Affinage

CASK

Kappa-casein · UniProt P07498

Length
182 aa
Mass
20.3 kDa
Annotated
2026-06-09
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1996 High

    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

    PMID:8786425

    Open questions at the time
    • Did not define the full presynaptic complex assembled on neurexin
    • No functional consequence for synapse formation established
  2. 1996 High

    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

    PMID:8565857

    Open questions at the time
    • Did not address neuronal functions
    • Structural vs enzymatic role left open for vertebrate contexts
  3. 1998 High

    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

    PMID:9660868 PMID:9660869

    Open questions at the time
    • Mechanism of cytoskeletal coupling not yet reconstituted
    • Did not test functional requirement for junction integrity
  4. 2000 High

    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

    PMID:10749215

    Open questions at the time
    • Signal triggering nuclear translocation unclear
    • Stoichiometry of nuclear vs membrane CASK pools undefined
  5. 2001 High

    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

    PMID:11604393

    Open questions at the time
    • In vivo requirement for synaptic actin organization not tested
    • Regulation of complex assembly unaddressed
  6. 2002 High

    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

    PMID:12040031 PMID:12110687

    Open questions at the time
    • Functional difference between Mint1 vs Caskin1 complexes not resolved
    • What selects between complexes in vivo unknown
  7. 2002 High

    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

    PMID:11865057

    Open questions at the time
    • Downstream cargo of SAP97 not yet defined
    • Did not connect to receptor sorting
  8. 2004 High

    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

    PMID:14960569 PMID:15066269 PMID:15584924

    Open questions at the time
    • How synaptic activity signals to nuclear CASK mechanistically incomplete
    • Genome-wide target set undefined
  9. 2007 High

    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

    PMID:17287346 PMID:18054859

    Open questions at the time
    • Cause of perinatal lethality not pinpointed
    • How release asymmetry arises mechanistically unclear
  10. 2008 High

    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

    PMID:18423203 PMID:18606847

    Open questions at the time
    • Physiological substrate repertoire beyond neurexin unknown
    • Regulation of an inherently constitutive kinase unclear
  11. 2009 High

    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

    PMID:19620977

    Open questions at the time
    • Molecular determinants of the bypass pathway incomplete
    • Selectivity for NMDAR vs AMPAR not yet mechanistic
  12. 2010 High

    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

    PMID:20067577 PMID:20424264

    Open questions at the time
    • Biological advantage of Mg2+ inhibition untested in vivo
    • Crosstalk between membrane and nuclear PKA-CASK pools undefined
  13. 2011 High

    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

    PMID:21763699 PMID:21855798

    Open questions at the time
    • How TIAM1 motif binding integrates into signaling unclear
    • In vivo competition dynamics not measured
  14. 2013 High

    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

    PMID:23751498 PMID:23864692

    Open questions at the time
    • How conformational state is dynamically switched in vivo unknown
    • Quantitative coupling to synaptic receptor content untested
  15. 2016 High

    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

    PMID:27036546 PMID:27364017

    Open questions at the time
    • Mechanism restricting NaV1.5 to the lateral membrane incomplete
    • Relationship between neuronal vs systemic CASK loss unresolved
  16. 2017 High

    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

    PMID:28234597

    Open questions at the time
    • Transcriptional targets driving extinction not identified
    • Circuit locus of the deficit undefined
  17. 2018 High

    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

    PMID:29610457

    Open questions at the time
    • Direct mechanistic link to GluA1 localization incomplete
    • Whether kinase or scaffold activity is required untested
  18. 2019 High

    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

    PMID:31289196

    Open questions at the time
    • How CASK is itself positioned for spindle cues unknown
    • Connection to neurodevelopmental phenotypes untested
  19. 2020 High

    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

    PMID:32348748 PMID:33090494

    Open questions at the time
    • Functional output of neurexin-induced oligomerization unclear
    • In vivo relevance of competition relief untested
  20. 2022 High

