{"gene":"CASK","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1996,"finding":"CASK was identified as a novel protein that binds the cytoplasmic domains of all three neurexins via a salt-labile interaction dependent on the C-terminal three residues of neurexin I; CASK is enriched in synaptic plasma membranes of brain.","method":"Yeast two-hybrid screen, biochemical binding assays, subcellular fractionation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus biochemical validation, foundational paper replicated by many subsequent studies","pmids":["8786425"],"is_preprint":false},{"year":1996,"finding":"In C. elegans, lin-2 (CASK ortholog) acts downstream of lin-3/EGF and upstream of let-60/ras to allow the 1° vulval cell fate, placing it in the RTK/Ras signaling pathway; mutant transgenes lacking kinase or guanylate kinase activity are functional, indicating a structural rather than enzymatic role in vulval induction.","method":"Genetic epistasis analysis, loss-of-function mutants, transgene rescue with domain-mutant constructs","journal":"Development","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic epistasis with mutagenesis in a defined pathway, replicated by subsequent work","pmids":["8565857"],"is_preprint":false},{"year":1998,"finding":"Human CASK/LIN-2 binds syndecan-2 via its PDZ domain (confirmed by yeast two-hybrid and in vitro binding assays) and also binds actin-binding protein 4.1, localizing to basolateral membrane domains of epithelial cells.","method":"Yeast two-hybrid, in vitro binding assays, immunofluorescence colocalization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, independently replicated by Hsueh et al. 1998","pmids":["9660868"],"is_preprint":false},{"year":1998,"finding":"CASK PDZ domain specifically interacts with the C-terminal tail of syndecan-2; syndecan-2 and CASK colocalize at synaptic junctions in brain and the interaction was confirmed by co-immunoprecipitation from heterologous cells.","method":"Yeast two-hybrid, co-immunoprecipitation, immunogold EM","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus ultrastructural localization, replicated across two labs same year","pmids":["9660869"],"is_preprint":false},{"year":2000,"finding":"CASK translocates to the nucleus and interacts with the T-box transcription factor Tbr-1 via its guanylate kinase domain; the CASK-Tbr-1 complex binds the T-element DNA sequence and CASK acts as a coactivator to induce transcription of T-element-containing genes including reelin.","method":"Yeast two-hybrid, co-immunoprecipitation, nuclear fractionation, DNA-binding assays, transcriptional reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, DNA binding, transcription assay), widely replicated","pmids":["10749215"],"is_preprint":false},{"year":2001,"finding":"CASK binds a brain-enriched isoform of protein 4.1 and nucleates local assembly of actin/spectrin filaments on the cytosolic tail of neurexins; neurexins, CASK, and protein 4.1 can be co-recovered with actin filaments from rat brain extracts.","method":"In vitro reconstitution, actin co-sedimentation from brain extracts, pulldown assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution of actin nucleation complex, multiple biochemical methods in one study","pmids":["11604393"],"is_preprint":false},{"year":2001,"finding":"Parkin interacts with CASK via a class II PDZ-binding motif at parkin's extreme C-terminus; parkin co-localizes with CASK at synapses and co-precipitates with CASK and the NMDA receptor-signaling complex in rat brain in vivo; parkin does not ubiquitinate CASK despite having E2-dependent ubiquitin ligase activity.","method":"Co-immunoprecipitation, subcellular fractionation, ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from brain, functional ubiquitination assay (negative result explicitly confirmed), single lab","pmids":["11679592"],"is_preprint":false},{"year":2002,"finding":"The L27N domain of CASK/mLin-2 directly binds the N-terminus of SAP97, and this interaction is required for lateral membrane localization of SAP97 in MDCK epithelial cells; a dominant-negative CASK disrupts SAP97 lateral localization.","method":"Biochemical domain mapping, dominant-negative overexpression, immunofluorescence colocalization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical mapping plus functional dominant-negative rescue, evolutionarily conserved interaction demonstrated","pmids":["11865057"],"is_preprint":false},{"year":2002,"finding":"The CaM kinase domain of CASK binds Caskin 1 (a novel brain-specific adaptor) at the same site as Mint 1, and Caskin 1 and Mint 1 compete for CASK binding; CASK and Velis form alternative tripartite complexes with either Mint 1 or Caskin 1.","method":"Yeast two-hybrid, co-immunoprecipitation, affinity chromatography with neurexin tail","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus affinity chromatography competition assay, multiple domain mapping experiments","pmids":["12040031"],"is_preprint":false},{"year":2002,"finding":"L27 domains from LIN-2/CASK and LIN-7 form an obligate heterodimer; individually the isolated domains are largely unfolded, but heterodimerization induces cooperative folding with significant gain of helicity.","method":"Circular dichroism spectroscopy, biophysical co-folding analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biophysical reconstitution with CD spectroscopy showing cooperative folding, rigorous in vitro characterization","pmids":["12110687"],"is_preprint":false},{"year":2003,"finding":"The C-terminus of PMCA4b binds directly to the PDZ domain of CASK; co-precipitation was confirmed from brain and kidney tissue; PMCA4b expression reduces CASK-Tbr-1-dependent T-element transcriptional activity in a Ca2+-pump-activity-dependent manner, linking plasma membrane Ca2+ extrusion to nuclear gene regulation via CASK.","method":"Co-immunoprecipitation from tissue, transcriptional reporter assay, site-directed mutagenesis of PMCA Ca2+ pumping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from tissue plus functional reporter assay with mutant controls, single lab","pmids":["12511555"],"is_preprint":false},{"year":2004,"finding":"CASK binds CINAP (a nucleosome assembly protein) which in turn recruits histones; CASK-CINAP-Tbr-1 form a transcriptional complex that regulates NR2b and reelin gene expression; NMDA stimulation reduces CINAP protein levels via proteasomal degradation, modulating the complex's activity.","method":"Co-immunoprecipitation, RNA interference knockdown in neurons, luciferase reporter assay, proteasome inhibitor treatment","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, RNAi, reporter assay, pharmacological), single lab with comprehensive validation","pmids":["15066269"],"is_preprint":false},{"year":2004,"finding":"A complex of SAP97, CASK, Veli, and Mint1 associates with Kir2.1, Kir2.2, and Kir2.3 channels via C-terminal PDZ-binding motifs; CASK is recruited indirectly via direct SAP97 or Veli binding to Kir2 channels; dominant-interfering CASK causes Kir2.2 to mislocalize from basolateral membrane in epithelial cells.","method":"Affinity pulldown, co-immunoprecipitation, dominant-negative overexpression with immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biochemical methods plus functional mislocalization assay, comprehensive domain mapping","pmids":["14960569"],"is_preprint":false},{"year":2004,"finding":"Tbr-1/CASK complex coactivates promoters of NR2b, glycine transporter, IL-7R, and OX-2 through non-palindromic T-elements; deletion of T-elements abrogates induction; NR2b expression is reduced in Tbr-1 knockout mice.","method":"Luciferase reporter assay with deletion constructs, in vivo Tbr-1 knockout analysis","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter deletion mapping plus in vivo knockout validation, multiple target genes","pmids":["15584924"],"is_preprint":false},{"year":2005,"finding":"CASK is a component of the nephrin multiprotein complex; CASK was pulled down by GST-nephrin cytoplasmic domain from glomerular lysates and co-localizes with nephrin in podocyte foot processes.","method":"GST pulldown from glomerular lysate, mass spectrometry, immunofluorescence colocalization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-validated pulldown from native tissue, single lab","pmids":["15994232"],"is_preprint":false},{"year":2006,"finding":"Drosophila CASK (Camguk/dCASK) acts as a gain controller on CaMKII autonomy: loss of dCASK increases activity-dependent autophosphorylation of CaMKII at T287 (activating site) by inducing autophosphorylation at T306 in the CaM-binding domain, which blocks Ca2+/CaM binding and lowers the probability of T287 intersubunit phosphorylation.","method":"Genetic loss-of-function, in vivo phosphorylation analysis, epistasis with CaMKII autophosphorylation site mutants","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with defined phosphorylation-site mutants, multiple sensory stimulation paradigms tested","pmids":["16880127"],"is_preprint":false},{"year":2007,"finding":"Cdk5 phosphorylates CASK and regulates its distribution to membranes; without Cdk5-dependent phosphorylation, CASK is not recruited to developing synapses and fails to interact with presynaptic components; Cdk5 regulates the CASK-liprin-alpha interaction.","method":"In vitro kinase assay, co-immunoprecipitation, dominant-negative Cdk5 expression, confocal imaging of membrane distribution","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus cellular redistribution experiments with Cdk5 dominant-negative, multiple methods","pmids":["18054859"],"is_preprint":false},{"year":2007,"finding":"CASK KO mice die at birth; CASK-deficient neurons show decreased levels of Mints, Veli/Mals, and neurexins but increased neuroligin 1; glutamatergic spontaneous release is increased and GABAergic spontaneous release is decreased, while evoked release is unchanged.","method":"Conditional and full knockout mouse, electrophysiology (mEPSCs/mIPSCs, evoked EPSCs), Western blotting","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — full KO with multiple electrophysiological and biochemical readouts, rigorous controls","pmids":["17287346"],"is_preprint":false},{"year":2008,"finding":"CASK CaM-kinase domain functions as an active Mg2+-independent protein kinase: crystal structures reveal a constitutively active conformation that binds ATP and catalyzes phosphotransfer without Mg2+; CASK phosphorylates itself and neurexin-1 as a physiological substrate recruited via the PDZ domain.","method":"High-resolution X-ray crystallography, in vitro kinase assay, phosphotransfer assays without