-induced synapse loss. Reduced brain KIBRA and increased CSF KIBRA are associated with cognitive impairment and pathological tau in disease.","method":"CT-KIBRA expression in tau transgenic mice, electrophysiology (LTP), PKMzeta protein level measurement, behavioral memory tests, human CSF/brain biomarker analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo rescue in transgenic mice + mechanistic PKMzeta stabilization + human biomarker, multiple orthogonal methods","pmids":["38299587"],"is_preprint":false},{"year":2024,"finding":"Phosphorylation of LATS1/2 by upstream kinases MST1/2 enhances the interaction between WWC1 and LATS1/2, sequestering WWC1 from AMPAR complexes. Pharmacological inhibition of MST1/2 promotes dissociation of WWC1 from LATS1/2, increasing WWC1 in AMPAR-containing complexes, enhancing synaptic transmission, and improving cognition in healthy mice, Alzheimer's disease models, and aging models.","method":"Phosphorylation assays, co-immunoprecipitation, MST1/2 pharmacological inhibition in mice and human brain organoids, electrophysiology, cognitive behavioral assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical mechanistic dissection + pharmacological in vivo intervention + human organoids + behavioral assays, multiple orthogonal methods","pmids":["38687825"],"is_preprint":false},{"year":2016,"finding":"KIBRA is a physiological substrate of ATM kinase; ATM phosphorylates KIBRA at Thr1006 within an SQ consensus motif. T1006 phosphorylation is essential for optimal DNA double-strand break repair, and KIBRA depletion compromises DNA repair functions, likely via the NHEJ pathway.","method":"Site-directed mutagenesis, phospho-(S/T)Q antibody, γ-H2AX assay, pulsed-field gel electrophoresis, Comet assay, TUNEL assay, clonogenic survival assay, shRNA knockdown, CRISPR-Cas9 knockout","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis + multiple DNA repair assays + KD/KO/KI, single lab with multiple methods","pmids":["26929199"],"is_preprint":false},{"year":2015,"finding":"In Drosophila, Kibra is required for starvation-induced autophagy; absence of Kibra caused defects in autophagic vesicle formation and autophagic degradation. aPKC interacts with Kibra in S2 cells and Drosophila larva, and constitutively active aPKC decreased autophagic vesicle formation upstream of Kibra.","method":"Drosophila genetics, autophagy flux assays, co-immunoprecipitation in S2 cells, immunostaining","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function + functional autophagy assay + Co-IP, single lab","pmids":["26551466"],"is_preprint":false}],"current_model":"KIBRA/WWC1 is a multifunctional postsynaptic scaffold protein that activates the Hippo pathway by forming apical complexes with Merlin/NF2 and Expanded, directly binding and activating LATS1/2 kinases (thereby promoting YAP/TAZ phosphorylation and cytoplasmic retention), while in neurons it anchors PKMzeta at activated synapses to prevent its proteasomal degradation and maintain late-LTP and long-term memory, and also regulates AMPA receptor trafficking and synaptic plasticity by being released from inhibitory LATS1/2 sequestration to join AMPAR-regulatory complexes; additionally, KIBRA inhibits aPKC kinase activity to control epithelial polarity and apical exocytosis, stabilizes Rab27a to control exosome secretion, stabilizes angiomotin proteins via USP9X recruitment, undergoes cell cycle-dependent phosphorylation by Aurora, CDK1, ERK, and RSK kinases, and is subject to ATM-mediated phosphorylation required for DNA repair."},"narrative":{"mechanistic_narrative":"WWC1/KIBRA is a multidomain WW- and C2-domain scaffold that couples cell-junctional and cytoskeletal cues to the Hippo growth-control pathway and, in neurons, to synaptic plasticity machinery [PMID:12559952, PMID:20159598]. As a conserved upstream Hippo component it forms an apical complex with Merlin and Expanded that recruits Salvador and the Hippo/Warts kinases to activate the core cascade [PMID:20159598, PMID:20159599, PMID:20159600, PMID:28292426]; in mammalian cells KIBRA associates with and stimulates LATS1/2 hydrophobic-motif phosphorylation and stabilizes LATS2 against ubiquitination, thereby driving YAP Ser127 phosphorylation and cytoplasmic sequestration in an MST-independent manner [PMID:21233212, PMID:22614006]. This activity is integrated with mechanotransduction through cooperation with PTPN14 to restrain YAP/TAZ nuclear entry and suppress migration, EMT, and metastasis [PMID:25023289, PMID:29562176], and KIBRA is epigenetically silenced via an EZH2–H3K27me3–DNMT1 complex in triple-negative breast cancer [PMID:30121333]. KIBRA additionally controls epithelial apical polarity and exocytosis by binding the PAR3–aPKC–PAR6 complex and directly inhibiting aPKC kinase activity [PMID:21497093], and stabilizes Rab27a by blocking its ubiquitination to govern exosome secretion [PMID:30967557] and angiomotin proteins by recruiting USP9X for their deubiquitination [PMID:37528078]. In the nervous system KIBRA is a postsynaptic density scaffold that anchors PKMzeta at activated synapses and protects it from proteasomal degradation to maintain late-LTP and long-term memory [PMID:24117625, PMID:38924398, PMID:38299587], regulates GluA1-AMPAR recycling and surface expression and dendritic spine morphology [PMID:21943600, PMID:27498008, PMID:25750616], and joins AMPAR-regulatory complexes when released from inhibitory sequestration by LATS1/2; MST1/2-driven LATS phosphorylation strengthens WWC1–LATS binding and withholds WWC1 from AMPAR complexes, so disrupting this interaction enhances synaptic transmission and cognition [PMID:36476872, PMID:38687825]. KIBRA is heavily phospho-regulated across the cell cycle by Aurora, CDK1, ERK, and RSK kinases [PMID:21878642, PMID:22904328, PMID:22784093, PMID:24269383] and is an ATM substrate required for DNA double-strand break repair [PMID:26929199].","teleology":[{"year":2003,"claim":"Establishing KIBRA's domain architecture defined it as a WW/C2 scaffold capable of binding PPxY-motif partners, framing all subsequent interaction work.","evidence":"Yeast two-hybrid, in vitro PPxY binding, and transfection localization of Myc-tagged KIBRA","pmids":["12559952"],"confidence":"Medium","gaps":["No physiological in vivo partner identified at this stage","Function of C2 and glutamate-rich domains undefined"]},{"year":2004,"claim":"Identifying PKCzeta as a KIBRA interactor and kinase linked KIBRA to atypical PKC signaling, an axis later extended to neuronal PKMzeta and epithelial aPKC.","evidence":"Co-IP and in vitro kinase assay","pmids":["15081397"],"confidence":"Medium","gaps":["Functional consequence of phosphorylation not defined","Cellular context not established"]},{"year":2006,"claim":"Linking KIBRA to DLC1 and histone H3 at ER-responsive promoters proposed a nuclear/transcriptional co-regulatory role distinct from its later scaffold functions.","evidence":"Reciprocal Co-IP, in vitro pulldown, ChIP","pmids":["16684779"],"confidence":"Medium","gaps":["Nuclear role not integrated with predominantly cytoplasmic localization","Not independently extended in later corpus"]},{"year":2008,"claim":"Multiple partner and dimerization studies established KIBRA as a polarity- and receptor-associated scaffold (PATJ, synaptopodin, DDR1) that self-associates and concentrates at the postsynaptic density.","evidence":"Yeast two-hybrid, Co-IP, knockdown migration assays, in vitro dimerization binding, IHC/fractionation","pmids":["18596123","18190796","18672031"],"confidence":"Medium","gaps":["Functional hierarchy among partners unclear","Postsynaptic role not yet mechanistically defined"]},{"year":2010,"claim":"Three concurrent Drosophila studies placed Kibra as a conserved upstream Hippo pathway component acting with Merlin and Expanded to drive the core kinase cascade and Yorkie phosphorylation.","evidence":"Genetic epistasis, Co-IP, immunofluorescence, RNAi with phosphorylation readouts; conservation tested in human cells","pmids":["20159598","20159599","20159600"],"confidence":"High","gaps":["Direct mammalian kinase target not yet defined","Mechanism of cascade activation by the complex unresolved"]},{"year":2011,"claim":"Mammalian KIBRA was shown to directly activate LATS1/2 and stabilize LATS2, providing the biochemical mechanism by which it promotes YAP phosphorylation and cytoplasmic retention.","evidence":"Co-IP, kinase/phosphorylation assays, ubiquitination assay, KD/OE","pmids":["21233212"],"confidence":"High","gaps":["Structural basis of LATS activation not resolved","Regulation of KIBRA-LATS engagement not yet defined"]},{"year":2011,"claim":"KIBRA's role in epithelial polarity was mechanistically defined as direct aPKC inhibition controlling apical domain size and exocytosis.","evidence":"Co-IP, shRNA in MDCK 3D cysts, aPKC in vitro kinase