    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

    PMID:29426960 PMID:35149592

    Open questions at the time
    • Molecular trigger of degeneration unknown
    • Why granule cells are selectively vulnerable unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 3 GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0003677 DNA binding 1 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 3 GO:0005783 endoplasmic reticulum 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-112316 Neuronal System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 1
Partners
CASKIN1DLG1 (SAP97)EPB41 (PROTEIN 4.1)LIN7 (VELI)MINT1 (APBA1)NRXN1PPFIA (LIPRIN-ALPHA)TBR1
Complex memberships
CASK-CINAP-Tbr-1 transcriptional complexCASK/Veli(LIN-7)/Mint1 tripartite complexCASK/Veli/Caskin1 tripartite complexSAP97/CASK/Veli/Mint1-Kir2 channel complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Yeast two-hybrid screen, biochemical binding assays, subcellular fractionation The Journal of neuroscience High 8786425
1996 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. Genetic epistasis analysis, loss-of-function mutants, transgene rescue with domain-mutant constructs Development High 8565857
1998 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. Yeast two-hybrid, in vitro binding assays, immunofluorescence colocalization The Journal of cell biology High 9660868
1998 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. Yeast two-hybrid, co-immunoprecipitation, immunogold EM The Journal of cell biology High 9660869
2000 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. Yeast two-hybrid, co-immunoprecipitation, nuclear fractionation, DNA-binding assays, transcriptional reporter assays Nature High 10749215
2001 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. In vitro reconstitution, actin co-sedimentation from brain extracts, pulldown assays The Journal of biological chemistry High 11604393
2001 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. Co-immunoprecipitation, subcellular fractionation, ubiquitination assay The Journal of biological chemistry Medium 11679592
2002 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. Biochemical domain mapping, dominant-negative overexpression, immunofluorescence colocalization Molecular and cellular biology High 11865057
2002 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. Yeast two-hybrid, co-immunoprecipitation, affinity chromatography with neurexin tail The Journal of neuroscience High 12040031
2002 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. Circular dichroism spectroscopy, biophysical co-folding analysis The Journal of biological chemistry High 12110687
2003 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. Co-immunoprecipitation from tissue, transcriptional reporter assay, site-directed mutagenesis of PMCA Ca2+ pumping The Journal of biological chemistry Medium 12511555
2004 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. Co-immunoprecipitation, RNA interference knockdown in neurons, luciferase reporter assay, proteasome inhibitor treatment Neuron High 15066269
2004 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. Affinity pulldown, co-immunoprecipitation, dominant-negative overexpression with immunocytochemistry The Journal of biological chemistry High 14960569
2004 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. Luciferase reporter assay with deletion constructs, in vivo Tbr-1 knockout analysis Journal of neurochemistry High 15584924
2005 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. GST pulldown from glomerular lysate, mass spectrometry, immunofluorescence colocalization Proceedings of the National Academy of Sciences of the United States of America Medium 15994232
2006 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. Genetic loss-of-function, in vivo phosphorylation analysis, epistasis with CaMKII autophosphorylation site mutants Neuron High 16880127
2007 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. In vitro kinase assay, co-immunoprecipitation, dominant-negative Cdk5 expression, confocal imaging of membrane distribution Neuron High 18054859
2007 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. Conditional and full knockout mouse, electrophysiology (mEPSCs/mIPSCs, evoked EPSCs), Western blotting Proceedings of the National Academy of Sciences of the United States of America High 17287346
2008 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. High-resolution X-ray crystallography, in vitro kinase assay, phosphotransfer assays without Mg2+ Cell High 18423203
2008 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. RNA interference knockdown, SUMO1 fusion overexpression, co-immunoprecipitation to assess protein 4.1 binding, spine morphology quantification The Journal of cell biology High 18606847