Mg2+","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro kinase activity with substrate identification, landmark study","pmids":["18423203"],"is_preprint":false},{"year":2008,"finding":"CASK is SUMOylated (by SUMO1 conjugation); SUMOylation of CASK reduces its interaction with protein 4.1; overexpression of a CASK-SUMO1 fusion (mimicking SUMOylation) impairs dendritic spine formation; CASK knockdown by RNAi reduces spine density.","method":"RNA interference knockdown, SUMO1 fusion overexpression, co-immunoprecipitation to assess protein 4.1 binding, spine morphology quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — post-translational modification identified with functional consequence via multiple orthogonal approaches","pmids":["18606847"],"is_preprint":false},{"year":2009,"finding":"CASK and SAP97 mediate sorting of NMDARs into a specialized ER subcompartment that bypasses the somatic Golgi and merges with dendritic Golgi outposts; this ER subcompartment contains NR1/NR2B, KIF17, CASK, and SAP97, and NMDAR retention in this pathway requires both CASK and SAP97.","method":"Live-cell imaging, immunofluorescence, dominant-negative constructs, trafficking pathway dissection in hippocampal neurons","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple imaging approaches plus dominant-negative functional tests, novel pathway identification","pmids":["19620977"],"is_preprint":false},{"year":2009,"finding":"JAM (junctional adhesion molecule) interacts with CASK requiring the PDZ domain of CASK and the C-terminal Phe-Leu-Val PDZ-binding motif of JAM; this interaction is modulated during junction assembly when CASK is released from cytoskeletal associations.","method":"Co-immunoprecipitation, domain deletion mapping, Triton X-100 solubility fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, single lab","pmids":["11120739"],"is_preprint":false},{"year":2010,"finding":"CASK kinase activity evolved to be Mg2+-inhibited: substitution of four residues in the ATP-binding pocket converts it to a Mg2+-stimulated kinase (CASK4M); crystal structures show Mg2+ accelerates catalysis by stabilizing the transition state; phylogenetic analysis confirms these four residues were substituted during early animal evolution.","method":"Site-directed mutagenesis, X-ray crystallography, kinetic analyses, phylogenetic analysis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus kinetics, multiple orthogonal methods in one rigorous study","pmids":["20424264"],"is_preprint":false},{"year":2010,"finding":"PKA phosphorylates CASK at residues S562 (PDZ domain) and T724 (guanylate kinase domain); T724 phosphorylation upregulates the CASK-Tbr-1 interaction and the PKA pathway stimulates NR2b promoter activity in a T724- and Tbr-1-binding-site-dependent manner.","method":"In vitro PKA kinase assay, site-directed mutagenesis, co-immunoprecipitation, luciferase reporter assay in cortical neurons","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, multiple domain-specific effects validated by reporter assay","pmids":["20067577"],"is_preprint":false},{"year":2010,"finding":"CASK interacts with Bcl11A/CTIP1 (both Bcl11A-S and -L isoforms) in transfected cells and brain; CASK and Bcl11A colocalize in neuronal nuclei; CASK enhances Bcl11A-L-mediated restriction of axon outgrowth and branching in hippocampal neurons.","method":"Yeast two-hybrid, co-immunoprecipitation from brain, immunofluorescence, axon morphology assay with dominant-negative","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from brain plus functional neuronal morphology assay, single lab","pmids":["20623620"],"is_preprint":false},{"year":2011,"finding":"The liprin-α2/CASK complex structure reveals that three SAM domains of liprin-α form an integrated supramodule that binds to the CASK kinase-like domain; three XLMR-associated CASK mutants are defective in binding liprin-α; CASK/liprin-α/liprin-β ternary complex can form.","method":"X-ray crystallography, biochemical binding assays, cellular co-localization, XLMR mutant analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of complex plus mutant validation, multiple orthogonal methods","pmids":["21855798"],"is_preprint":false},{"year":2011,"finding":"A short linear ExIWVxR peptide motif from Caskin1 (and a related motif from Mint1) is necessary and sufficient for binding the CASK CaM kinase domain; the same binding site on CASK accommodates both Caskin1 and Mint1, explaining their competition; TIAM1 contains a similar peptide sufficient for CASK binding in vitro.","method":"Peptide binding assays, mutagenesis, in vitro pulldown","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — defined minimal peptide motifs with mutagenesis, rigorous biochemical mapping","pmids":["21763699"],"is_preprint":false},{"year":2012,"finding":"CASK directly interacts with Cx43 (connexin 43); CASK mainly interacts with the hypophosphorylated form of Cx43; CASK and Cx43 colocalize in brain astrocytes and at wound edges; individual expression of either protein inhibits cell migration but co-expression abrogates this inhibitory effect.","method":"Co-immunoprecipitation, in vitro binding, far-western blotting, scratch wound migration assay in MDCK cells, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods plus functional migration assay","pmids":["22389404"],"is_preprint":false},{"year":2012,"finding":"CASK interacts with PMCA4b and JAM-A on the sperm flagellum; CASK binds alternatively (not synergistically) with each via its single PDZ domain; in Jam-A null sperm, CASK-PMCA4b interaction is increased resulting in PMCA4b inhibition and Ca2+ accumulation, demonstrating that JAM-A positively regulates PMCA4b indirectly through CASK.","method":"Co-immunoprecipitation, immunofluorescence colocalization, Ca2+ measurement, PMCA4b enzymatic activity assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional Ca2+ and enzyme activity data, single lab","pmids":["22020416"],"is_preprint":false},{"year":2013,"finding":"Liprin-α2 promotes presynaptic recruitment of CASK; depletion of liprin-α2 reduces FRAP-measured turnover of CASK at presynaptic terminals, indicating liprin-α2 promotes dynamic CASK scaffolding for synaptic vesicle release.","method":"FRAP (fluorescence recovery after photobleaching), immunocytochemistry, co-immunoprecipitation, knockdown","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP and biochemical methods, single lab","pmids":["23751498"],"is_preprint":false},{"year":2013,"finding":"CASK regulates SAP97 conformation: CASK binding to SAP97 via L27 domains stabilizes SAP97 in an 'extended' conformation; unbound SAP97 adopts a 'compact' conformation preferentially associating with AMPARs (GluA1), while CASK-bound extended SAP97 preferentially colocalizes with NMDARs (GluN2B).","method":"Intramolecular FRET sensors, co-immunoprecipitation, confocal imaging in neurons and HEK cells","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — FRET conformational sensors plus biochemical and imaging validation, mechanistic link between CASK binding and receptor sorting","pmids":["23864692"],"is_preprint":false},{"year":2013,"finding":"CASK interacts with and controls P2X3 receptor expression in trigeminal ganglia neurons; CASK co-immunoprecipitates with P2X3 from ganglia and HEK co-transfected cells; CASK increases serine phosphorylation of P2X3; CASK silencing decreases cell-surface P2X3 expression via proteasomal degradation; NGF upregulates the CASK/P2X3 interaction.","method":"Co-immunoprecipitation, whole-cell patch clamp, biotinylation surface expression assay, proteasome inhibitor rescue, RNAi","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional electrophysiology and surface expression assays, single lab","pmids":["23600800"],"is_preprint":false},{"year":2013,"finding":"CASK interacts with FRMD7 at the plasma membrane; CASK promotes FRMD7 co-localization at the plasma membrane and CASK-induced neurite length enhancement; C-terminal CASK mutations that cause nystagmus specifically disrupt the CASK-FRMD7 interaction.","method":"IP-mass spectrometry, co-immunoprecipitation, immunofluorescence, neurite outgrowth assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus functional assay with disease mutations, single lab","pmids":["23406872"],"is_preprint":false},{"year":2016,"finding":"CASK neurexin1β phosphorylation modulates the CASK complex: liprin-α and Mint1 compete for direct binding to CASK, but neurexin1β eliminates this competition allowing all four proteins to form a complex; CASK phosphorylation of neurexin modulates liprin-α interaction; CASK stabilizes neurexin levels in neurons.","method":"Co-immunoprecipitation, in vitro kinase assay, cell culture with CASK knockdown and neurexin quantification","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical competition assays and kinase assay, single lab with multiple approaches","pmids":["27015872"],"is_preprint":false},{"year":2016,"finding":"CASK localizes to the lateral membrane of cardiac myocytes (associated with dystrophin) and directly interacts with the C-terminus of NaV1.5; CASK silencing increases INa by increasing NaV1.5 surface expression specifically at the lateral membrane, through a brefeldin-A-sensitive trafficking pathway.","method":"Whole-cell patch clamp, TIRF microscopy, biotinylation surface assay, pulldown, immunostaining","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction pulldown plus multiple functional assays (electrophysiology, surface expression, brefeldin-A block)","pmids":["27364017"],"is_preprint":false},{"year":2016,"finding":"In C. elegans, LIN-2/CASK interacts with kinesin-3 UNC-104/KIF1A on its stalk domain (mapped to L27 and GUK domains of LIN-2); LIN-2 knockout reduces UNC-104 motility and SNB-1/synaptobrevin cargo transport and increases motor clustering in axons; LIN-2 elevates UNC-104 run length more effectively than SYD-2/liprin-α.","method":"Yeast two-hybrid, co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), in vivo imaging of motor motility in C. elegans neurons","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods including in vivo motor motility assays, ortholog study in C. elegans","pmids":["27172328"],"is_preprint":false},{"year":2016,"finding":"Neuron-specific deletion of CASK in mice does not cause perinatal lethality but induces epileptic seizures and growth retardation; CASK haploinsufficiency is inconsequential in neurons alone; CASK can interact with metabolic proteins and CASK knockdown reduces cellular respiration.","method":"Cre-LoxP conditional knockout, video-EEG, biochemical affinity chromatography, metabolic assay","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotype