Affinage

CASK

Peripheral plasma membrane protein CASK · UniProt O14936

Length
926 aa
Mass
105.1 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CASK is a multi-domain MAGUK scaffold protein that organizes synaptic, epithelial, and nuclear signaling complexes through its N-terminal CaM-kinase domain, central PDZ/SH3/guanylate kinase domains, and L27 domains. Its CaM-kinase domain functions as a constitutively active, Mg²⁺-inhibited kinase that phosphorylates neurexin and itself, and also serves as a docking platform for Mint1, Caskin1, and liprin-α, which compete for binding via a shared peptide motif to assemble alternative presynaptic complexes that regulate synaptic vesicle pools and neurotransmitter release (PMID:18423203, PMID:8786425, PMID:12040031, PMID:21855798, PMID:23751498). In the nucleus, CASK acts as a coactivator within a Tbr-1/CINAP complex to drive transcription of reelin and NR2b, a function enhanced by PKA phosphorylation at T724 and modulated by PMCA4b-dependent calcium efflux (PMID:10749215, PMID:15066269, PMID:20067577). Through its L27 domains, CASK forms obligate heterodimers with Lin-7 and regulates SAP97 conformation to sort NMDA versus AMPA receptors in dendrites and direct basolateral channel trafficking in epithelia; Cdk5 phosphorylation and SUMOylation further tune CASK membrane recruitment and dendritic spine morphogenesis (PMID:12110687, PMID:23864692, PMID:18054859, PMID:18606847). Loss-of-function mutations in CASK cause microcephaly with pontine and cerebellar hypoplasia (MICPCH), and disease-associated missense mutations disrupt neurexin and liprin-α binding (PMID:27036546, PMID:29426960, PMID:21855798).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Identification of CASK as a neurexin-binding MAGUK with a CaM-kinase domain established the founding domain architecture and placed CASK at synaptic junctions, while C. elegans work showed that its scaffolding rather than enzymatic activity was essential for receptor tyrosine kinase signaling in vulval induction.

    Evidence Yeast two-hybrid and in vitro binding for neurexin interaction; genetic epistasis and transgene rescue in C. elegans

    PMID:8565857 PMID:8786425

    Open questions at the time
    • No catalytic activity had been tested for mammalian CASK
    • Structural basis for neurexin binding unknown
    • No loss-of-function data in mammals
  2. 1998 High

    Discovery that CASK PDZ domain binds syndecan-2 and recruits protein 4.1 extended its role beyond neurexin to heparan sulfate proteoglycans and the cortical cytoskeleton at both synaptic and epithelial basolateral membranes.

    Evidence Yeast two-hybrid, co-IP from brain, immunogold EM colocalization at synapses, epithelial immunofluorescence

    PMID:9660868 PMID:9660869

    Open questions at the time
    • Functional consequence of syndecan-2 binding not tested
    • Whether syndecan and neurexin compete for CASK PDZ unknown
  3. 2000 High

    The unexpected finding that CASK translocates to the nucleus and coactivates Tbr-1-dependent transcription of reelin established a dual synaptic-scaffold/transcriptional-coactivator paradigm for CASK.

    Evidence Nuclear fractionation, DNA binding assay, reporter gene activation in neurons

    PMID:10749215

    Open questions at the time
    • Signal triggering nuclear translocation unknown
    • Endogenous chromatin targets not mapped genome-wide
  4. 2001 High

    Reconstitution of the neurexin–CASK–protein 4.1 complex showed CASK nucleates local actin/spectrin assembly on neurexin tails, providing a direct link between synaptic adhesion and the cortical cytoskeleton.

    Evidence In vitro reconstitution on neurexin cytoplasmic tail, co-IP from brain, actin filament pull-down

    PMID:11604393

    Open questions at the time
    • In vivo relevance at synapses not tested with loss-of-function
    • Whether parkin–CASK PDZ interaction modulates this assembly unclear
  5. 2002 High

    Domain-level dissection of CASK's scaffolding capacity revealed that L27 domains form obligate heterodimers with Lin-7 and bind SAP97 to direct lateral membrane polarity, while the CaM-kinase domain docks Caskin1 and Mint1 in competing tripartite complexes on neurexin.