2009 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. Live-cell imaging, immunofluorescence, dominant-negative constructs, trafficking pathway dissection in hippocampal neurons Nature neuroscience High 19620977
2009 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. Co-immunoprecipitation, domain deletion mapping, Triton X-100 solubility fractionation The Journal of biological chemistry Medium 11120739
2010 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. Site-directed mutagenesis, X-ray crystallography, kinetic analyses, phylogenetic analysis Science signaling High 20424264
2010 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. In vitro PKA kinase assay, site-directed mutagenesis, co-immunoprecipitation, luciferase reporter assay in cortical neurons Journal of neurochemistry High 20067577
2010 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. Yeast two-hybrid, co-immunoprecipitation from brain, immunofluorescence, axon morphology assay with dominant-negative Journal of neuroscience research Medium 20623620
2011 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. X-ray crystallography, biochemical binding assays, cellular co-localization, XLMR mutant analysis Molecular cell High 21855798
2011 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. Peptide binding assays, mutagenesis, in vitro pulldown Journal of molecular biology High 21763699
2012 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. Co-immunoprecipitation, in vitro binding, far-western blotting, scratch wound migration assay in MDCK cells, immunofluorescence Journal of cell science High 22389404
2012 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. Co-immunoprecipitation, immunofluorescence colocalization, Ca2+ measurement, PMCA4b enzymatic activity assay Journal of cellular physiology Medium 22020416
2013 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. FRAP (fluorescence recovery after photobleaching), immunocytochemistry, co-immunoprecipitation, knockdown The Journal of cell biology Medium 23751498
2013 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). Intramolecular FRET sensors, co-immunoprecipitation, confocal imaging in neurons and HEK cells The Journal of neuroscience High 23864692
2013 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. Co-immunoprecipitation, whole-cell patch clamp, biotinylation surface expression assay, proteasome inhibitor rescue, RNAi Journal of neurochemistry Medium 23600800
2013 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. IP-mass spectrometry, co-immunoprecipitation, immunofluorescence, neurite outgrowth assay Human molecular genetics Medium 23406872
2016 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. Co-immunoprecipitation, in vitro kinase assay, cell culture with CASK knockdown and neurexin quantification Cellular and molecular life sciences Medium 27015872
2016 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. Whole-cell patch clamp, TIRF microscopy, biotinylation surface assay, pulldown, immunostaining Circulation research High 27364017
2016 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. Yeast two-hybrid, co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), in vivo imaging of motor motility in C. elegans neurons Traffic Medium 27172328
2016 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. Cre-LoxP conditional knockout, video-EEG, biochemical affinity chromatography, metabolic assay Acta neuropathologica communications Medium 27036546
2017 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. Gene knock-in (T740A point mutation), co-immunoprecipitation from brain, behavioral fear conditioning and extinction assays Journal of psychiatry & neuroscience High 28234597
2018 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. Yeast two-hybrid, Co-IP, proximity ligation assay, SIM/STED super-resolution imaging, shRNA knockdown, Cntnap2 KO mouse Molecular psychiatry High 29610457
2018 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. Co-immunoprecipitation with neurexin, protein aggregation assay, clinical genotype-phenotype analysis Human genetics Medium 29426960
2019 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. RNAi knockdown, interfering peptides, 3D organoid culture, immunofluorescence of spindle orientation markers Journal of cell science High 31289196
2020 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. Co-expression and co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) for oligomerization, molecular modeling Journal of neurochemistry Medium 33090494
2020 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. X-ray crystallography, ITC/biophysical binding assays, mutagenesis Structure High 32348748
2022 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. Human brain histopathology, conditional cerebellar knockout mouse (Cre-LoxP), immunohistochemistry for gliosis markers Journal of medical genetics High 35149592