plus biochemical interaction with metabolic proteins, single lab","pmids":["27036546"],"is_preprint":false},{"year":2017,"finding":"CASK T740A knock-in mice (disrupting CASK-Tbr1 interaction) show a specific defect in extinction of associative memory without affecting acquisition, demonstrating that the CASK-Tbr1 interaction is specifically required for cognitive flexibility rather than global memory.","method":"Gene knock-in (T740A point mutation), co-immunoprecipitation from brain, behavioral fear conditioning and extinction assays","journal":"Journal of psychiatry & neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in mouse with defined interaction disruption and specific behavioral phenotype","pmids":["28234597"],"is_preprint":false},{"year":2018,"finding":"CNTNAP2 stabilizes interneuron dendritic arbors through direct interaction with CASK's C-terminus; Cntnap2 KO mice show reduced CASK levels in the cortical membrane fraction; knockdown of either CNTNAP2 or CASK similarly alters GluA1 levels and localization in interneurons.","method":"Yeast two-hybrid, Co-IP, proximity ligation assay, SIM/STED super-resolution imaging, shRNA knockdown, Cntnap2 KO mouse","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including super-resolution microscopy and genetic rescue, KO mouse validation","pmids":["29610457"],"is_preprint":false},{"year":2018,"finding":"CASK missense mutations M519T (in PDZ domain) and G659D (in SH3 domain) both disrupt the CASK-neurexin interaction and cause severe MICPCH; G659D disrupts the PDZ-SH3 domain interface; neurexin binding to CASK but not Tbr-1 interaction is the critical determinant for microcephaly/cerebellar hypoplasia.","method":"Co-immunoprecipitation with neurexin, protein aggregation assay, clinical genotype-phenotype analysis","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction assays with disease mutations, pathway inference from human genetics, single lab","pmids":["29426960"],"is_preprint":false},{"year":2019,"finding":"CASK interaction with Dlg1 is required for mitotic spindle orientation in mammalian epithelial cells; CASK depletion or blocking the CASK-Dlg1 interaction causes misoriented cell divisions and multilumen formation; CASK is required for Dlg1 membrane localization and for correct positioning of the LGN-NuMA spindle orientation complex.","method":"RNAi knockdown, interfering peptides, 3D organoid culture, immunofluorescence of spindle orientation markers","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi plus specific inhibitory peptide plus domain deletion, functional spindle orientation and lumen formation assays","pmids":["31289196"],"is_preprint":false},{"year":2020,"finding":"Neurexin PDZ and GK domain mutations in CASK impair neurexin binding and neurexin-induced oligomerization of CASK; GK domain mutations additionally impair CINAP and Tbr1 binding; L27 domain mutation disrupts SAP97 binding; neurexin binding is not required for presynaptic localization of CASK.","method":"Co-expression and co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) for oligomerization, molecular modeling","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic Co-IP plus BiFC oligomerization assay, multiple mutations, single lab","pmids":["33090494"],"is_preprint":false},{"year":2020,"finding":"A Mint1 N-terminal fragment binds CASK-CaMK with ~7.5 nM affinity; the crystal structure reveals two contact surfaces: the C-lobe of CASK-CaMK binds a short sequence common to CaMK targets, and the N-lobe engages an α-helix unique to Mint1; Ca2+/CaM does not regulate the CASK-Mint1 interaction; several CASK disease mutations can be mechanistically explained by the structure.","method":"X-ray crystallography, ITC/biophysical binding assays, mutagenesis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure plus quantitative binding analysis and disease-mutation interpretation","pmids":["32348748"],"is_preprint":false},{"year":2022,"finding":"Complete CASK loss causes cerebellar degeneration through postmitotic neurodegeneration rather than defective neuronal migration or differentiation: a CASK-null human brain shows astrogliosis/microgliosis without migration defects; mouse cerebellum-specific CASK deletion causes granule cell degeneration postdevelopmentally; heterozygous female mice show no neurodegeneration due to 50% normal cells.","method":"Human brain histopathology, conditional cerebellar knockout mouse (Cre-LoxP), immunohistochemistry for gliosis markers","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human pathology combined with conditional murine KO model, multiple histological markers","pmids":["35149592"],"is_preprint":false}],"current_model":"CASK is a multidomain MAGUK scaffold protein whose CaM-kinase domain functions as a constitutively active, Mg2+-independent (indeed Mg2+-inhibited) kinase that phosphorylates substrates such as neurexin-1 recruited via its PDZ domain; it assembles alternative presynaptic tripartite complexes (CASK/Veli/Mint1 or CASK/Veli/Caskin1) on neurexin cytoplasmic tails, links neurexin to the actin cytoskeleton via protein 4.1, and is recruited to synapses through liprin-α; its guanylate kinase domain translocates to the nucleus to co-activate Tbr-1-driven transcription (regulating reelin, NR2b, and other genes) in a complex further modulated by CINAP, with this nuclear activity tuned by PKA phosphorylation at T724; CASK also regulates SAP97 conformation to sort AMPA vs. NMDA receptors, controls basolateral membrane localization of ion channels (Kir2, NaV1.5) and other receptors via its L27-SAP97 and PDZ-domain interactions, gates CaMKII autophosphorylation, and is required for oriented cell divisions by anchoring Dlg1 at the membrane to position the LGN-NuMA spindle complex."},"narrative":{"mechanistic_narrative":"CASK is a multidomain MAGUK scaffold protein that organizes presynaptic protein complexes, links membrane adhesion molecules to the cytoskeleton, and couples membrane events to nuclear transcription in neurons and epithelia [PMID:8786425, PMID:10749215]. It was first identified as a synaptic membrane protein binding the cytoplasmic tails of neurexins, and it nucleates tripartite presynaptic complexes with Veli/LIN-7 and either Mint1 or Caskin1, which compete for the same CaM-kinase-domain site via a short ExIWVxR peptide motif [PMID:8786425, PMID:12040031, PMID:21763699]. Through its PDZ domain CASK engages neurexin, syndecan-2, and other membrane partners, while protein 4.1 binding nucleates local actin/spectrin assembly on neurexin tails, physically coupling adhesion to the cytoskeleton [PMID:9660868, PMID:9660869, PMID:11604393]. CASK is recruited to synapses by liprin-α, whose SAM-domain supramodule binds the CASK kinase-like domain, with recruitment further regulated by Cdk5 phosphorylation [PMID:18054859, PMID:21855798, PMID:23751498]. Unusually, the CASK CaM-kinase domain is a constitutively active, Mg2+-independent kinase—an activity that evolved through substitution of four ATP-pocket residues to become Mg2+-inhibited—and it phosphorylates neurexin-1 recruited via the PDZ domain [PMID:18423203, PMID:20424264]. Its guanylate kinase domain translocates to the nucleus to co-activate Tbr-1-driven transcription of T-element genes including reelin and NR2b, in a complex with the nucleosome-assembly factor CINAP and tuned by PKA phosphorylation at T724 [PMID:10749215, PMID:15066269, PMID:15584924, PMID:20067577]. In epithelia, CASK directs basolateral membrane localization of SAP97 and ion channels and controls SAP97 conformation to sort AMPA versus NMDA receptors, and it is required for oriented cell division by anchoring Dlg1 to position the LGN-NuMA spindle complex [PMID:11865057, PMID:14960569, PMID:23864692, PMID:31289196]. CASK-null mice die at birth with altered neurotransmitter release, and human CASK mutations that disrupt neurexin binding cause severe MICPCH and cerebellar degeneration through postmitotic neurodegeneration [PMID:17287346, PMID:29426960, PMID:35149592].","teleology":[{"year":1996,"claim":"Established CASK as a synaptic membrane scaffold by identifying it as a direct binding partner of neurexin cytoplasmic tails, placing it at the presynaptic adhesion interface.","evidence":"Yeast two-hybrid and biochemical binding with subcellular fractionation of brain","pmids":["8786425"],"confidence":"High","gaps":["Did not define the full presynaptic complex assembled on neurexin","No functional consequence for synapse formation established"]},{"year":1996,"claim":"Genetic epistasis in C. elegans placed the CASK ortholog lin-2 in RTK/Ras vulval signaling and showed its kinase and guanylate kinase activities are dispensable there, implying a structural scaffolding role.","evidence":"Loss-of-function mutants and domain-mutant transgene rescue in C. elegans","pmids":["8565857"],"confidence":"High","gaps":["Did not address neuronal functions","Structural vs enzymatic role left open for vertebrate contexts"]},{"year":1998,"claim":"Defined CASK's PDZ-domain and protein 4.1 partnerships, linking it to syndecan-2 and the actin cytoskeleton at basolateral membranes and synaptic junctions.","evidence":"Yeast two-hybrid, in vitro binding, Co-IP, and immunogold EM in epithelia and brain","pmids":["9660868","9660869"],"confidence":"High","gaps":["Mechanism of cytoskeletal coupling not yet reconstituted","Did not test functional requirement for junction integrity"]},{"year":2000,"claim":"Revealed an unexpected nuclear role: CASK translocates to the nucleus and co-activates Tbr-1-driven transcription, coupling a membrane scaffold to gene regulation.","evidence":"Nuclear fractionation, Co-IP, DNA-binding and transcriptional reporter assays","pmids":["10749215"],"confidence":"High","gaps":["Signal triggering nuclear translocation unclear","Stoichiometry of nuclear vs membrane CASK pools undefined"]},{"year":2001,"claim":"Reconstituted CASK-protein 4.1-mediated nucleation of actin/spectrin on neurexin tails, establishing the molecular logic of adhesion-to-cytoskeleton coupling.","evidence":"In vitro reconstitution and actin co-sedimentation from brain extracts","pmids":["11604393"],"confidence":"High","gaps":["In vivo requirement for synaptic actin organization not tested","Regulation of complex assembly unaddressed"]},{"year":2002,"claim":"Showed CASK assembles alternative presynaptic tripartite complexes by binding Caskin1 or Mint1 competitively at one CaM-kinase-domain site, defining combinatorial scaffold output.","evidence":"Yeast two-hybrid, Co-IP, and neurexin-tail affinity competition assays; plus CD spectroscopy showing obligate L27 heterodimer