    Evidence Biophysical CD spectroscopy for L27 folding; yeast two-hybrid, competition binding, and co-IP from brain for Caskin1/Mint1

    PMID:11865057 PMID:12040031 PMID:12110687

    Open questions at the time
    • Competition dynamics in vivo not measured
    • Whether SAP97 and Lin-7 bind CASK simultaneously unclear
  6. 2004 High

    Identification of the CINAP–CASK–Tbr-1 ternary complex and its regulation by NMDA-induced proteasomal degradation of CINAP showed how synaptic activity feeds back onto CASK-dependent NR2b transcription, while a parallel study showed CASK/SAP97/Mint1/Veli mediates Kir channel basolateral trafficking.

    Evidence Co-IP, RNAi in hippocampal neurons, proteasome inhibition; pull-down and dominant-negative mislocalization of Kir2 channels

    PMID:14960569 PMID:15066269

    Open questions at the time
    • Genome-wide target identification for CASK-Tbr-1 not done
    • Relative contribution of each scaffold subunit to Kir trafficking not resolved
  7. 2006 High

    Drosophila studies revealed that CASK controls CaMKII autophosphorylation dynamics: loss of dCASK shifts the T306/T287 phosphorylation balance, increasing activity-dependent CaMKII activation, which alters calcium signaling and memory.

    Evidence Drosophila genetic loss-of-function, phospho-specific immunostaining, electrophysiology, behavioral assays

    PMID:16880127 PMID:23543616

    Open questions at the time
    • Whether mammalian CASK regulates CaMKII phosphorylation in the same manner untested
    • Direct physical mechanism for CASK-CaMKII interaction not established
  8. 2007 High

    CASK knockout mice die perinatally with altered spontaneous neurotransmitter release (increased glutamatergic, decreased GABAergic) and destabilized Mints/Veli/neurexins, proving CASK is essential for balanced synaptic function and stabilization of its binding partners in vivo.

    Evidence Complete and conditional gene knockout, electrophysiology, immunoblotting

    PMID:17287346

    Open questions at the time
    • Evoked release was largely unaffected, leaving the mechanism of spontaneous release regulation unclear
    • Circuit-level consequences not dissected
  9. 2007 High

    Cdk5 phosphorylation of CASK was shown to be required for membrane recruitment and synaptogenesis, specifically by regulating the CASK–liprin-α interaction, establishing post-translational control of CASK localization.

    Evidence In vitro kinase assay, subcellular fractionation, co-IP, calcium imaging with Cdk5 manipulation in neurons

    PMID:18054859

    Open questions at the time
    • Specific Cdk5 phosphorylation site(s) on CASK not fully mapped
    • Whether Cdk5 regulation is developmental or activity-dependent unclear
  10. 2008 High

    Crystal structures revealed CASK CaM-kinase domain as a constitutively active, Mg²⁺-inhibited kinase that phosphorylates neurexin-1, overturning the assumption that it was a pseudokinase; separately, SUMOylation of CASK was shown to reduce protein 4.1 binding and impair dendritic spine formation.

    Evidence X-ray crystallography with in vitro kinase assays and mutagenesis; SUMOylation assays with RNAi and spine morphometry in hippocampal neurons

    PMID:18423203 PMID:18606847

    Open questions at the time
    • In vivo substrates beyond neurexin not identified
    • SUMOylation sites and the E3 ligase responsible not mapped
  11. 2010 High

    Structural and kinetic analysis showed Mg²⁺ inhibits CASK by stabilizing the catalytic transition state, and identified residues that confer this unusual property; PKA phosphorylation at T724 was shown to upregulate CASK–Tbr-1 interaction and NR2b transcription, linking cAMP signaling to CASK's nuclear function.

    Evidence X-ray crystallography, mutagenesis, kinetic analysis; in vitro PKA assay with reporter gene and co-IP

    PMID:20067577 PMID:20424264

    Open questions at the time
    • Physiological conditions under which Mg²⁺ inhibition is relieved in vivo unknown
    • Whether PKA phosphorylation triggers nuclear translocation not tested
  12. 2011 High

    Crystal structures of CASK–liprin-α and the minimal ExIWVxR binding motif for Mint1/Caskin1 provided atomic-resolution maps of two key interaction interfaces; X-linked mental retardation mutations were shown to disrupt liprin-α binding, linking structure to disease.