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. The Journal of neuroscience : the official journal of the Society for Neuroscience 445 8786425
1998 Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. The Journal of cell biology 315 9660868
2000 Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 307 10749215
1998 Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses. The Journal of cell biology 279 9660869
2008 CASK Functions as a Mg2+-independent neurexin kinase. Cell 223 18423203
2008 Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nature genetics 223 19165920
2009 SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nature neuroscience 181 19620977
1996 The C. elegans vulval induction gene lin-2 encodes a member of the MAGUK family of cell junction proteins. Development (Cambridge, England) 178 8565857
2007 Deletion of CASK in mice is lethal and impairs synaptic function. Proceedings of the National Academy of Sciences of the United States of America 176 17287346
1999 Regulated expression and subcellular localization of syndecan heparan sulfate proteoglycans and the syndecan-binding protein CASK/LIN-2 during rat brain development. The Journal of neuroscience : the official journal of the Society for Neuroscience 171 10460248
2006 The role of the MAGUK protein CASK in neural development and synaptic function. Current medicinal chemistry 164 16842202
2001 Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain. The Journal of biological chemistry 152 11679592
2001 CASK and protein 4.1 support F-actin nucleation on neurexins. The Journal of biological chemistry 141 11604393
2005 Cell junction-associated proteins IQGAP1, MAGI-2, CASK, spectrins, and alpha-actinin are components of the nephrin multiprotein complex. Proceedings of the National Academy of Sciences of the United States of America 136 15994232
2004 A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels. The Journal of biological chemistry 130 14960569
2004 Transcriptional modification by a CASK-interacting nucleosome assembly protein. Neuron 130 15066269
2002 A novel and conserved protein-protein interaction domain of mammalian Lin-2/CASK binds and recruits SAP97 to the lateral surface of epithelia. Molecular and cellular biology 119 11865057
2000 Association of junctional adhesion molecule with calcium/calmodulin-dependent serine protein kinase (CASK/LIN-2) in human epithelial caco-2 cells. The Journal of biological chemistry 110 11120739
2011 Phenotypic spectrum associated with CASK loss-of-function mutations. Journal of medical genetics 106 21954287
2002 CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with caskin 1, a novel CASK-binding protein. The Journal of neuroscience : the official journal of the Society for Neuroscience 95 12040031
2013 Liprin-α2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission. The Journal of cell biology 93 23751498
2009 CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes. European journal of human genetics : EJHG 92 20029458
2007 Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK. Neuron 91 18054859
2003 Interaction of the plasma membrane Ca2+ pump 4b/CI with the Ca2+/calmodulin-dependent membrane-associated kinase CASK. The Journal of biological chemistry 88 12511555
2008 SUMOylation of the MAGUK protein CASK regulates dendritic spinogenesis. The Journal of cell biology 85 18606847
2012 Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient. Orphanet journal of rare diseases 83 22452838
1999 Molecular analysis of the X11-mLin-2/CASK complex in brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 9952408
2011 Liprin-mediated large signaling complex organization revealed by the liprin-α/CASK and liprin-α/liprin-β complex structures. Molecular cell 80 21855798
2009 A missense mutation in CASK causes FG syndrome in an Italian family. American journal of human genetics 77 19200522
2004 Nephrin forms a complex with adherens junction proteins and CASK in podocytes and in Madin-Darby canine kidney cells expressing nephrin. The American journal of pathology 77 15331416
2004 Identification of Tbr-1/CASK complex target genes in neurons. Journal of neurochemistry 71 15584924
2015 Phenotypic and molecular insights into CASK-related disorders in males. Orphanet journal of rare diseases 67 25886057
2012 CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia. Epilepsia 66 22709267
2014 Down-regulation of miR-203 induced by Helicobacter pylori infection promotes the proliferation and invasion of gastric cancer by targeting CASK. Oncotarget 62 25373785
2009 High levels of structural disorder in scaffold proteins as exemplified by a novel neuronal protein, CASK-interactive protein1. The FEBS journal 61 19523119