folding with LIN-7","pmids":["12040031","12110687"],"confidence":"High","gaps":["Functional difference between Mint1 vs Caskin1 complexes not resolved","What selects between complexes in vivo unknown"]},{"year":2002,"claim":"Identified the CASK L27N-SAP97 interaction as required for SAP97 lateral membrane targeting, extending CASK scaffolding to epithelial polarity.","evidence":"Biochemical domain mapping and dominant-negative rescue in MDCK cells","pmids":["11865057"],"confidence":"High","gaps":["Downstream cargo of SAP97 not yet defined","Did not connect to receptor sorting"]},{"year":2004,"claim":"Elaborated the nuclear transcription module: CASK recruits CINAP and Tbr-1 to regulate NR2b and reelin, with NMDA-driven CINAP degradation tuning activity across multiple T-element target genes.","evidence":"Co-IP, RNAi, luciferase reporters with promoter deletions, and in vivo Tbr-1 KO; plus Kir2 channel complex mapping","pmids":["15066269","15584924","14960569"],"confidence":"High","gaps":["How synaptic activity signals to nuclear CASK mechanistically incomplete","Genome-wide target set undefined"]},{"year":2007,"claim":"Defined upstream regulation and organismal requirement: Cdk5 phosphorylation controls CASK membrane recruitment and liprin-α binding, and CASK loss is perinatally lethal with altered spontaneous neurotransmitter release.","evidence":"In vitro kinase assay, Co-IP, dominant-negative Cdk5 imaging, and full KO mouse electrophysiology","pmids":["18054859","17287346"],"confidence":"High","gaps":["Cause of perinatal lethality not pinpointed","How release asymmetry arises mechanistically unclear"]},{"year":2008,"claim":"Solved the central enzymatic paradox: crystal structures showed the CASK CaM-kinase domain is constitutively active and Mg2+-independent, phosphorylating neurexin-1 recruited via the PDZ domain.","evidence":"X-ray crystallography and Mg2+-free in vitro kinase assays with substrate identification; plus SUMOylation regulation of protein 4.1 binding","pmids":["18423203","18606847"],"confidence":"High","gaps":["Physiological substrate repertoire beyond neurexin unknown","Regulation of an inherently constitutive kinase unclear"]},{"year":2009,"claim":"Connected CASK/SAP97 scaffolding to receptor trafficking, defining a specialized ER-to-dendritic-Golgi pathway for NMDAR sorting.","evidence":"Live-cell imaging and dominant-negative trafficking dissection in hippocampal neurons","pmids":["19620977"],"confidence":"High","gaps":["Molecular determinants of the bypass pathway incomplete","Selectivity for NMDAR vs AMPAR not yet mechanistic"]},{"year":2010,"claim":"Refined kinase evolution and post-translational control: four ATP-pocket residues evolved to make CASK Mg2+-inhibited, and PKA phosphorylation at T724 upregulates the CASK-Tbr-1 interaction to drive NR2b transcription.","evidence":"Mutagenesis, crystallography, kinetics, phylogenetics; in vitro PKA kinase assay and reporters","pmids":["20424264","20067577"],"confidence":"High","gaps":["Biological advantage of Mg2+ inhibition untested in vivo","Crosstalk between membrane and nuclear PKA-CASK pools undefined"]},{"year":2011,"claim":"Provided structural and motif-level rules for CASK assembly: liprin-α SAM supramodule binds the kinase-like domain, XLMR mutants disrupt this, and an ExIWVxR peptide motif governs Mint1/Caskin1 competition.","evidence":"X-ray crystallography of liprin-α/CASK, peptide binding assays, and disease-mutant analysis","pmids":["21855798","21763699"],"confidence":"High","gaps":["How TIAM1 motif binding integrates into signaling unclear","In vivo competition dynamics not measured"]},{"year":2013,"claim":"Established a conformational mechanism for receptor sorting: CASK binding holds SAP97 in an extended conformation favoring NMDAR association, while unbound compact SAP97 favors AMPARs.","evidence":"Intramolecular FRET sensors, Co-IP, and confocal imaging in neurons and HEK cells; plus liprin-α2 FRAP-measured presynaptic CASK turnover","pmids":["23864692","23751498"],"confidence":"High","gaps":["How conformational state is dynamically switched in vivo unknown","Quantitative coupling to synaptic receptor content untested"]},{"year":2016,"claim":"Extended CASK function beyond neurons to cardiac channel trafficking and revealed neuron-specific deletion phenotypes, distinguishing scaffolding roles by tissue.","evidence":"Patch clamp, TIRF, surface biotinylation in myocytes; conditional neuronal KO with video-EEG","pmids":["27364017","27036546"],"confidence":"High","gaps":["Mechanism restricting NaV1.5 to the lateral membrane incomplete","Relationship between neuronal vs systemic CASK loss unresolved"]},{"year":2017,"claim":"Demonstrated in vivo specificity of the nuclear module: a T740A knock-in disrupting CASK-Tbr1 selectively impairs memory extinction, separating transcriptional from scaffolding functions behaviorally.","evidence":"Point-mutation knock-in mouse, brain Co-IP, and fear extinction behavior","pmids":["28234597"],"confidence":"High","gaps":["Transcriptional targets driving extinction not identified","Circuit locus of the deficit undefined"]},{"year":2018,"claim":"Linked CASK to autism-associated CNTNAP2 in stabilizing interneuron arbors and controlling GluA1, integrating CASK into neurodevelopmental disease networks.","evidence":"Y2H, Co-IP, PLA, super-resolution imaging, knockdown, and Cntnap2 KO mouse","pmids":["29610457"],"confidence":"High","gaps":["Direct mechanistic link to GluA1 localization incomplete","Whether kinase or scaffold activity is required untested"]},{"year":2019,"claim":"Revealed a mitotic function: CASK anchors Dlg1 at the membrane to position the LGN-NuMA complex and orient the spindle, expanding CASK roles to tissue architecture.","evidence":"RNAi, interfering peptides, and 3D organoid spindle/lumen assays","pmids":["31289196"],"confidence":"High","gaps":["How CASK is itself positioned for spindle cues unknown","Connection to neurodevelopmental phenotypes untested"]},{"year":2020,"claim":"Refined complex architecture and disease mechanism: structures and BiFC mapping showed neurexin binding promotes CASK oligomerization, neurexin eliminates liprin-α/Mint1 competition, and Mint1 binds CASK-CaMK with nanomolar affinity at defined surfaces explaining disease mutations.","evidence":"Crystallography, ITC, BiFC oligomerization, and systematic Co-IP of domain mutants","pmids":["33090494","32348748"],"confidence":"High","gaps":["Functional output of neurexin-induced oligomerization unclear","In vivo relevance of competition relief untested"]},{"year":2022,"claim":"Defined the cellular basis of CASK-related cerebellar disease as postmitotic neurodegeneration rather than migration/differentiation failure, with neurexin binding identified as the critical determinant for microcephaly/cerebellar hypoplasia.","evidence":"Human brain histopathology and cerebellum-specific conditional KO mouse; disease-mutation Co-IP with neurexin","pmids":["35149592","29426960"],"confidence":"High","gaps":["Molecular trigger of degeneration unknown","Why granule cells are selectively vulnerable unclear"]},{"year":null,"claim":"It remains unresolved how the constitutive, Mg2+-inhibited kinase activity is biologically deployed and how membrane scaffolding, kinase signaling, and nuclear transcription are coordinately regulated within a single CASK protein in vivo.","evidence":"No timeline discovery directly reconciles the three functional modes under physiological signaling","pmids":[],"confidence":"Low","gaps":["Full physiological substrate set of the kinase undefined","Signals partitioning CASK among membrane, cytoskeletal, and nuclear pools unknown","Integration of mitotic spindle role with neuronal functions unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[18,22]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[18,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,8,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,11,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,12,34]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,11,24]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,17,20]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,11,13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,12,20,34]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[40]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[38,43]}],"complexes":["CASK/Veli(LIN-7)/Mint1 tripartite complex","CASK/Veli/Caskin1 tripartite complex","CASK-CINAP-Tbr-1 transcriptional complex","SAP97/CASK/Veli/Mint1-Kir2 channel complex"],"partners":["NRXN1","LIN7 (VELI)","MINT1 (APBA1)","CASKIN1","DLG1 (SAP97)","PPFIA (LIPRIN-ALPHA)","TBR1","EPB41 (PROTEIN 4.1)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07498","full_name":"Kappa-casein","aliases":[],"length_aa":182,"mass_kda":20.3,"function":"Kappa-casein stabilizes micelle formation, preventing casein precipitation in milk","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P07498/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CASK","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":"SRP14","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CASK","total_profiled":1310},"omim":[{"mim_id":"616484","title":"TAX1-BINDING PROTEIN 3; TAX1BP3","url":"https://www.omim.org/entry/616484"},{"mim_id":"612332","title":"LIN7 HOMOLOG C, CRUMBS CELL POLARITY COMPLEX COMPONENT; LIN7C","url":"https://www.omim.org/entry/612332"},{"mim_id":"612331","title":"LIN7 HOMOLOG B, CRUMBS CELL POLARITY COMPLEX COMPONENT; LIN7B","url":"https://www.omim.org/entry/612331"},{"mim_id":"612185","title":"CASK-INTERACTING PROTEIN 2; CASKIN2","url":"https://www.omim.org/entry/612185"},{"mim_id":"612184","title":"CASK-INTERACTING PROTEIN 1; CASKIN1","url":"https://www.omim.org/entry/612184"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CASK"},"hgnc":{"alias_symbol":["LIN2","CAGH39","FGS4"],"prev_symbol":["TNRC8"]},"alphafold":{"accession":"P07498","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07498","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07498-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07498-F1-predicted_aligned_error_v6.png","plddt_mean":58.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CASK","jax_strain_url":"https://www.jax.org/strain/search?query=CASK"},"sequence":{"accession":"P07498","fasta_url":"https://rest.uniprot.org/uniprotkb/P07498.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07498/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07498"}},"corpus_meta":[{"pmid":"8786425","id":"PMC_8786425","title":"CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with 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CASK is enriched in synaptic plasma membranes of brain.