assay, immunofluorescence","pmids":["21497093"],"confidence":"High","gaps":["Relationship between aPKC inhibition and Hippo activation unresolved","In vivo epithelial relevance not tested here"]},{"year":2011,"claim":"KIBRA was established as a postsynaptic regulator of AMPAR trafficking and plasticity, with knockout mice showing LTP/LTD and memory deficits, anchoring its neuronal function.","evidence":"Co-IP with PICK1/AMPAR, AMPAR recycling assay, electrophysiology and behavior in KIBRA KO mice","pmids":["21943600"],"confidence":"High","gaps":["Molecular link between KIBRA and recycling machinery incomplete","Relationship to Hippo signaling in neurons not addressed"]},{"year":2011,"claim":"KIBRA was shown to undergo cell-cycle-dependent, Aurora-driven phosphorylation reversed by PP1, connecting it to mitotic regulation and phospho-dependent Merlin binding.","evidence":"In vitro kinase assay, site-directed mutagenesis, Co-IP, phospho-specific antibodies, cell-cycle synchronization","pmids":["21878642"],"confidence":"High","gaps":["Functional output of Ser539 phosphorylation beyond Merlin binding unclear"]},{"year":2012,"claim":"Mitotic studies expanded KIBRA's cell-cycle role to Aurora-A activation, LATS2 centrosome targeting, and CDK1/CDC14-regulated mitotic exit under spindle stress.","evidence":"In vitro kinase/phosphatase assays, mutagenesis, Co-IP, siRNA mitotic phenotyping","pmids":["22904328","22784093"],"confidence":"Medium","gaps":["Integration with interphase Hippo signaling unclear","Physiological significance of spindle-stress phospho-sites untested in vivo"]},{"year":2012,"claim":"Loss of KIBRA was shown to drive EMT through MST-independent reduction of LATS/YAP phosphorylation, framing KIBRA as a tumor suppressor branch of Hippo signaling.","evidence":"shRNA KD, phosphorylation Westerns, 3D morphogenesis, expression analysis","pmids":["22614006"],"confidence":"Medium","gaps":["Upstream activator substituting for MST not identified","In vivo tumor relevance not tested here"]},{"year":2013,"claim":"KIBRA was defined as the stabilizer that protects PKMzeta from proteasomal degradation, providing the molecular basis for its role in maintaining long-term memory.","evidence":"Co-IP, proteasome inhibition, KIBRA KD in rats and KO in mice, behavioral assays","pmids":["24117625"],"confidence":"High","gaps":["Structural basis of the C-terminal PKMzeta-binding motif not yet solved","Mechanism preventing degradation not detailed"]},{"year":2013,"claim":"Identification of ERK/RSK phosphorylation sites tied KIBRA's phospho-state to cell migration and proliferation control in cancer cells.","evidence":"In vitro kinase assay, mutagenesis, Co-IP, migration/proliferation assays","pmids":["24269383"],"confidence":"Medium","gaps":["Downstream effectors of these phospho-sites unclear","Interplay with Hippo phospho-regulation unresolved"]},{"year":2013,"claim":"Common C2-domain SNPs were shown to alter Ca2+-dependent phosphoinositide binding, providing a structural rationale for KIBRA membrane association and genetic variation.","evidence":"Lipid binding assays, structural modeling, genetic association","pmids":["23778582"],"confidence":"Medium","gaps":["Cellular consequence of altered lipid binding not demonstrated","Link to memory phenotypes correlative"]},{"year":2014,"claim":"PTPN14 was identified as a KIBRA partner that cooperatively activates LATS1 and stabilizes it, extending KIBRA's Hippo regulatory network and migration control.","evidence":"Co-IP, LATS1 kinase assay, shRNA KD, 3D morphogenesis, rescue","pmids":["25023289"],"confidence":"Medium","gaps":["Whether KIBRA and PTPN14 act in one complex or parallel pathways unresolved"]},{"year":2015,"claim":"KIBRA knockout altered dendritic spine morphology and synaptic ultrastructure, linking it to structural plasticity beyond receptor trafficking.","evidence":"KIBRA KO mice, Golgi staining, immunofluorescence, electron microscopy","pmids":["25750616"],"confidence":"Medium","gaps":["Molecular driver of spine morphology changes not identified"]},{"year":2015,"claim":"Drosophila work implicated Kibra in starvation-induced autophagy downstream of aPKC, broadening its functional repertoire.","evidence":"Drosophila genetics, autophagy flux assays, Co-IP in S2 cells","pmids":["26551466"],"confidence":"Medium","gaps":["Mammalian conservation of autophagy role untested","Mechanism connecting Kibra to autophagosome formation unclear"]},{"year":2016,"claim":"KIBRA was identified as an ATM substrate (Thr1006) required for efficient double-strand break repair, revealing a genome-maintenance function.","evidence":"Mutagenesis, phospho-(S/T)Q antibody, γ-H2AX/Comet/PFGE/TUNEL assays, KD/KO/KI","pmids":["26929199"],"confidence":"Medium","gaps":["Direct role in NHEJ machinery not defined","Relationship to cytoplasmic scaffold functions unclear"]},{"year":2016,"claim":"Two neuronal studies showed KIBRA is required for activity-dependent actin remodeling, AMPAR insertion, and GluA1 recycling, and that its loss underlies tau-acetylation LTP deficits.","evidence":"Tau transgenic and lentiviral OE/KD mice, electrophysiology, AMPAR/actin assays, KIBRA rescue","pmids":["27041503","27498008"],"confidence":"High","gaps":["Direct biochemical link between KIBRA and actin machinery not defined"]},{"year":2017,"claim":"Drosophila and podocyte studies refined KIBRA's spatial Hippo regulation (medial cortex, Salvador recruitment, Crumbs sequestration) and established its YAP-dependent control of cytoskeleton and injury resistance in vivo.","evidence":"Drosophila genetics/localization; KIBRA OE/KO in podocytes and mice with phosphorylation and injury models","pmids":["28292426","28982981"],"confidence":"High","gaps":["Mammalian counterpart of medial-cortex localization not mapped","Crumbs-equivalent sequestration in mammals untested"]},{"year":2018,"claim":"KIBRA was shown to cooperate with PTPN14 in mechanotransduction-controlled YAP/TAZ exclusion and to suppress metastasis, while EZH2-mediated promoter silencing explained KIBRA loss in TNBC.","evidence":"In vivo metastasis and tumorsphere assays, Co-IP, fractionation; ChIP/MeDIP/bisulfite sequencing with EZH2 KD","pmids":["29562176","30121333"],"confidence":"Medium","gaps":["Mechanosensing input upstream of KIBRA not molecularly defined"]},{"year":2019,"claim":"KIBRA was established as a stabilizer of partner proteins by blocking their ubiquitination — stabilizing Rab27a to control exosome secretion and binding Dendrin via its WW12 tandem with structurally defined nanomolar affinity to support synaptic transmission and memory.","evidence":"Co-IP, ubiquitination assay, KO mice, exosome quantification; crystal structure, ITC, peptide inhibitor, electrophysiology, behavior","pmids":["30967557","30784589"],"confidence":"High","gaps":["Selectivity determinants for KIBRA's stabilization targets incompletely defined","Disease mutation effects on Dendrin binding only partly characterized"]},{"year":2019,"claim":"Aplysia work demonstrated isoform-specific KIBRA–PKM stabilization, showing structural 'handle' selectivity governs which PKM is protected and which memory is maintained.","evidence":"Isoform overexpression and dominant-negative competition in Aplysia sensorimotor neurons, facilitation assays","pmids":["31537706"],"confidence":"Medium","gaps":["Mammalian isoform selectivity not tested","Structural handle not resolved at atomic level"]},{"year":2021,"claim":"Hippo activation was shown to feedback-degrade Kibra via SCFSlimb ubiquitination patterned by mechanical tension, revealing autoregulation of the pathway.","evidence":"Drosophila genetics, ubiquitination assays, live imaging","pmids":["33555257"],"confidence":"Medium","gaps":["Mammalian conservation of Slimb/βTrCP-mediated KIBRA turnover untested"]},{"year":2022,"claim":"Studies established that LATS kinases sequester WWC1 from AMPAR complexes under basal conditions, so disrupting WWC1–LATS binding boosts synaptic WWC1 and memory, unifying the Hippo and plasticity functions.","evidence":"Cell-surface proteomics, point-mutation knock-in mice, inducible KO, electrophysiology, behavior","pmids":["36476872","36465112"],"confidence":"High","gaps":["Trigger releasing WWC1 from LATS during plasticity not fully defined here"]},{"year":2023,"claim":"Work resolved upstream control of KIBRA localization/activity (aPKC junctional tethering vs actomyosin medial activation) and defined the WWC–USP9X–angiomotin stabilization axis as critical for spine density and memory.","evidence":"Drosophila live imaging/genetics; Co-IP, deubiquitination assays, neuron-specific conditional KO and AMOT rescue","pmids":["37729921","37528078"],"confidence":"High","gaps":["Mammalian aPKC/actomyosin control of KIBRA localization not directly tested","How AMOT stabilization feeds neuronal plasticity unresolved"]},{"year":2024,"claim":"Multiple