2002 Basolateral membrane expression of the Kir 2.3 channel is coordinated by PDZ interaction with Lin-7/CASK complex. American journal of physiology. Cell physiology 59 11742811
2002 CASK and its target gene Reelin were co-upregulated in human esophageal carcinoma. Cancer letters 57 11880184
1998 Murine CASK is disrupted in a sex-linked cleft palate mouse mutant. Genomics 56 9787075
2016 CASK stabilizes neurexin and links it to liprin-α in a neuronal activity-dependent manner. Cellular and molecular life sciences : CMLS 55 27015872
2013 A novel interaction between FRMD7 and CASK: evidence for a causal role in idiopathic infantile nystagmus. Human molecular genetics 51 23406872
2017 Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH). PloS one 50 28783747
2006 Neuronal expression and interaction with the synaptic protein CASK suggest a role for Neph1 and Neph2 in synaptogenesis. The Journal of comparative neurology 48 16874800
1997 Camguk, Lin-2, and CASK: novel membrane-associated guanylate kinase homologs that also contain CaM kinase domains. Mechanisms of development 45 9178262
2010 Evolution of CASK into a Mg2+-sensitive kinase. Science signaling 44 20424264
2016 Lateral Membrane-Specific MAGUK CASK Down-Regulates NaV1.5 Channel in Cardiac Myocytes. Circulation research 43 27364017
2013 CASK and CaMKII function in the mushroom body α'/β' neurons during Drosophila memory formation. Frontiers in neural circuits 43 23543616
2013 CASK regulates SAP97 conformation and its interactions with AMPA and NMDA receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 43 23864692
2018 CNTNAP2 stabilizes interneuron dendritic arbors through CASK. Molecular psychiatry 42 29610457
2013 CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning. Frontiers in molecular neuroscience 42 24062638
2008 The CASK gene harbored in a deletion detected by array-CGH as a potential candidate for a gene causative of X-linked dominant mental retardation. American journal of medical genetics. Part A 39 18629876
2005 Drosophila CAKI/CMG protein, a homolog of human CASK, is essential for regulation of neurotransmitter vesicle release. Journal of neurophysiology 39 15872064
2016 X-linked intellectual disability gene CASK regulates postnatal brain growth in a non-cell autonomous manner. Acta neuropathologica communications 38 27036546
2006 Activity-dependent gating of CaMKII autonomous activity by Drosophila CASK. Neuron 38 16880127
2011 Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Human genetics 37 21735175
2010 X-linked mental retardation gene CASK interacts with Bcl11A/CTIP1 and regulates axon branching and outgrowth. Journal of neuroscience research 37 20623620
2012 CASK (LIN2) interacts with Cx43 in wounded skin and their coexpression affects cell migration. Journal of cell science 36 22389404
2001 The scaffolding protein CASK mediates the interaction between rabphilin3a and beta-neurexins. FEBS letters 36 11377421
2011 The molecular basis of the Caskin1 and Mint1 interaction with CASK. Journal of molecular biology 35 21763699
2010 Central regulation of locomotor behavior of Drosophila melanogaster depends on a CASK isoform containing CaMK-like and L27 domains. Genetics 35 21059886
2018 Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction. Human genetics 32 29426960
2011 Pre and postsynaptic roles for Drosophila CASK. Molecular and cellular neurosciences 32 21820054
2010 Neuroradiologic features of CASK mutations. AJNR. American journal of neuroradiology 32 20595373
2012 CASK interacts with PMCA4b and JAM-A on the mouse sperm flagellum to regulate Ca2+ homeostasis and motility. Journal of cellular physiology 30 22020416
2020 Presynaptic dysfunction in CASK-related neurodevelopmental disorders. Translational psychiatry 29 32929080
2011 Targeted deletion of CASK-interacting nucleosome assembly protein causes higher locomotor and exploratory activities. Neuro-Signals 28 21576927
2013 Scaffolding proteins DLG1 and CASK cooperate to maintain the nephron progenitor population during kidney development. Journal of the American Society of Nephrology : JASN 26 23661808
2010 CASK phosphorylation by PKA regulates the protein-protein interactions of CASK and expression of the NMDAR2b gene. Journal of neurochemistry 25 20067577
2002 Coordinated folding and association of the LIN-2, -7 (L27) domain. An obligate heterodimerization involved in assembly of signaling and cell polarity complexes. The Journal of biological chemistry 25 12110687
2019 Circulating CASK is associated with recurrent focal segmental glomerulosclerosis after transplantation. PloS one 24 31356645