\",\n      \"method\": \"Yeast two-hybrid screen, biochemical binding assays, subcellular fractionation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus biochemical validation, foundational paper replicated by many subsequent studies\",\n      \"pmids\": [\"8786425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"In C. elegans, lin-2 (CASK ortholog) acts downstream of lin-3/EGF and upstream of let-60/ras to allow the 1° vulval cell fate, placing it in the RTK/Ras signaling pathway; mutant transgenes lacking kinase or guanylate kinase activity are functional, indicating a structural rather than enzymatic role in vulval induction.\",\n      \"method\": \"Genetic epistasis analysis, loss-of-function mutants, transgene rescue with domain-mutant constructs\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic epistasis with mutagenesis in a defined pathway, replicated by subsequent work\",\n      \"pmids\": [\"8565857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human CASK/LIN-2 binds syndecan-2 via its PDZ domain (confirmed by yeast two-hybrid and in vitro binding assays) and also binds actin-binding protein 4.1, localizing to basolateral membrane domains of epithelial cells.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays, immunofluorescence colocalization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, independently replicated by Hsueh et al. 1998\",\n      \"pmids\": [\"9660868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CASK PDZ domain specifically interacts with the C-terminal tail of syndecan-2; syndecan-2 and CASK colocalize at synaptic junctions in brain and the interaction was confirmed by co-immunoprecipitation from heterologous cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunogold EM\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus ultrastructural localization, replicated across two labs same year\",\n      \"pmids\": [\"9660869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CASK translocates to the nucleus and interacts with the T-box transcription factor Tbr-1 via its guanylate kinase domain; the CASK-Tbr-1 complex binds the T-element DNA sequence and CASK acts as a coactivator to induce transcription of T-element-containing genes including reelin.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, nuclear fractionation, DNA-binding assays, transcriptional reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, DNA binding, transcription assay), widely replicated\",\n      \"pmids\": [\"10749215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CASK binds a brain-enriched isoform of protein 4.1 and nucleates local assembly of actin/spectrin filaments on the cytosolic tail of neurexins; neurexins, CASK, and protein 4.1 can be co-recovered with actin filaments from rat brain extracts.\",\n      \"method\": \"In vitro reconstitution, actin co-sedimentation from brain extracts, pulldown assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution of actin nucleation complex, multiple biochemical methods in one study\",\n      \"pmids\": [\"11604393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Parkin interacts with CASK via a class II PDZ-binding motif at parkin's extreme C-terminus; parkin co-localizes with CASK at synapses and co-precipitates with CASK and the NMDA receptor-signaling complex in rat brain in vivo; parkin does not ubiquitinate CASK despite having E2-dependent ubiquitin ligase activity.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from brain, functional ubiquitination assay (negative result explicitly confirmed), single lab\",\n      \"pmids\": [\"11679592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The L27N domain of CASK/mLin-2 directly binds the N-terminus of SAP97, and this interaction is required for lateral membrane localization of SAP97 in MDCK epithelial cells; a dominant-negative CASK disrupts SAP97 lateral localization.\",\n      \"method\": \"Biochemical domain mapping, dominant-negative overexpression, immunofluorescence colocalization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical mapping plus functional dominant-negative rescue, evolutionarily conserved interaction demonstrated\",\n      \"pmids\": [\"11865057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The CaM kinase domain of CASK binds Caskin 1 (a novel brain-specific adaptor) at the same site as Mint 1, and Caskin 1 and Mint 1 compete for CASK binding; CASK and Velis form alternative tripartite complexes with either Mint 1 or Caskin 1.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, affinity chromatography with neurexin tail\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus affinity chromatography competition assay, multiple domain mapping experiments\",\n      \"pmids\": [\"12040031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"L27 domains from LIN-2/CASK and LIN-7 form an obligate heterodimer; individually the isolated domains are largely unfolded, but heterodimerization induces cooperative folding with significant gain of helicity.\",\n      \"method\": \"Circular dichroism spectroscopy, biophysical co-folding analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical reconstitution with CD spectroscopy showing cooperative folding, rigorous in vitro characterization\",\n      \"pmids\": [\"12110687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The C-terminus of PMCA4b binds directly to the PDZ domain of CASK; co-precipitation was confirmed from brain and kidney tissue; PMCA4b expression reduces CASK-Tbr-1-dependent T-element transcriptional activity in a Ca2+-pump-activity-dependent manner, linking plasma membrane Ca2+ extrusion to nuclear gene regulation via CASK.\",\n      \"method\": \"Co-immunoprecipitation from tissue, transcriptional reporter assay, site-directed mutagenesis of PMCA Ca2+ pumping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from tissue plus functional reporter assay with mutant controls, single lab\",\n      \"pmids\": [\"12511555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CASK binds CINAP (a nucleosome assembly protein) which in turn recruits histones; CASK-CINAP-Tbr-1 form a transcriptional complex that regulates NR2b and reelin gene expression; NMDA stimulation reduces CINAP protein levels via proteasomal degradation, modulating the complex's activity.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference knockdown in neurons, luciferase reporter assay, proteasome inhibitor treatment\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, RNAi, reporter assay, pharmacological), single lab with comprehensive validation\",\n      \"pmids\": [\"15066269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A complex of SAP97, CASK, Veli, and Mint1 associates with Kir2.1, Kir2.2, and Kir2.3 channels via C-terminal PDZ-binding motifs; CASK is recruited indirectly via direct SAP97 or Veli binding to Kir2 channels; dominant-interfering CASK causes Kir2.2 to mislocalize from basolateral membrane in epithelial cells.\",\n      \"method\": \"Affinity pulldown, co-immunoprecipitation, dominant-negative overexpression with immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple biochemical methods plus functional mislocalization assay, comprehensive domain mapping\",\n      \"pmids\": [\"14960569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tbr-1/CASK complex coactivates promoters of NR2b, glycine transporter, IL-7R, and OX-2 through non-palindromic T-elements; deletion of T-elements abrogates induction; NR2b expression is reduced in Tbr-1 knockout mice.\",\n      \"method\": \"Luciferase reporter assay with deletion constructs, in vivo Tbr-1 knockout analysis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter deletion mapping plus in vivo knockout validation, multiple target genes\",\n      \"pmids\": [\"15584924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CASK is a component of the nephrin multiprotein complex; CASK was pulled down by GST-nephrin cytoplasmic domain from glomerular lysates and co-localizes with nephrin in podocyte foot processes.\",\n      \"method\": \"GST pulldown from glomerular lysate, mass spectrometry, immunofluorescence colocalization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-validated pulldown from native tissue, single lab\",\n      \"pmids\": [\"15994232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Drosophila CASK (Camguk/dCASK) acts as a gain controller on CaMKII autonomy: loss of dCASK increases activity-dependent autophosphorylation of CaMKII at T287 (activating site) by inducing autophosphorylation at T306 in the CaM-binding domain, which blocks Ca2+/CaM binding and lowers the probability of T287 intersubunit phosphorylation.\",\n      \"method\": \"Genetic loss-of-function, in vivo phosphorylation analysis, epistasis with CaMKII autophosphorylation site mutants\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with defined phosphorylation-site mutants, multiple sensory stimulation paradigms tested\",\n      \"pmids\": [\"16880127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cdk5 phosphorylates CASK and regulates its distribution to membranes; without Cdk5-dependent phosphorylation, CASK is not recruited to developing synapses and fails to interact with presynaptic components; Cdk5 regulates the CASK-liprin-alpha interaction.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, dominant-negative Cdk5 expression, confocal imaging of membrane distribution\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus cellular redistribution experiments with Cdk5 dominant-negative, multiple methods\",\n      \"pmids\": [\"18054859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CASK KO mice die at birth; CASK-deficient neurons show decreased levels of Mints, Veli/Mals, and neurexins but increased neuroligin 1; glutamatergic spontaneous release is increased and GABAergic spontaneous release is decreased, while evoked release is unchanged.\",\n      \"method\": \"Conditional and full knockout mouse, electrophysiology (mEPSCs/mIPSCs, evoked EPSCs), Western blotting\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — full KO with multiple electrophysiological and biochemical readouts, rigorous controls\",\n      \"pmids\": [\"17287346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CASK CaM-kinase domain functions as an active Mg2+-independent protein kinase: crystal structures reveal a constitutively active conformation that binds ATP and catalyzes phosphotransfer without Mg2+; CASK phosphorylates itself and neurexin-1 as a physiological substrate recruited via the PDZ domain.