studies converged on the WWC1–PKMzeta and WWC1–LATS/MST axes as pharmacologically tractable nodes: PKMzeta-anchoring antagonists erase memory, CT-KIBRA rescues tau-driven deficits, and MST1/2 inhibition releases WWC1 to enhance cognition in disease models.","evidence":"Peptide antagonists with PKMzeta KO epistasis, CT-KIBRA in tau transgenics with human biomarkers, MST1/2 inhibition in mice/organoids with electrophysiology and behavior","pmids":["38924398","38299587","38687825"],"confidence":"High","gaps":["Long-term safety/specificity of disrupting WWC1 interactions unknown","Structural basis of KIBRA-PKMzeta dimer not solved"]},{"year":null,"claim":"How KIBRA's diverse functions — Hippo activation, aPKC/polarity control, PKMzeta anchoring, partner stabilization, mitotic regulation, and DNA repair — are coordinated through a single phospho- and localization-regulated scaffold remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model integrating WW, C2, and C-terminal motif engagements","Switch logic determining which partner KIBRA engages in a given context unknown","Mammalian conservation of several Drosophila regulatory mechanisms untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,7,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,12,29,36]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[20]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[12,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[26,22]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[11,19,37]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13,15,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,25]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[29]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[40]}],"complexes":["Kibra-Merlin-Expanded apical Hippo complex","PAR3-aPKC-PAR6 polarity complex","KIBRA-PKMzeta synaptic complex","KIBRA-DDR1-PKCzeta trimeric complex"],"partners":["LATS1","LATS2","PKMZETA","PRKCZ","NF2","PTPN14","USP9X","RAB27A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IX03","full_name":"Protein KIBRA","aliases":["HBeAg-binding protein 3","Kidney and brain protein","KIBRA","WW domain-containing protein 1"],"length_aa":1113,"mass_kda":125.3,"function":"Regulator of the Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway (PubMed:24682284). Enhances phosphorylation of LATS1 and YAP1 and negatively regulates cell proliferation and organ growth due to a suppression of the transcriptional activity of YAP1, the major effector of the Hippo pathway (PubMed:24682284). Along with NF2 can synergistically induce the phosphorylation of LATS1 and LATS2 and function in the regulation of Hippo signaling pathway (PubMed:20159598). Acts as a transcriptional coactivator of ESR1 which plays an essential role in DYNLL1-mediated ESR1 transactivation (PubMed:16684779). Regulates collagen-stimulated activation of the ERK/MAPK cascade (PubMed:18190796). Modulates directional migration of podocytes (PubMed:18596123). Plays a role in cognition and memory performance (PubMed:18672031). Plays an important role in regulating AMPA-selective glutamate receptors (AMPARs) trafficking underlying synaptic plasticity and learning (By similarity)","subcellular_location":"Cytoplasm, perinuclear region; Nucleus; Cell projection, ruffle membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q8IX03/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WWC1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WWC1","total_profiled":1310},"omim":[{"mim_id":"620110","title":"WW AND C2 DOMAINS-CONTAINING PROTEIN 2; WWC2","url":"https://www.omim.org/entry/620110"},{"mim_id":"615602","title":"MEMORY QUANTITATIVE TRAIT LOCUS; MEMRYQTL","url":"https://www.omim.org/entry/615602"},{"mim_id":"611675","title":"KIAA0513 GENE; KIAA0513","url":"https://www.omim.org/entry/611675"},{"mim_id":"610533","title":"WW AND C2 DOMAINS-CONTAINING PROTEIN 1; WWC1","url":"https://www.omim.org/entry/610533"},{"mim_id":"301089","title":"WWC FAMILY, MEMBER 3; WWC3","url":"https://www.omim.org/entry/301089"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"salivary gland","ntpm":134.1}],"url":"https://www.proteinatlas.org/search/WWC1"},"hgnc":{"alias_symbol":["KIBRA","KIAA0869","PPP1R168"],"prev_symbol":[]},"alphafold":{"accession":"Q8IX03","domains":[{"cath_id":"2.20.70.10","chopping":"13-92","consensus_level":"medium","plddt":80.7234,"start":13,"end":92},{"cath_id":"2.60.40.150","chopping":"662-783","consensus_level":"high","plddt":89.4686,"start":662,"end":783}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IX03","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IX03-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IX03-F1-predicted_aligned_error_v6.png","plddt_mean":60.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WWC1","jax_strain_url":"https://www.jax.org/strain/search?query=WWC1"},"sequence":{"accession":"Q8IX03","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IX03.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IX03/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IX03"}},"corpus_meta":[{"pmid":"20159598","id":"PMC_20159598","title":"Kibra 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/20159600","citation_count":266,"is_preprint":false},{"pmid":"27041503","id":"PMC_27041503","title":"Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss.","date":"2016","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/27041503","citation_count":226,"is_preprint":false},{"pmid":"30967557","id":"PMC_30967557","title":"KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30967557","citation_count":193,"is_preprint":false},{"pmid":"21233212","id":"PMC_21233212","title":"KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases.","date":"2011","source":"The Journal of biological 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podocytes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/18596123","citation_count":108,"is_preprint":false},{"pmid":"28292426","id":"PMC_28292426","title":"Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded.","date":"2017","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/28292426","citation_count":96,"is_preprint":false},{"pmid":"18789830","id":"PMC_18789830","title":"Evidence for an association between KIBRA and late-onset Alzheimer's disease.","date":"2008","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/18789830","citation_count":95,"is_preprint":false},{"pmid":"15081397","id":"PMC_15081397","title":"KIBRA is a novel substrate for protein kinase Czeta.","date":"2004","source":"Biochemical and biophysical research 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episodic memory in later life, but does not increase the risk of mild cognitive impairment.","date":"2008","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18194457","citation_count":78,"is_preprint":false},{"pmid":"18672031","id":"PMC_18672031","title":"Temporal-spatial expression and novel biochemical properties of the memory-related protein KIBRA.","date":"2008","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/18672031","citation_count":73,"is_preprint":false},{"pmid":"24117625","id":"PMC_24117625","title":"KIBRA (KIdney/BRAin protein) regulates learning and memory and stabilizes Protein kinase Mζ.","date":"2013","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24117625","citation_count":70,"is_preprint":false},{"pmid":"23065961","id":"PMC_23065961","title":"Association of KIBRA with episodic and working memory: a meta-analysis.","date":"2012","source":"American journal of medical genetics. 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The first WW domain specifically binds PPxY motifs in vitro. Transient transfection showed cytoplasmic localization with perinuclear enrichment.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro interaction studies, transient transfection with Myc-tagged constructs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay + localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"12559952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Protein kinase C zeta (PKCzeta) was identified as a KIBRA-interacting protein, and KIBRA is a novel substrate for PKCzeta phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro kinase assay, single lab\",\n      \"pmids\": [\"15081397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KIBRA interacts with dynein light chain 1 (DLC1) both in vitro and in vivo, and the KIBRA-DLC1 complex is recruited to ER-responsive promoters. KIBRA-DLC1 interaction is required for estrogen receptor transactivation. KIBRA interacts with histone H3 via its glutamic acid-rich region, facilitating optimal ER transactivation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro pulldown, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, in vitro binding, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16684779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIBRA was identified as an interaction partner of the polarity protein PATJ via yeast two-hybrid screen; the last four amino acids of KIBRA mediate binding to the eighth PDZ domain of PATJ. KIBRA also directly binds to synaptopodin. Stable knockdown of KIBRA in podocytes impaired directed cell migration.