    Evidence X-ray crystallography, ITC, peptide binding, biochemical assays with disease mutants

    PMID:21763699 PMID:21855798

    Open questions at the time
    • Full-length CASK structure not determined
    • How CASK CaMK domain simultaneously accommodates liprin-α and Mint1/Caskin1 motifs in different binding modes not resolved
  13. 2013 High

    CASK binding was shown to regulate SAP97 conformation (compact→extended), which switches SAP97's preference from AMPARs to NMDARs, providing a molecular mechanism for CASK-dependent receptor sorting in dendrites; liprin-α2 was shown to control CASK presynaptic turnover dynamics and synaptic vesicle pool size.

    Evidence Intramolecular FRET sensors with receptor co-IP in hippocampal neurons; FRAP with shRNA knockdown and electrophysiology

    PMID:23751498 PMID:23864692

    Open questions at the time
    • Whether CASK–SAP97 conformational switch operates at specific developmental stages unknown
    • Stoichiometry of the CASK–liprin-α complex at individual synapses not determined
  14. 2016 High

    CASK was found to regulate NaV1.5 surface expression at the lateral membrane of cardiomyocytes (silencing increases sodium current), and heterozygous CASK knockout female mice recapitulated MICPCH phenotypes, while disease mutations were mapped to neurexin-binding interfaces.

    Evidence Patch clamp and TIRF in cardiomyocytes with shRNA; Cre-LoxP conditional KO and CASK+/- phenotyping; co-IP with disease mutants

    PMID:27015872 PMID:27036546 PMID:27364017 PMID:29426960

    Open questions at the time
    • Cardiac-specific CASK partners beyond NaV1.5 not identified
    • Metabolic function of CASK only preliminarily described
  15. 2019 High

    CASK was shown to direct mitotic spindle orientation in epithelial organoids by localizing Dlg1 and the LGN-NuMA complex, extending its scaffolding function beyond post-mitotic neurons to dividing epithelial cells.

    Evidence shRNA and interfering peptides in 3D organoid culture with spindle orientation quantification

    PMID:31289196

    Open questions at the time
    • Whether CASK kinase activity contributes to spindle orientation not tested
    • In vivo epithelial phenotypes not reported
  16. 2020 High

    Neurexin was shown to induce CASK oligomerization through PDZ and GK domains, and high-resolution structures of the CASK CaMK–Mint1 complex defined dual-lobe engagement at nanomolar affinity, refining understanding of how CASK assembles multi-protein signaling hubs.

    Evidence BiFC oligomerization assay with systematic mutagenesis; X-ray crystallography with ITC

    PMID:32348748 PMID:33090494

    Open questions at the time
    • Oligomerization stoichiometry in vivo not determined
    • Whether neurexin-induced oligomerization modulates kinase activity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full repertoire of in vivo CASK kinase substrates, the structural basis for full-length CASK autoinhibition and activation, the signals controlling nuclear–cytoplasmic shuttling, and the mechanistic basis of CASK's emerging metabolic functions.
  • No full-length CASK structure available
  • In vivo kinase substrates beyond neurexin not validated
  • Mechanism linking CASK to cellular respiration not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9609507 Protein localization 3
Partners
CASKIN1DLG1EPB41LIN7AMINT1NRXN1PPFIA2TBR1
Complex memberships
CASK-SAP97-Lin-7CASK-Tbr-1-CINAPCASK-liprin-αCASK-neurexin-Mint1-Veli