\",\n      \"method\": \"High-resolution X-ray crystallography, in vitro kinase assay, phosphotransfer assays without Mg2+\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro kinase activity with substrate identification, landmark study\",\n      \"pmids\": [\"18423203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CASK is SUMOylated (by SUMO1 conjugation); SUMOylation of CASK reduces its interaction with protein 4.1; overexpression of a CASK-SUMO1 fusion (mimicking SUMOylation) impairs dendritic spine formation; CASK knockdown by RNAi reduces spine density.\",\n      \"method\": \"RNA interference knockdown, SUMO1 fusion overexpression, co-immunoprecipitation to assess protein 4.1 binding, spine morphology quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — post-translational modification identified with functional consequence via multiple orthogonal approaches\",\n      \"pmids\": [\"18606847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CASK and SAP97 mediate sorting of NMDARs into a specialized ER subcompartment that bypasses the somatic Golgi and merges with dendritic Golgi outposts; this ER subcompartment contains NR1/NR2B, KIF17, CASK, and SAP97, and NMDAR retention in this pathway requires both CASK and SAP97.\",\n      \"method\": \"Live-cell imaging, immunofluorescence, dominant-negative constructs, trafficking pathway dissection in hippocampal neurons\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple imaging approaches plus dominant-negative functional tests, novel pathway identification\",\n      \"pmids\": [\"19620977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JAM (junctional adhesion molecule) interacts with CASK requiring the PDZ domain of CASK and the C-terminal Phe-Leu-Val PDZ-binding motif of JAM; this interaction is modulated during junction assembly when CASK is released from cytoskeletal associations.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mapping, Triton X-100 solubility fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, single lab\",\n      \"pmids\": [\"11120739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CASK kinase activity evolved to be Mg2+-inhibited: substitution of four residues in the ATP-binding pocket converts it to a Mg2+-stimulated kinase (CASK4M); crystal structures show Mg2+ accelerates catalysis by stabilizing the transition state; phylogenetic analysis confirms these four residues were substituted during early animal evolution.\",\n      \"method\": \"Site-directed mutagenesis, X-ray crystallography, kinetic analyses, phylogenetic analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus kinetics, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"20424264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PKA phosphorylates CASK at residues S562 (PDZ domain) and T724 (guanylate kinase domain); T724 phosphorylation upregulates the CASK-Tbr-1 interaction and the PKA pathway stimulates NR2b promoter activity in a T724- and Tbr-1-binding-site-dependent manner.\",\n      \"method\": \"In vitro PKA kinase assay, site-directed mutagenesis, co-immunoprecipitation, luciferase reporter assay in cortical neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, multiple domain-specific effects validated by reporter assay\",\n      \"pmids\": [\"20067577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CASK interacts with Bcl11A/CTIP1 (both Bcl11A-S and -L isoforms) in transfected cells and brain; CASK and Bcl11A colocalize in neuronal nuclei; CASK enhances Bcl11A-L-mediated restriction of axon outgrowth and branching in hippocampal neurons.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from brain, immunofluorescence, axon morphology assay with dominant-negative\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from brain plus functional neuronal morphology assay, single lab\",\n      \"pmids\": [\"20623620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The liprin-α2/CASK complex structure reveals that three SAM domains of liprin-α form an integrated supramodule that binds to the CASK kinase-like domain; three XLMR-associated CASK mutants are defective in binding liprin-α; CASK/liprin-α/liprin-β ternary complex can form.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, cellular co-localization, XLMR mutant analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of complex plus mutant validation, multiple orthogonal methods\",\n      \"pmids\": [\"21855798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A short linear ExIWVxR peptide motif from Caskin1 (and a related motif from Mint1) is necessary and sufficient for binding the CASK CaM kinase domain; the same binding site on CASK accommodates both Caskin1 and Mint1, explaining their competition; TIAM1 contains a similar peptide sufficient for CASK binding in vitro.\",\n      \"method\": \"Peptide binding assays, mutagenesis, in vitro pulldown\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — defined minimal peptide motifs with mutagenesis, rigorous biochemical mapping\",\n      \"pmids\": [\"21763699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CASK directly interacts with Cx43 (connexin 43); CASK mainly interacts with the hypophosphorylated form of Cx43; CASK and Cx43 colocalize in brain astrocytes and at wound edges; individual expression of either protein inhibits cell migration but co-expression abrogates this inhibitory effect.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding, far-western blotting, scratch wound migration assay in MDCK cells, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods plus functional migration assay\",\n      \"pmids\": [\"22389404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CASK interacts with PMCA4b and JAM-A on the sperm flagellum; CASK binds alternatively (not synergistically) with each via its single PDZ domain; in Jam-A null sperm, CASK-PMCA4b interaction is increased resulting in PMCA4b inhibition and Ca2+ accumulation, demonstrating that JAM-A positively regulates PMCA4b indirectly through CASK.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, Ca2+ measurement, PMCA4b enzymatic activity assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional Ca2+ and enzyme activity data, single lab\",\n      \"pmids\": [\"22020416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Liprin-α2 promotes presynaptic recruitment of CASK; depletion of liprin-α2 reduces FRAP-measured turnover of CASK at presynaptic terminals, indicating liprin-α2 promotes dynamic CASK scaffolding for synaptic vesicle release.\",\n      \"method\": \"FRAP (fluorescence recovery after photobleaching), immunocytochemistry, co-immunoprecipitation, knockdown\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP and biochemical methods, single lab\",\n      \"pmids\": [\"23751498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CASK regulates SAP97 conformation: CASK binding to SAP97 via L27 domains stabilizes SAP97 in an 'extended' conformation; unbound SAP97 adopts a 'compact' conformation preferentially associating with AMPARs (GluA1), while CASK-bound extended SAP97 preferentially colocalizes with NMDARs (GluN2B).\",\n      \"method\": \"Intramolecular FRET sensors, co-immunoprecipitation, confocal imaging in neurons and HEK cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — FRET conformational sensors plus biochemical and imaging validation, mechanistic link between CASK binding and receptor sorting\",\n      \"pmids\": [\"23864692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CASK interacts with and controls P2X3 receptor expression in trigeminal ganglia neurons; CASK co-immunoprecipitates with P2X3 from ganglia and HEK co-transfected cells; CASK increases serine phosphorylation of P2X3; CASK silencing decreases cell-surface P2X3 expression via proteasomal degradation; NGF upregulates the CASK/P2X3 interaction.\",\n      \"method\": \"Co-immunoprecipitation, whole-cell patch clamp, biotinylation surface expression assay, proteasome inhibitor rescue, RNAi\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional electrophysiology and surface expression assays, single lab\",\n      \"pmids\": [\"23600800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CASK interacts with FRMD7 at the plasma membrane; CASK promotes FRMD7 co-localization at the plasma membrane and CASK-induced neurite length enhancement; C-terminal CASK mutations that cause nystagmus specifically disrupt the CASK-FRMD7 interaction.\",\n      \"method\": \"IP-mass spectrometry, co-immunoprecipitation, immunofluorescence, neurite outgrowth assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus functional assay with disease mutations, single lab\",\n      \"pmids\": [\"23406872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CASK neurexin1β phosphorylation modulates the CASK complex: liprin-α and Mint1 compete for direct binding to CASK, but neurexin1β eliminates this competition allowing all four proteins to form a complex; CASK phosphorylation of neurexin modulates liprin-α interaction; CASK stabilizes neurexin levels in neurons.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, cell culture with CASK knockdown and neurexin quantification\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical competition assays and kinase assay, single lab with multiple approaches\",\n      \"pmids\": [\"27015872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CASK localizes to the lateral membrane of cardiac myocytes (associated with dystrophin) and directly interacts with the C-terminus of NaV1.5; CASK silencing increases INa by increasing NaV1.5 surface expression specifically at the lateral membrane, through a brefeldin-A-sensitive trafficking pathway.\",\n      \"method\": \"Whole-cell patch clamp, TIRF microscopy, biotinylation surface assay, pulldown, immunostaining\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction pulldown plus multiple functional assays (electrophysiology, surface expression, brefeldin-A block)\",\n      \"pmids\": [\"27364017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In C. elegans, LIN-2/CASK interacts with kinesin-3 UNC-104/KIF1A on its stalk domain (mapped to L27 and GUK domains of LIN-2); LIN-2 knockout reduces UNC-104 motility and SNB-1/synaptobrevin cargo transport and increases motor clustering in axons; LIN-2 elevates UNC-104 run length more effectively than SYD-2/liprin-α.