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, stable knockdown, directed migration assay\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid, Co-IP, functional KD phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18596123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIBRA binds via its WW domains to a PPxY motif in the tyrosine kinase receptor DDR1, and this interaction is disrupted by DDR1 ligands collagen type I or IV. KIBRA, DDR1, and PKCzeta form a trimeric complex. Overexpression and knockdown studies showed KIBRA promotes collagen-stimulated MAPK cascade activation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, MAPK activation assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional gain/loss-of-function, single lab, multiple methods\",\n      \"pmids\": [\"18190796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIBRA can form head-to-tail homodimers, and dimerization is mediated by the internal C2-like domain. KIBRA is enriched at the postsynaptic density in hippocampal neurons with somatodendritic distribution.\",\n      \"method\": \"Binding studies (in vitro), immunohistochemistry, subcellular fractionation\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus localization experiments, single lab\",\n      \"pmids\": [\"18672031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KIBRA co-immunoprecipitates with PKMzeta (the brain-specific variant of PKCzeta) in adult mouse brain, and co-localizes with PKMzeta in hippocampal CA1, CA3, and dentate gyrus neurons.\",\n      \"method\": \"Co-immunoprecipitation using anti-KIBRA antibody, immunohistochemistry, in situ hybridization\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from native brain tissue plus co-localization, single lab\",\n      \"pmids\": [\"19129633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Kibra functions as an upstream component of the Hippo signaling pathway together with Merlin and Expanded, forming a protein complex localized to the apical domain of epithelial cells. This complex regulates the Hippo kinase cascade via direct binding to Hpo and Sav. Kibra loss phenocopies hippo pathway mutants.\",\n      \"method\": \"Genetic epistasis in Drosophila, co-immunoprecipitation, immunofluorescence localization, loss-of-function analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across three concurrent independent papers, genetic epistasis plus Co-IP plus localization\",\n      \"pmids\": [\"20159598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Kibra colocalizes and associates with Merlin (Mer) and Expanded (Ex), promotes the Mer/Ex association, and this association is conserved in human cells. Kibra complexes with Warts and Kibra depletion in tissue culture cells induces marked reduction in Yki phosphorylation without affecting the Yki/Wts interaction.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, phosphorylation assays, immunofluorescence\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independently replicated, multiple orthogonal methods, conserved in human cells\",\n      \"pmids\": [\"20159599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Kibra acts upstream of Hippo and Merlin in the Hippo signaling pathway, acts synergistically with Expanded, and physically interacts with Merlin. Kibra predominantly acts in the Merlin branch upstream of the core kinase cascade.\",\n      \"method\": \"Genetic epistasis in Drosophila, co-immunoprecipitation, loss-of-function analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent labs simultaneously published, genetic epistasis plus Co-IP\",\n      \"pmids\": [\"20159600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human KIBRA associates with and activates LATS1 and LATS2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates YAP phosphorylation; depletion reduces YAP phosphorylation. KIBRA stabilizes LATS2 by inhibiting its ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, RNAi knockdown, overexpression, ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, kinase assay, ubiquitination assay, KD/OE), single rigorous study\",\n      \"pmids\": [\"21233212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIBRA directly binds to PICK1 and forms a complex with AMPA receptors (AMPARs) in neurons. KIBRA knockdown accelerates the rate of AMPAR recycling following NMDA receptor-induced internalization. Genetic deletion of KIBRA in mice impairs both LTD and LTP at hippocampal Schaffer collateral-CA1 synapses and causes severe deficits in contextual fear learning and memory.\",\n      \"method\": \"Co-immunoprecipitation, AMPAR recycling assay, electrophysiology in KIBRA knockout mice, behavioral memory tests\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knockout mouse with electrophysiology + behavioral phenotype + molecular binding assays, multiple orthogonal methods\",\n      \"pmids\": [\"21943600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIBRA binds to the PAR3-aPKC-PAR6 complex and localizes at tight junctions and apical domains in epithelial cells. KIBRA knockdown causes expansion of the apical domain and suppresses apical-containing vacuole formation through enhanced de novo apical exocytosis. KIBRA directly inhibits the kinase activity of aPKC in vitro.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown in MDCK 3D cysts, aPKC in vitro kinase assay, immunofluorescence\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay demonstrating direct inhibition plus Co-IP plus functional 3D cyst assay, single lab with multiple rigorous methods\",\n      \"pmids\": [\"21497093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KIBRA is phosphorylated in a cell cycle-dependent manner with highest phosphorylation in mitosis. Aurora-A and Aurora-B kinases phosphorylate KIBRA both in vitro and in vivo, with Ser539 as the primary phosphorylation site. Wild-type (but not catalytically inactive) protein phosphatase 1 (PP1) associates with KIBRA and dephosphorylates Aurora-phosphorylated KIBRA. KIBRA associates with NF2/Merlin in a Ser539 phosphorylation-dependent manner. KIBRA depletion impairs Aurora-A/PP1 interaction.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, phospho-specific antibodies, cell cycle synchronization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + Co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21878642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Drosophila R8 photoreceptors, Kibra (together with Merlin and Lgl, but not Expanded or Fat) is required for Warts expression and activity to specify Rh6 fate, demonstrating a cell-type-specific subset of the Hippo pathway operating in postmitotic neuronal fate specification.\",\n      \"method\": \"Drosophila genetic loss-of-function, epistasis analysis, immunostaining\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis in Drosophila, single lab\",\n      \"pmids\": [\"22055343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KIBRA activates Aurora kinases and is required for full Aurora kinase activation during mitosis. KIBRA promotes phosphorylation of LATS2 on Ser83 by activating Aurora-A, controlling LATS2 centrosome localization. Aurora-A is not required for KIBRA to associate with LATS2. KIBRA knockdown causes mitotic abnormalities including spindle/centrosome defects and chromosome misalignment.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, siRNA knockdown, immunofluorescence, mitotic phenotype analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + kinase assay + siRNA KD phenotype, single lab\",\n      \"pmids\": [\"22904328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KIBRA is phosphorylated by CDK1 at Ser542 and Ser931 in response to spindle damage stress. CDC14A/B phosphatases associate with KIBRA and dephosphorylate CDK1-phosphorylated KIBRA in vitro and in cells. CDK1-non-phosphorylatable KIBRA shows reduced interaction with CDC14B. Phospho-regulation of KIBRA by CDK1 and CDC14 is involved in mitotic exit under spindle stress.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, inducible expression cell lines, phospho-specific antibodies\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase/phosphatase assay + mutagenesis + Co-IP, single lab\",\n      \"pmids\": [\"22784093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of KIBRA in MCF10A cells produces epithelial-to-mesenchymal transition (EMT) features with decreased LATS and YAP phosphorylation but not MST1/2, demonstrating MST-independent regulation of Hippo signaling. Ectopic KIBRA expression antagonizes YAP via serine 127 phosphorylation.