2018 An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy. American journal of medical genetics. Part A 24 30549415
2017 Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice. Journal of psychiatry & neuroscience : JPN 24 28234597
2007 Lin-7 targets the Kir 2.3 channel on the basolateral membrane via a L27 domain interaction with CASK. American journal of physiology. Cell physiology 24 17913842
2006 Neural activity- and development-dependent expression and distribution of CASK interacting nucleosome assembly protein in mouse brain. The Journal of comparative neurology 24 16374801
2002 Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family. Human genetics 23 12522552
2005 CASK inhibits ECV304 cell growth and interacts with Id1. Biochemical and biophysical research communications 22 15694377
2005 Camguk/CASK enhances Ether-á-go-go potassium current by a phosphorylation-dependent mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 15901771
2008 The MAGUK-family protein CASK is targeted to nuclei of the basal epidermis and controls keratinocyte proliferation. Journal of cell science 21 18664494
2020 Missense mutations in CASK, coding for the calcium-/calmodulin-dependent serine protein kinase, interfere with neurexin binding and neurexin-induced oligomerization. Journal of neurochemistry 20 33090494
2019 The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia. Journal of cell science 20 31289196
2017 A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly. Intractable & rare diseases research 20 28944139
2016 Identification and Characterization of LIN-2(CASK) as a Regulator of Kinesin-3 UNC-104(KIF1A) Motility and Clustering in Neurons. Traffic (Copenhagen, Denmark) 20 27172328
2009 CASK point mutation regulates protein-protein interactions and NR2b promoter activity. Biochemical and biophysical research communications 20 19275891
2009 CASK deletion in intestinal epithelia causes mislocalization of LIN7C and the DLG1/Scrib polarity complex without affecting cell polarity. Molecular biology of the cell 20 19726564
2004 CASK and Dlg form a PDZ protein complex at the mammalian neuromuscular junction. Muscle & nerve 19 15266631
1997 A 32 kb nucleotide sequence from the region of the lincomycin-resistance gene (22 degrees-25 degrees) of the Bacillus subtilis chromosome and identification of the site of the lin-2 mutation. Microbiology (Reading, England) 19 9274031
2020 CASK, the Soluble Glomerular Permeability Factor, Is Secreted by Macrophages in Patients With Recurrent Focal and Segmental Glomerulo-Sclerosis. Frontiers in immunology 18 32477353
2013 Calcium/calmodulin-dependent serine protein kinase (CASK) is a new intracellular modulator of P2X3 receptors. Journal of neurochemistry 18 23600800
2013 Structural constraints and functional divergences in CASK evolution. Biochemical Society transactions 18 23863172
2020 Haploinsufficiency of X-linked intellectual disability gene CASK induces post-transcriptional changes in synaptic and cellular metabolic pathways. Experimental neurology 17 32305418
2019 The CNTNAP2-CASK complex modulates GluA1 subcellular distribution in interneurons. Neuroscience letters 17 30779956
2015 Late-onset epileptic spasms in a female patient with a CASK mutation. Brain & development 17 25765806
2014 Identification and glycerol-induced correction of misfolding mutations in the X-linked mental retardation gene CASK. PloS one 17 24505460
2009 Characterisation of the interaction between syndecan-2, neurofibromin and CASK: dependence of interaction on syndecan dimerization. Biochemical and biophysical research communications 17 20006588
1991 Sheep gene mapping: additional DNA markers included (CASB, CASK, LALBA, IGF-1 and AMH). Animal genetics 17 1892247
2021 Long Noncoding RNA AATBC Promotes the Proliferation and Migration of Prostate Cancer Cell Through miR-1245b-5p/CASK Axis. Cancer management and research 16 34234553
2020 Structural Basis for the High-Affinity Interaction between CASK and Mint1. Structure (London, England : 1993) 16 32348748
2006 CASK associates with glutamate receptor interacting protein and signaling molecules. Biochemical and biophysical research communications 16 17084383
2022 Complete loss of the X-linked gene CASK causes severe cerebellar degeneration. Journal of medical genetics 15 35149592
2021 CASK regulates Notch pathway and functions as a tumor promoter in pancreatic cancer. Archives of biochemistry and biophysics 15 33548214
2017 A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus. American journal of medical genetics. Part A 15 28139025

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