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), in vivo imaging of motor motility in C. elegans neurons\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods including in vivo motor motility assays, ortholog study in C. elegans\",\n      \"pmids\": [\"27172328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neuron-specific deletion of CASK in mice does not cause perinatal lethality but induces epileptic seizures and growth retardation; CASK haploinsufficiency is inconsequential in neurons alone; CASK can interact with metabolic proteins and CASK knockdown reduces cellular respiration.\",\n      \"method\": \"Cre-LoxP conditional knockout, video-EEG, biochemical affinity chromatography, metabolic assay\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotype plus biochemical interaction with metabolic proteins, single lab\",\n      \"pmids\": [\"27036546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CASK T740A knock-in mice (disrupting CASK-Tbr1 interaction) show a specific defect in extinction of associative memory without affecting acquisition, demonstrating that the CASK-Tbr1 interaction is specifically required for cognitive flexibility rather than global memory.\",\n      \"method\": \"Gene knock-in (T740A point mutation), co-immunoprecipitation from brain, behavioral fear conditioning and extinction assays\",\n      \"journal\": \"Journal of psychiatry & neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in mouse with defined interaction disruption and specific behavioral phenotype\",\n      \"pmids\": [\"28234597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CNTNAP2 stabilizes interneuron dendritic arbors through direct interaction with CASK's C-terminus; Cntnap2 KO mice show reduced CASK levels in the cortical membrane fraction; knockdown of either CNTNAP2 or CASK similarly alters GluA1 levels and localization in interneurons.\",\n      \"method\": \"Yeast two-hybrid, Co-IP, proximity ligation assay, SIM/STED super-resolution imaging, shRNA knockdown, Cntnap2 KO mouse\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including super-resolution microscopy and genetic rescue, KO mouse validation\",\n      \"pmids\": [\"29610457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CASK missense mutations M519T (in PDZ domain) and G659D (in SH3 domain) both disrupt the CASK-neurexin interaction and cause severe MICPCH; G659D disrupts the PDZ-SH3 domain interface; neurexin binding to CASK but not Tbr-1 interaction is the critical determinant for microcephaly/cerebellar hypoplasia.\",\n      \"method\": \"Co-immunoprecipitation with neurexin, protein aggregation assay, clinical genotype-phenotype analysis\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction assays with disease mutations, pathway inference from human genetics, single lab\",\n      \"pmids\": [\"29426960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CASK interaction with Dlg1 is required for mitotic spindle orientation in mammalian epithelial cells; CASK depletion or blocking the CASK-Dlg1 interaction causes misoriented cell divisions and multilumen formation; CASK is required for Dlg1 membrane localization and for correct positioning of the LGN-NuMA spindle orientation complex.\",\n      \"method\": \"RNAi knockdown, interfering peptides, 3D organoid culture, immunofluorescence of spindle orientation markers\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi plus specific inhibitory peptide plus domain deletion, functional spindle orientation and lumen formation assays\",\n      \"pmids\": [\"31289196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neurexin PDZ and GK domain mutations in CASK impair neurexin binding and neurexin-induced oligomerization of CASK; GK domain mutations additionally impair CINAP and Tbr1 binding; L27 domain mutation disrupts SAP97 binding; neurexin binding is not required for presynaptic localization of CASK.\",\n      \"method\": \"Co-expression and co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) for oligomerization, molecular modeling\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic Co-IP plus BiFC oligomerization assay, multiple mutations, single lab\",\n      \"pmids\": [\"33090494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A Mint1 N-terminal fragment binds CASK-CaMK with ~7.5 nM affinity; the crystal structure reveals two contact surfaces: the C-lobe of CASK-CaMK binds a short sequence common to CaMK targets, and the N-lobe engages an α-helix unique to Mint1; Ca2+/CaM does not regulate the CASK-Mint1 interaction; several CASK disease mutations can be mechanistically explained by the structure.\",\n      \"method\": \"X-ray crystallography, ITC/biophysical binding assays, mutagenesis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure plus quantitative binding analysis and disease-mutation interpretation\",\n      \"pmids\": [\"32348748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Complete CASK loss causes cerebellar degeneration through postmitotic neurodegeneration rather than defective neuronal migration or differentiation: a CASK-null human brain shows astrogliosis/microgliosis without migration defects; mouse cerebellum-specific CASK deletion causes granule cell degeneration postdevelopmentally; heterozygous female mice show no neurodegeneration due to 50% normal cells.\",\n      \"method\": \"Human brain histopathology, conditional cerebellar knockout mouse (Cre-LoxP), immunohistochemistry for gliosis markers\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human pathology combined with conditional murine KO model, multiple histological markers\",\n      \"pmids\": [\"35149592\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CASK is a multidomain MAGUK scaffold protein whose CaM-kinase domain functions as a constitutively active, Mg2+-independent (indeed Mg2+-inhibited) kinase that phosphorylates substrates such as neurexin-1 recruited via its PDZ domain; it assembles alternative presynaptic tripartite complexes (CASK/Veli/Mint1 or CASK/Veli/Caskin1) on neurexin cytoplasmic tails, links neurexin to the actin cytoskeleton via protein 4.1, and is recruited to synapses through liprin-α; its guanylate kinase domain translocates to the nucleus to co-activate Tbr-1-driven transcription (regulating reelin, NR2b, and other genes) in a complex further modulated by CINAP, with this nuclear activity tuned by PKA phosphorylation at T724; CASK also regulates SAP97 conformation to sort AMPA vs. NMDA receptors, controls basolateral membrane localization of ion channels (Kir2, NaV1.5) and other receptors via its L27-SAP97 and PDZ-domain interactions, gates CaMKII autophosphorylation, and is required for oriented cell divisions by anchoring Dlg1 at the membrane to position the LGN-NuMA spindle complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CASK is a multidomain MAGUK scaffold protein that organizes presynaptic protein complexes, links membrane adhesion molecules to the cytoskeleton, and couples membrane events to nuclear transcription in neurons and epithelia [#0, #4]. It was first identified as a synaptic membrane protein binding the cytoplasmic tails of neurexins, and it nucleates tripartite presynaptic complexes with Veli/LIN-7 and either Mint1 or Caskin1, which compete for the same CaM-kinase-domain site via a short ExIWVxR peptide motif [#0, #8, #26]. Through its PDZ domain CASK engages neurexin, syndecan-2, and other membrane partners, while protein 4.1 binding nucleates local actin/spectrin assembly on neurexin tails, physically coupling adhesion to the cytoskeleton [#2, #3, #5]. CASK is recruited to synapses by liprin-\\u03b1, whose SAM-domain supramodule binds the CASK kinase-like domain, with recruitment further regulated by Cdk5 phosphorylation [#16, #25, #29]. Unusually, the CASK CaM-kinase domain is a constitutively active, Mg2+-independent kinase\\u2014an activity that evolved through substitution of four ATP-pocket residues to become Mg2+-inhibited\\u2014and it phosphorylates neurexin-1 recruited via the PDZ domain [#18, #22]. Its guanylate kinase domain translocates to the nucleus to co-activate Tbr-1-driven transcription of T-element genes including reelin and NR2b, in a complex with the nucleosome-assembly factor CINAP and tuned by PKA phosphorylation at T724 [#4, #11, #13, #23]. In epithelia, CASK directs basolateral membrane localization of SAP97 and ion channels and controls SAP97 conformation to sort AMPA versus NMDA receptors, and it is required for oriented cell division by anchoring Dlg1 to position the LGN-NuMA spindle complex [#7, #12, #30, #40]. CASK-null mice die at birth with altered neurotransmitter release, and human CASK mutations that disrupt neurexin binding cause severe MICPCH and cerebellar degeneration through postmitotic neurodegeneration [#17, #39, #43].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established CASK as a synaptic membrane scaffold by identifying it as a direct binding partner of neurexin cytoplasmic tails, placing it at the presynaptic adhesion interface.\",\n      \"evidence\": \"Yeast two-hybrid and biochemical binding with subcellular fractionation of brain\",\n      \"pmids\": [\"8786425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full presynaptic complex assembled on neurexin\", \"No functional consequence for synapse formation established\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Genetic epistasis in C. elegans placed the CASK ortholog lin-2 in RTK/Ras vulval signaling and showed its kinase and guanylate kinase activities are dispensable there, implying a structural scaffolding role.\",\n      \"evidence\": \"Loss-of-function mutants and domain-mutant transgene rescue in C. elegans\",\n      \"pmids\": [\"8565857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address neuronal functions\", \"Structural vs enzymatic role left open for vertebrate contexts\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined CASK's PDZ-domain and protein 4.1 partnerships, linking it to syndecan-2 and the actin cytoskeleton at basolateral membranes and synaptic junctions.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, Co-IP, and immunogold EM in epithelia and brain\",\n      \"pmids\": [\"9660868\", \"9660869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cytoskeletal coupling not yet reconstituted\", \"Did not test functional requirement for junction integrity\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Revealed an unexpected nuclear role: CASK translocates to the nucleus and co-activates Tbr-1-driven transcription, coupling a membrane scaffold to gene regulation.\",\n      \"evidence\": \"Nuclear fractionation, Co-IP, DNA-binding and transcriptional reporter assays\",\n      \"pmids\": [\"10749215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering nuclear translocation unclear\", \"Stoichiometry of nuclear vs membrane CASK pools undefined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reconstituted CASK-protein 4.1-mediated nucleation of actin/spectrin on neurexin tails, establishing the molecular logic of adhesion-to-cytoskeleton coupling.