\",\n      \"method\": \"shRNA knockdown, phosphorylation assays by Western blot, 3D morphogenesis assay, gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined molecular phenotype plus phosphorylation assays, single lab\",\n      \"pmids\": [\"22614006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIBRA is phosphorylated by ERK1/2 at Ser548 and by RSK1/2 at Thr929 and Ser947 in vitro and in cells. RSK-mediated phosphorylation is required for KIBRA binding to RSK1 but not RSK2. KIBRA knockdown impaired cell migration and proliferation in breast cancer cells; phospho-regulation by ERK1/2 and RSK1/2 is required for proper cell proliferation and migration.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, inducible expression cell lines, migration/proliferation assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + functional assays, single lab\",\n      \"pmids\": [\"24269383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIBRA is necessary and sufficient to stabilize PKMzeta against proteasomal degradation. A short amino acid motif near the C-terminus of KIBRA mediates binding to PKMzeta. Hippocampal knockdown of KIBRA in rats and KIBRA knockout in mice both result in decreased spatial memory performance and decreased PKMzeta protein levels.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor experiments, KIBRA knockdown/knockout, behavioral memory assays, Western blot\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, KD in rats, KO in mice, behavioral + molecular phenotypes), single rigorous study\",\n      \"pmids\": [\"24117625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Two common missense SNPs (rs3822660G/T [M734I], rs3822659T/G [S735A]) in the C2 domain of KIBRA produce variants with distinct Ca2+-dependent binding preferences for monophosphorylated phosphatidylinositols, likely due to differences in dynamics and folding of the lipid-binding pocket.\",\n      \"method\": \"Lipid binding assays, structural modeling/dynamics analysis, genetic association\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional lipid binding assays with structural analysis, single lab\",\n      \"pmids\": [\"23778582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPN14 interacts with KIBRA through the PPXY domain of PTPN14 and WW domain of KIBRA. PTPN14 and KIBRA can activate LATS1 independently and cooperatively. PTPN14 increases LATS1 protein stability. KIBRA re-expression rescues PTPN14-knockdown-induced cell migration defects and aberrant 3D morphogenesis through LATS1 activation and cytoplasmic YAP sequestration.\",\n      \"method\": \"Co-immunoprecipitation, LATS1 kinase assay, shRNA knockdown, 3D morphogenesis assay, rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional KD/rescue, kinase assays, single lab with multiple methods\",\n      \"pmids\": [\"25023289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Deletion of KIBRA in mice increases filopodial-like long dendritic spines in neocortical and hippocampal neurons both in vivo (Golgi staining) and in vitro. Electron microscopy revealed fewer perforated synapses and spinules in KIBRA knockout neurons.\",\n      \"method\": \"Constitutive KIBRA knockout mice, Golgi impregnation, immunofluorescence, electron microscopy\",\n      \"journal\": \"Frontiers in neuroanatomy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with multiple morphological readouts, single lab\",\n      \"pmids\": [\"25750616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Acetylation of tau at K274 and K281 (mimicked by tauKQ mutation) reduces postsynaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. LTP deficits from tauKQ were rescued by promoting actin polymerization or by KIBRA expression.\",\n      \"method\": \"Transgenic mouse model, electrophysiology (LTP), AMPAR insertion assay, actin polymerization assay, KIBRA rescue expression\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse + electrophysiology + rescue experiments + molecular mechanism defined, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"27041503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIBRA overexpression increases constitutive recycling of GluA1-containing AMPA receptors and favors their activity-dependent surface expression, increases LTP but prevents LTD induction, and causes dendritic rearrangements. KIBRA knockdown abolishes LTP, decreases GluA1-AMPAR recycling, and reduces dendritic arborization.\",\n      \"method\": \"Lentiviral KIBRA overexpression/knockdown in mice, electrophysiology (LTP/LTD), AMPAR surface expression assay, confocal microscopy of dendritic morphology\",\n      \"journal\": \"Neurobiology of learning and memory\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo manipulation with electrophysiology + AMPAR assay + morphology, multiple orthogonal methods\",\n      \"pmids\": [\"27498008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Drosophila, Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain (the medial apical cortex). Merlin and Kibra together recruit the adapter protein Salvador, which recruits Hippo kinase. Crumbs has a dual effect: promotes Expanded function but sequesters Kibra to downregulate Hippo signaling.\",\n      \"method\": \"Drosophila genetics (loss-of-function, epistasis), immunofluorescence localization, protein interaction assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus spatial localization analysis plus binding assays, single rigorous study\",\n      \"pmids\": [\"28292426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIBRA overexpression in murine podocytes promoted LATS kinase phosphorylation leading to YAP Ser-127 phosphorylation, YAP cytoplasmic sequestration, and reduction in YAP target gene expression. KIBRA overexpression induced actin cytoskeletal disruption and reduction of focal adhesions, rescued by YAP overexpression. Constitutive KIBRA knockout mice displayed reduced phospho-YAP and were protected from acute podocyte foot process effacement.\",\n      \"method\": \"KIBRA overexpression/knockout in podocytes and mice, phosphorylation assays, immunofluorescence, in vivo protamine sulfate injury model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse in vivo model plus in vitro gain/loss of function with rescue, multiple orthogonal methods\",\n      \"pmids\": [\"28982981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIBRA functions cooperatively with PTPN14 to trigger mechanotransduction-regulated signals that inhibit nuclear localization of YAP/TAZ. Re-expression of KIBRA impairs metastasis in vivo and inhibits tumorsphere formation by TNBC cells in vitro.\",\n      \"method\": \"In vivo metastasis assay, tumorsphere formation assay, co-immunoprecipitation, nuclear/cytoplasmic fractionation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo metastasis assay plus Co-IP plus YAP localization, single lab\",\n      \"pmids\": [\"29562176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The EZH2-H3K27me3-DNMT1 complex is enriched at the wwc1 promoter and mediates epigenetic silencing of KIBRA in triple-negative breast cancer cells. EZH2 knockdown leads to partial increase in KIBRA expression and reduction in H3K27me3 and DNMT1 at the promoter.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, bisulfite sequencing, MeDIP, ChIP-qPCR, shRNA knockdown\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple epigenetic methods (ChIP, MeDIP, bisulfite sequencing, Co-IP), single lab\",\n      \"pmids\": [\"30121333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIBRA stabilizes Rab27a by preventing its ubiquitination and proteasomal degradation through direct protein interaction. KIBRA knockdown or overexpression in neuronal and podocyte cell lines decreases or increases exosome secretion respectively. KIBRA depletion increases MVB size and number. KIBRA knockout mouse brains show significantly decreased Rab27a.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, KIBRA KO mouse, nanoparticle tracking analysis (exosome quantification), electron microscopy of MVBs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse plus in vitro binding plus ubiquitination assay plus functional exosome readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30967557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Kibra binds to postsynaptic density-enriched Dendrin via its N-terminal WW1-WW2 tandem domains with nanomolar affinity. Crystal structure of Kibra WW12 in complex with Dendrin PY motifs was determined. A peptide inhibitor blocking Kibra-Dendrin interaction attenuated excitatory synaptic transmission, blocked LTP induction, and impaired spatial learning and memory. A Tourette syndrome patient mutation in Kibra causes defects in Dendrin binding.\",\n      \"method\": \"Crystal structure determination, isothermal titration calorimetry (ITC), peptide inhibitor design, electrophysiology, behavioral memory assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + ITC + functional inhibitor + electrophysiology + behavioral assays, multiple rigorous orthogonal methods\",\n      \"pmids\": [\"30784589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KIBRA stabilization of PKMzeta is isoform-specific in Aplysia: different splice isoforms of KIBRA in a conserved C-terminal region stabilize different PKM isoforms based on an isoform-specific α-helix 'handle' in PKMs. Isoform-specific competition for KIBRA stabilization determines the selectivity of dominant-negative PKMs in erasing long-term facilitation.\",\n      \"method\": \"Overexpression in Aplysia sensorimotor neurons, dominant-negative PKM isoform competition, synaptic facilitation assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional isoform-specific rescue/competition assays in Aplysia, single lab\",\n      \"pmids\": [\"31537706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Drosophila, Hippo pathway activation promotes Kibra degradation via SCFSlimb-mediated ubiquitination independently of Yorkie-mediated transcription. This mechanism requires Merlin, Salvador, Hpo, and Warts, and functions independently of other upstream Hippo pathway activators. Kibra degradation is patterned by differences in mechanical tension across the wing.\",\n      \"method\": \"Drosophila genetics, ubiquitination assays, epistasis analysis, live imaging\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus ubiquitination assays, single lab\",\n      \"pmids\": [\"33555257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Under basal conditions, WWC1 and LATS kinases are associated, sequestering WWC1 from synaptic AMPAR complexes. A point mutation disrupting WWC1/LATS binding elevates WWC1 abundance in AMPAR complexes and improves hippocampal-dependent learning and memory in mice.\",\n      \"method\": \"Cell-surface proteomics in hippocampal tissue of Wwc1-deficient mice, hippocampus-specific interactome, point mutation knock-in, behavioral memory tests\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics + knock-in mutation + behavioral assays, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"36476872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Adult-onset (but not juvenile-onset) deletion of KIBRA in forebrain neurons impairs LTP and long-term spatial memory. Adult KIBRA deletion decreases extrasynaptic AMPAR levels under basal conditions and impairs LTP-induced AMPAR upregulation.\",\n      \"method\": \"Inducible KIBRA knockout mouse, electrophysiology (LTP), AMPAR surface expression assay, behavioral memory tests\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible KO mouse with electrophysiology and AMPAR assay, single lab\",\n      \"pmids\": [\"36465112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Drosophila epithelial cells, apical polarity network (via aPKC) tethers Kibra at the junctional cortex to silence its activity, while medial actomyosin flows promote Kibra-mediated Hippo complex formation at the medial cortex to activate the pathway.\",\n      \"method\": \"Drosophila genetics, live imaging, immunofluorescence, actomyosin perturbation experiments\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with genetic perturbations, single lab\",\n      \"pmids\": [\"37729921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WWC1 and its paralogs (WWC2/3) bind directly to angiomotin (AMOT) family proteins and recruit USP9X to deubiquitinate and stabilize Motins. Neuron-specific deletion of Wwc1 and Wwc2 reduces Molin levels, decreases dendritic spine density, and impairs memory and learning. Ectopic AMOT expression partially rescues these neuronal phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assays, neuron-specific conditional knockout mice, dendritic spine quantification, behavioral memory tests, rescue expression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP + deubiquitination assay + conditional KO mouse + rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37528078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIBRA complexes with PKMzeta at activated synapses, anchoring the kinase's potentiating action to maintain late-phase LTP and long-term spatial memory. Two structurally distinct KIBRA-PKMzeta dimerization antagonists disrupt established late-LTP and long-term memory without affecting basal synaptic transmission. The effect of both antagonists requires PKMzeta (no effect in PKMzeta knockout mice).\",\n      \"method\": \"Peptide antagonists of KIBRA-PKMzeta interaction, electrophysiology (late-LTP), PKMzeta knockout mouse epistasis, behavioral memory assays, co-immunoprecipitation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — two structurally distinct antagonists + KO epistasis + electrophysiology + behavioral assays, rigorous multi-method study\",\n      \"pmids\": [\"38924398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The C-terminus of KIBRA (CT-KIBRA) restores synaptic plasticity and memory in transgenic mice expressing pathogenic human tau by stabilizing PKMzeta, without altering tau levels or preventing tau-induced synapse loss. Reduced brain KIBRA and increased CSF KIBRA are associated with cognitive impairment and pathological tau in disease.\",\n      \"method\": \"CT-KIBRA expression in tau transgenic mice, electrophysiology (LTP), PKMzeta protein level measurement, behavioral memory tests, human CSF/brain biomarker analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo rescue in transgenic mice + mechanistic PKMzeta stabilization + human biomarker, multiple orthogonal methods\",\n      \"pmids\": [\"38299587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Phosphorylation of LATS1/2 by upstream kinases MST1/2 enhances the interaction between WWC1 and LATS1/2, sequestering WWC1 from AMPAR complexes. Pharmacological inhibition of MST1/2 promotes dissociation of WWC1 from LATS1/2, increasing WWC1 in AMPAR-containing complexes, enhancing synaptic transmission, and improving cognition in healthy mice, Alzheimer's disease models, and aging models.\",\n      \"method\": \"Phosphorylation assays, co-immunoprecipitation, MST1/2 pharmacological inhibition in mice and human brain organoids, electrophysiology, cognitive behavioral assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical mechanistic dissection + pharmacological in vivo intervention + human organoids + behavioral assays, multiple orthogonal methods\",\n      \"pmids\": [\"38687825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIBRA is a physiological substrate of ATM kinase; ATM phosphorylates KIBRA at Thr1006 within an SQ consensus motif. T1006 phosphorylation is essential for optimal DNA double-strand break repair, and KIBRA depletion compromises DNA repair functions, likely via the NHEJ pathway.\",\n      \"method\": \"Site-directed mutagenesis, phospho-(S/T)Q antibody, γ-H2AX assay, pulsed-field gel electrophoresis, Comet assay, TUNEL assay, clonogenic survival assay, shRNA knockdown, CRISPR-Cas9 knockout\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis + multiple DNA repair assays + KD/KO/KI, single lab with multiple methods\",\n      \"pmids\": [\"26929199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Drosophila, Kibra is required for starvation-induced autophagy; absence of Kibra caused defects in autophagic vesicle formation and autophagic degradation. aPKC interacts with Kibra in S2 cells and Drosophila larva, and constitutively active aPKC decreased autophagic vesicle formation upstream of Kibra.