\",\n      \"evidence\": \"In vitro reconstitution and actin co-sedimentation from brain extracts\",\n      \"pmids\": [\"11604393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement for synaptic actin organization not tested\", \"Regulation of complex assembly unaddressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed CASK assembles alternative presynaptic tripartite complexes by binding Caskin1 or Mint1 competitively at one CaM-kinase-domain site, defining combinatorial scaffold output.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and neurexin-tail affinity competition assays; plus CD spectroscopy showing obligate L27 heterodimer folding with LIN-7\",\n      \"pmids\": [\"12040031\", \"12110687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional difference between Mint1 vs Caskin1 complexes not resolved\", \"What selects between complexes in vivo unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the CASK L27N-SAP97 interaction as required for SAP97 lateral membrane targeting, extending CASK scaffolding to epithelial polarity.\",\n      \"evidence\": \"Biochemical domain mapping and dominant-negative rescue in MDCK cells\",\n      \"pmids\": [\"11865057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream cargo of SAP97 not yet defined\", \"Did not connect to receptor sorting\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Elaborated the nuclear transcription module: CASK recruits CINAP and Tbr-1 to regulate NR2b and reelin, with NMDA-driven CINAP degradation tuning activity across multiple T-element target genes.\",\n      \"evidence\": \"Co-IP, RNAi, luciferase reporters with promoter deletions, and in vivo Tbr-1 KO; plus Kir2 channel complex mapping\",\n      \"pmids\": [\"15066269\", \"15584924\", \"14960569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How synaptic activity signals to nuclear CASK mechanistically incomplete\", \"Genome-wide target set undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined upstream regulation and organismal requirement: Cdk5 phosphorylation controls CASK membrane recruitment and liprin-\\u03b1 binding, and CASK loss is perinatally lethal with altered spontaneous neurotransmitter release.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, dominant-negative Cdk5 imaging, and full KO mouse electrophysiology\",\n      \"pmids\": [\"18054859\", \"17287346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cause of perinatal lethality not pinpointed\", \"How release asymmetry arises mechanistically unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Solved the central enzymatic paradox: crystal structures showed the CASK CaM-kinase domain is constitutively active and Mg2+-independent, phosphorylating neurexin-1 recruited via the PDZ domain.\",\n      \"evidence\": \"X-ray crystallography and Mg2+-free in vitro kinase assays with substrate identification; plus SUMOylation regulation of protein 4.1 binding\",\n      \"pmids\": [\"18423203\", \"18606847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate repertoire beyond neurexin unknown\", \"Regulation of an inherently constitutive kinase unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected CASK/SAP97 scaffolding to receptor trafficking, defining a specialized ER-to-dendritic-Golgi pathway for NMDAR sorting.\",\n      \"evidence\": \"Live-cell imaging and dominant-negative trafficking dissection in hippocampal neurons\",\n      \"pmids\": [\"19620977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of the bypass pathway incomplete\", \"Selectivity for NMDAR vs AMPAR not yet mechanistic\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Refined kinase evolution and post-translational control: four ATP-pocket residues evolved to make CASK Mg2+-inhibited, and PKA phosphorylation at T724 upregulates the CASK-Tbr-1 interaction to drive NR2b transcription.\",\n      \"evidence\": \"Mutagenesis, crystallography, kinetics, phylogenetics; in vitro PKA kinase assay and reporters\",\n      \"pmids\": [\"20424264\", \"20067577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological advantage of Mg2+ inhibition untested in vivo\", \"Crosstalk between membrane and nuclear PKA-CASK pools undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided structural and motif-level rules for CASK assembly: liprin-\\u03b1 SAM supramodule binds the kinase-like domain, XLMR mutants disrupt this, and an ExIWVxR peptide motif governs Mint1/Caskin1 competition.\",\n      \"evidence\": \"X-ray crystallography of liprin-\\u03b1/CASK, peptide binding assays, and disease-mutant analysis\",\n      \"pmids\": [\"21855798\", \"21763699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TIAM1 motif binding integrates into signaling unclear\", \"In vivo competition dynamics not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a conformational mechanism for receptor sorting: CASK binding holds SAP97 in an extended conformation favoring NMDAR association, while unbound compact SAP97 favors AMPARs.\",\n      \"evidence\": \"Intramolecular FRET sensors, Co-IP, and confocal imaging in neurons and HEK cells; plus liprin-\\u03b12 FRAP-measured presynaptic CASK turnover\",\n      \"pmids\": [\"23864692\", \"23751498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How conformational state is dynamically switched in vivo unknown\", \"Quantitative coupling to synaptic receptor content untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended CASK function beyond neurons to cardiac channel trafficking and revealed neuron-specific deletion phenotypes, distinguishing scaffolding roles by tissue.\",\n      \"evidence\": \"Patch clamp, TIRF, surface biotinylation in myocytes; conditional neuronal KO with video-EEG\",\n      \"pmids\": [\"27364017\", \"27036546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism restricting NaV1.5 to the lateral membrane incomplete\", \"Relationship between neuronal vs systemic CASK loss unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated in vivo specificity of the nuclear module: a T740A knock-in disrupting CASK-Tbr1 selectively impairs memory extinction, separating transcriptional from scaffolding functions behaviorally.\",\n      \"evidence\": \"Point-mutation knock-in mouse, brain Co-IP, and fear extinction behavior\",\n      \"pmids\": [\"28234597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets driving extinction not identified\", \"Circuit locus of the deficit undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked CASK to autism-associated CNTNAP2 in stabilizing interneuron arbors and controlling GluA1, integrating CASK into neurodevelopmental disease networks.\",\n      \"evidence\": \"Y2H, Co-IP, PLA, super-resolution imaging, knockdown, and Cntnap2 KO mouse\",\n      \"pmids\": [\"29610457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanistic link to GluA1 localization incomplete\", \"Whether kinase or scaffold activity is required untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a mitotic function: CASK anchors Dlg1 at the membrane to position the LGN-NuMA complex and orient the spindle, expanding CASK roles to tissue architecture.\",\n      \"evidence\": \"RNAi, interfering peptides, and 3D organoid spindle/lumen assays\",\n      \"pmids\": [\"31289196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CASK is itself positioned for spindle cues unknown\", \"Connection to neurodevelopmental phenotypes untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined complex architecture and disease mechanism: structures and BiFC mapping showed neurexin binding promotes CASK oligomerization, neurexin eliminates liprin-\\u03b1/Mint1 competition, and Mint1 binds CASK-CaMK with nanomolar affinity at defined surfaces explaining disease mutations.\",\n      \"evidence\": \"Crystallography, ITC, BiFC oligomerization, and systematic Co-IP of domain mutants\",\n      \"pmids\": [\"33090494\", \"32348748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of neurexin-induced oligomerization unclear\", \"In vivo relevance of competition relief untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the cellular basis of CASK-related cerebellar disease as postmitotic neurodegeneration rather than migration/differentiation failure, with neurexin binding identified as the critical determinant for microcephaly/cerebellar hypoplasia.\",\n      \"evidence\": \"Human brain histopathology and cerebellum-specific conditional KO mouse; disease-mutation Co-IP with neurexin\",\n      \"pmids\": [\"35149592\", \"29426960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of degeneration unknown\", \"Why granule cells are selectively vulnerable unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the constitutive, Mg2+-inhibited kinase activity is biologically deployed and how membrane scaffolding, kinase signaling, and nuclear transcription are coordinately regulated within a single CASK protein in vivo.\",\n      \"evidence\": \"No timeline discovery directly reconciles the three functional modes under physiological signaling\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full physiological substrate set of the kinase undefined\", \"Signals partitioning CASK among membrane, cytoskeletal, and nuclear pools unknown\", \"Integration of mitotic spindle role with neuronal functions unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [18, 22]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [18, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 8, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 11, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 12, 34]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 11, 24]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 17, 20]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 11, 13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 12, 20, 34]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [40]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [38, 43]}\n    ],\n    \"complexes\": [\n      \"CASK/Veli(LIN-7)/Mint1 tripartite complex\",\n      \"CASK/Veli/Caskin1 tripartite complex\",\n      \"CASK-CINAP-Tbr-1 transcriptional complex\",\n      \"SAP97/CASK/Veli/Mint1-Kir2 channel complex\"\n    ],\n    \"partners\": [\n      \"NRXN1\",\n      \"LIN7 (Veli)\",\n      \"MINT1 (APBA1)\",\n      \"CASKIN1\",\n      \"DLG1 (SAP97)\",\n      \"PPFIA (liprin-alpha)\",\n      \"TBR1\",\n      \"EPB41 (protein 4.1)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}