\",\n      \"method\": \"Drosophila genetics, autophagy flux assays, co-immunoprecipitation in S2 cells, immunostaining\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function + functional autophagy assay + Co-IP, single lab\",\n      \"pmids\": [\"26551466\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIBRA/WWC1 is a multifunctional postsynaptic scaffold protein that activates the Hippo pathway by forming apical complexes with Merlin/NF2 and Expanded, directly binding and activating LATS1/2 kinases (thereby promoting YAP/TAZ phosphorylation and cytoplasmic retention), while in neurons it anchors PKMzeta at activated synapses to prevent its proteasomal degradation and maintain late-LTP and long-term memory, and also regulates AMPA receptor trafficking and synaptic plasticity by being released from inhibitory LATS1/2 sequestration to join AMPAR-regulatory complexes; additionally, KIBRA inhibits aPKC kinase activity to control epithelial polarity and apical exocytosis, stabilizes Rab27a to control exosome secretion, stabilizes angiomotin proteins via USP9X recruitment, undergoes cell cycle-dependent phosphorylation by Aurora, CDK1, ERK, and RSK kinases, and is subject to ATM-mediated phosphorylation required for DNA repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WWC1/KIBRA is a multidomain WW- and C2-domain scaffold that couples cell-junctional and cytoskeletal cues to the Hippo growth-control pathway and, in neurons, to synaptic plasticity machinery [#0, #7]. As a conserved upstream Hippo component it forms an apical complex with Merlin and Expanded that recruits Salvador and the Hippo/Warts kinases to activate the core cascade [#7, #8, #9, #25]; in mammalian cells KIBRA associates with and stimulates LATS1/2 hydrophobic-motif phosphorylation and stabilizes LATS2 against ubiquitination, thereby driving YAP Ser127 phosphorylation and cytoplasmic sequestration in an MST-independent manner [#10, #17]. This activity is integrated with mechanotransduction through cooperation with PTPN14 to restrain YAP/TAZ nuclear entry and suppress migration, EMT, and metastasis [#21, #27], and KIBRA is epigenetically silenced via an EZH2–H3K27me3–DNMT1 complex in triple-negative breast cancer [#28]. KIBRA additionally controls epithelial apical polarity and exocytosis by binding the PAR3–aPKC–PAR6 complex and directly inhibiting aPKC kinase activity [#12], and stabilizes Rab27a by blocking its ubiquitination to govern exosome secretion [#29] and angiomotin proteins by recruiting USP9X for their deubiquitination [#36]. In the nervous system KIBRA is a postsynaptic density scaffold that anchors PKMzeta at activated synapses and protects it from proteasomal degradation to maintain late-LTP and long-term memory [#19, #37, #38], regulates GluA1-AMPAR recycling and surface expression and dendritic spine morphology [#11, #24, #22], and joins AMPAR-regulatory complexes when released from inhibitory sequestration by LATS1/2; MST1/2-driven LATS phosphorylation strengthens WWC1–LATS binding and withholds WWC1 from AMPAR complexes, so disrupting this interaction enhances synaptic transmission and cognition [#33, #39]. KIBRA is heavily phospho-regulated across the cell cycle by Aurora, CDK1, ERK, and RSK kinases [#13, #15, #16, #18] and is an ATM substrate required for DNA double-strand break repair [#40].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing KIBRA's domain architecture defined it as a WW/C2 scaffold capable of binding PPxY-motif partners, framing all subsequent interaction work.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro PPxY binding, and transfection localization of Myc-tagged KIBRA\",\n      \"pmids\": [\"12559952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physiological in vivo partner identified at this stage\", \"Function of C2 and glutamate-rich domains undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying PKCzeta as a KIBRA interactor and kinase linked KIBRA to atypical PKC signaling, an axis later extended to neuronal PKMzeta and epithelial aPKC.\",\n      \"evidence\": \"Co-IP and in vitro kinase assay\",\n      \"pmids\": [\"15081397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of phosphorylation not defined\", \"Cellular context not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking KIBRA to DLC1 and histone H3 at ER-responsive promoters proposed a nuclear/transcriptional co-regulatory role distinct from its later scaffold functions.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro pulldown, ChIP\",\n      \"pmids\": [\"16684779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear role not integrated with predominantly cytoplasmic localization\", \"Not independently extended in later corpus\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Multiple partner and dimerization studies established KIBRA as a polarity- and receptor-associated scaffold (PATJ, synaptopodin, DDR1) that self-associates and concentrates at the postsynaptic density.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, knockdown migration assays, in vitro dimerization binding, IHC/fractionation\",\n      \"pmids\": [\"18596123\", \"18190796\", \"18672031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional hierarchy among partners unclear\", \"Postsynaptic role not yet mechanistically defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Three concurrent Drosophila studies placed Kibra as a conserved upstream Hippo pathway component acting with Merlin and Expanded to drive the core kinase cascade and Yorkie phosphorylation.\",\n      \"evidence\": \"Genetic epistasis, Co-IP, immunofluorescence, RNAi with phosphorylation readouts; conservation tested in human cells\",\n      \"pmids\": [\"20159598\", \"20159599\", \"20159600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mammalian kinase target not yet defined\", \"Mechanism of cascade activation by the complex unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mammalian KIBRA was shown to directly activate LATS1/2 and stabilize LATS2, providing the biochemical mechanism by which it promotes YAP phosphorylation and cytoplasmic retention.\",\n      \"evidence\": \"Co-IP, kinase/phosphorylation assays, ubiquitination assay, KD/OE\",\n      \"pmids\": [\"21233212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LATS activation not resolved\", \"Regulation of KIBRA-LATS engagement not yet defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"KIBRA's role in epithelial polarity was mechanistically defined as direct aPKC inhibition controlling apical domain size and exocytosis.\",\n      \"evidence\": \"Co-IP, shRNA in MDCK 3D cysts, aPKC in vitro kinase assay, immunofluorescence\",\n      \"pmids\": [\"21497093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between aPKC inhibition and Hippo activation unresolved\", \"In vivo epithelial relevance not tested here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"KIBRA was established as a postsynaptic regulator of AMPAR trafficking and plasticity, with knockout mice showing LTP/LTD and memory deficits, anchoring its neuronal function.\",\n      \"evidence\": \"Co-IP with PICK1/AMPAR, AMPAR recycling assay, electrophysiology and behavior in KIBRA KO mice\",\n      \"pmids\": [\"21943600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between KIBRA and recycling machinery incomplete\", \"Relationship to Hippo signaling in neurons not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"KIBRA was shown to undergo cell-cycle-dependent, Aurora-driven phosphorylation reversed by PP1, connecting it to mitotic regulation and phospho-dependent Merlin binding.\",\n      \"evidence\": \"In vitro kinase assay, site-directed mutagenesis, Co-IP, phospho-specific antibodies, cell-cycle synchronization\",\n      \"pmids\": [\"21878642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of Ser539 phosphorylation beyond Merlin binding unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mitotic studies expanded KIBRA's cell-cycle role to Aurora-A activation, LATS2 centrosome targeting, and CDK1/CDC14-regulated mitotic exit under spindle stress.\",\n      \"evidence\": \"In vitro kinase/phosphatase assays, mutagenesis, Co-IP, siRNA mitotic phenotyping\",\n      \"pmids\": [\"22904328\", \"22784093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration with interphase Hippo signaling unclear\", \"Physiological significance of spindle-stress phospho-sites untested in vivo\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Loss of KIBRA was shown to drive EMT through MST-independent reduction of LATS/YAP phosphorylation, framing KIBRA as a tumor suppressor branch of Hippo signaling.\",\n      \"evidence\": \"shRNA KD, phosphorylation Westerns, 3D morphogenesis, expression analysis\",\n      \"pmids\": [\"22614006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream activator substituting for MST not identified\", \"In vivo tumor relevance not tested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"KIBRA was defined as the stabilizer that protects PKMzeta from proteasomal degradation, providing the molecular basis for its role in maintaining long-term memory.\",\n      \"evidence\": \"Co-IP, proteasome inhibition, KIBRA KD in rats and KO in mice, behavioral assays\",\n      \"pmids\": [\"24117625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the C-terminal PKMzeta-binding motif not yet solved\", \"Mechanism preventing degradation not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of ERK/RSK phosphorylation sites tied KIBRA's phospho-state to cell migration and proliferation control in cancer cells.\",\n      \"evidence\": \"In vitro kinase assay, mutagenesis, Co-IP, migration/proliferation assays\",\n      \"pmids\": [\"24269383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of these phospho-sites unclear\", \"Interplay with Hippo phospho-regulation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Common C2-domain SNPs were shown to alter Ca2+-dependent phosphoinositide binding, providing a structural rationale for KIBRA membrane association and genetic variation.\",\n      \"evidence\": \"Lipid binding assays, structural modeling, genetic association\",\n      \"pmids\": [\"23778582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular consequence of altered lipid binding not demonstrated\", \"Link to memory phenotypes correlative\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"PTPN14 was identified as a KIBRA partner that cooperatively activates LATS1 and stabilizes it, extending KIBRA's Hippo regulatory network and migration control.\",\n      \"evidence\": \"Co-IP, LATS1 kinase assay, shRNA KD, 3D morphogenesis, rescue\",\n      \"pmids\": [\"25023289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KIBRA and PTPN14 act in one complex or parallel pathways unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"KIBRA knockout altered dendritic spine morphology and synaptic ultrastructure, linking it to structural plasticity beyond receptor trafficking.\",\n      \"evidence\": \"KIBRA KO mice, Golgi staining, immunofluorescence, electron microscopy\",\n      \"pmids\": [\"25750616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular driver of spine morphology changes not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Drosophila work implicated Kibra in starvation-induced autophagy downstream of aPKC, broadening its functional repertoire.\",\n      \"evidence\": \"Drosophila genetics, autophagy flux assays, Co-IP in S2 cells\",\n      \"pmids\": [\"26551466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian conservation of autophagy role untested\", \"Mechanism connecting Kibra to autophagosome formation unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"KIBRA was identified as an ATM substrate (Thr1006) required for efficient double-strand break repair, revealing a genome-maintenance function.\",\n      \"evidence\": \"Mutagenesis, phospho-(S/T)Q antibody, γ-H2AX/Comet/PFGE/TUNEL assays, KD/KO/KI\",\n      \"pmids\": [\"26929199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role in NHEJ machinery not defined\", \"Relationship to cytoplasmic scaffold functions unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Two neuronal studies showed KIBRA is required for activity-dependent actin remodeling, AMPAR insertion, and GluA1 recycling, and that its loss underlies tau-acetylation LTP deficits.\",\n      \"evidence\": \"Tau transgenic and lentiviral OE/KD mice, electrophysiology, AMPAR/actin assays, KIBRA rescue\",\n      \"pmids\": [\"27041503\", \"27498008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between KIBRA and actin machinery not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Drosophila and podocyte studies refined KIBRA's spatial Hippo regulation (medial cortex, Salvador recruitment, Crumbs sequestration) and established its YAP-dependent control of cytoskeleton and injury resistance in vivo.\",\n      \"evidence\": \"Drosophila genetics/localization; KIBRA OE/KO in podocytes and mice with phosphorylation and injury models\",\n      \"pmids\": [\"28292426\", \"28982981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian counterpart of medial-cortex localization not mapped\", \"Crumbs-equivalent sequestration in mammals untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"KIBRA was shown to cooperate with PTPN14 in mechanotransduction-controlled YAP/TAZ exclusion and to suppress metastasis, while EZH2-mediated promoter silencing explained KIBRA loss in TNBC.\",\n      \"evidence\": \"In vivo metastasis and tumorsphere assays, Co-IP, fractionation; ChIP/MeDIP/bisulfite sequencing with EZH2 KD\",\n      \"pmids\": [\"29562176\", \"30121333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanosensing input upstream of KIBRA not molecularly defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"KIBRA was established as a stabilizer of partner proteins by blocking their ubiquitination — stabilizing Rab27a to control exosome secretion and binding Dendrin via its WW12 tandem with structurally defined nanomolar affinity to support synaptic transmission and memory.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, KO mice, exosome quantification; crystal structure, ITC, peptide inhibitor, electrophysiology, behavior\",\n      \"pmids\": [\"30967557\", \"30784589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity determinants for KIBRA's stabilization targets incompletely defined\", \"Disease mutation effects on Dendrin binding only partly characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Aplysia work demonstrated isoform-specific KIBRA–PKM stabilization, showing structural 'handle' selectivity governs which PKM is protected and which memory is maintained.\",\n      \"evidence\": \"Isoform overexpression and dominant-negative competition in Aplysia sensorimotor neurons, facilitation assays\",\n      \"pmids\": [\"31537706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian isoform selectivity not tested\", \"Structural handle not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Hippo activation was shown to feedback-degrade Kibra via SCFSlimb ubiquitination patterned by mechanical tension, revealing autoregulation of the pathway.\",\n      \"evidence\": \"Drosophila genetics, ubiquitination assays, live imaging\",\n      \"pmids\": [\"33555257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian conservation of Slimb/βTrCP-mediated KIBRA turnover untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Studies established that LATS kinases sequester WWC1 from AMPAR complexes under basal conditions, so disrupting WWC1–LATS binding boosts synaptic WWC1 and memory, unifying the Hippo and plasticity functions.\",\n      \"evidence\": \"Cell-surface proteomics, point-mutation knock-in mice, inducible KO, electrophysiology, behavior\",\n      \"pmids\": [\"36476872\", \"36465112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger releasing WWC1 from LATS during plasticity not fully defined here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Work resolved upstream control of KIBRA localization/activity (aPKC junctional tethering vs actomyosin medial activation) and defined the WWC–USP9X–angiomotin stabilization axis as critical for spine density and memory.\",\n      \"evidence\": \"Drosophila live imaging/genetics; Co-IP, deubiquitination assays, neuron-specific conditional KO and AMOT rescue\",\n      \"pmids\": [\"37729921\", \"37528078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian aPKC/actomyosin control of KIBRA localization not directly tested\", \"How AMOT stabilization feeds neuronal plasticity unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple studies converged on the WWC1–PKMzeta and WWC1–LATS/MST axes as pharmacologically tractable nodes: PKMzeta-anchoring antagonists erase memory, CT-KIBRA rescues tau-driven deficits, and MST1/2 inhibition releases WWC1 to enhance cognition in disease models.\",\n      \"evidence\": \"Peptide antagonists with PKMzeta KO epistasis, CT-KIBRA in tau transgenics with human biomarkers, MST1/2 inhibition in mice/organoids with electrophysiology and behavior\",\n      \"pmids\": [\"38924398\", \"38299587\", \"38687825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety/specificity of disrupting WWC1 interactions unknown\", \"Structural basis of KIBRA-PKMzeta dimer not solved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KIBRA's diverse functions — Hippo activation, aPKC/polarity control, PKMzeta anchoring, partner stabilization, mitotic regulation, and DNA repair — are coordinated through a single phospho- and localization-regulated scaffold remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model integrating WW, C2, and C-terminal motif engagements\", \"Switch logic determining which partner KIBRA engages in a given context unknown\", \"Mammalian conservation of several Drosophila regulatory mechanisms untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 7, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 12, 29, 36]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [26, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [11, 19, 37]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13, 15, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 25]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [40]}\n    ],\n    \"complexes\": [\n      \"Kibra-Merlin-Expanded apical Hippo complex\",\n      \"PAR3-aPKC-PAR6 polarity complex\",\n      \"KIBRA-PKMzeta synaptic complex\",\n      \"KIBRA-DDR1-PKCzeta trimeric complex\"\n    ],\n    \"partners\": [\n      \"LATS1\",\n      \"LATS2\",\n      \"PKMzeta\",\n      \"PRKCZ\",\n      \"NF2\",\n      \"PTPN14\",\n      \"USP9X\",\n      \"RAB27A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}