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CASK was identified as a neurexin-interacting protein containing an N-terminal CaM-kinase domain and C-terminal MAGUK domains (PDZ, SH3, guanylate kinase); the cytoplasmic domains of all three neurexins bind CASK in a salt-labile interaction dependent on the C-terminal three residues of neurexin I. Yeast two-hybrid screen, in vitro binding assays The Journal of Neuroscience High 8786425
1996 C. elegans LIN-2 (CASK ortholog) acts downstream of lin-3 EGF and upstream of let-60 ras in vulval precursor cells to allow LET-23 receptor tyrosine kinase signaling; transgenes lacking kinase or guanylate kinase activity are functional, indicating a structural/scaffolding rather than enzymatic role in vulval induction. Genetic epistasis analysis, mutant transgene rescue Development High 8565857
1998 Human CASK PDZ domain binds the C-terminal tail of syndecan-2 heparan sulfate proteoglycan, and CASK also binds the actin-binding protein 4.1; CASK localizes to basolateral membrane domains in epithelial cells. Yeast two-hybrid screen, in vitro binding assays, immunofluorescence colocalization The Journal of Cell Biology High 9660868
1998 The PDZ domain of CASK interacts with the C-terminal tail of syndecan-2 in neurons; CASK and syndecan-2 co-localize at synaptic junctions and were co-immunoprecipitated from brain. Yeast two-hybrid screen, co-immunoprecipitation from heterologous cells and brain, immunogold EM The Journal of Cell Biology High 9660869
2000 CASK interacts with the T-box transcription factor Tbr-1 via its guanylate kinase domain, translocates to the nucleus, and acts as a transcriptional coactivator binding to T-element DNA sequences in a complex with Tbr-1 to induce transcription of reelin and other forebrain development genes. Yeast two-hybrid, co-immunoprecipitation, nuclear fractionation, DNA binding assay, reporter gene assay Nature High 10749215
2001 CASK binds a brain-enriched isoform of protein 4.1 and supports nucleation of local actin/spectrin filament assembly on the cytosolic tail of neurexins; neurexins, CASK, and protein 4.1 are co-recruited into actin filaments from rat brain extracts. In vitro reconstitution, co-immunoprecipitation from brain, actin filament pull-down The Journal of Biological Chemistry High 11604393
2001 The extreme C-terminus of parkin functions as a class II PDZ-binding motif that specifically binds the PDZ domain of CASK; parkin and CASK co-immunoprecipitate and co-localize in postsynaptic densities and lipid rafts in brain; parkin does not ubiquitinate CASK, suggesting a scaffolding rather than substrate relationship. Co-immunoprecipitation, PDZ binding assay, colocalization in neurons and brain fractions The Journal of Biological Chemistry Medium 11679592
2002 The L27N domain of CASK binds the N-terminus of SAP97 (another MAGUK), and this interaction is required for lateral membrane localization of SAP97 in epithelial MDCK cells; dominant-negative CASK disrupts SAP97 lateral localization. Yeast two-hybrid, biochemical pull-down, dominant-negative overexpression with immunofluorescence Molecular and Cellular Biology High 11865057
2002 CASK CaM kinase domain binds to a novel brain-specific adaptor Caskin 1; Caskin 1 and Mint 1 bind the same site on the CASK CaM kinase domain and compete with each other; CASK and Caskin 1 co-assemble on the cytoplasmic tail of neurexin 1, forming alternative tripartite complexes with Velis. Yeast two-hybrid, affinity chromatography, co-immunoprecipitation from brain The Journal of Neuroscience High 12040031
2004 CASK acts as a coactivator for Tbr-1 by binding CINAP (a nucleosome assembly protein that binds histones); CINAP-CASK-Tbr-1 form a complex regulating NR2b and reelin gene expression; NMDA stimulation causes proteasomal degradation of CINAP, reducing NR2b transcription. Co-immunoprecipitation, reporter gene assay, RNA interference in hippocampal neurons, proteasome inhibitor treatment Neuron High 15066269
2004 SAP97, CASK, Veli, and Mint1 form a multiprotein trafficking complex that associates with Kir2.1, Kir2.2, and Kir2.3 channels via their C-terminal PDZ-binding motifs; a dominant-interfering form of CASK causes Kir2.2 channels to mislocalize from the basolateral membrane in polarized epithelial cells. Affinity pull-down, co-immunoprecipitation from brain and transfected cells, immunocytochemistry, dominant-negative expression The Journal of Biological Chemistry High 14960569
2007 CASK knockout is lethal in mice; CASK-deficient neurons show decreased levels of Mints, Veli/Mals, and neurexins, increased neuroligin 1, increased glutamatergic spontaneous synaptic release, and decreased GABAergic spontaneous release, while evoked release is largely unaffected. Conditional and complete gene knockout (KO), electrophysiology, immunoblotting PNAS High 17287346
2007 Cdk5 phosphorylates CASK and regulates its distribution to membranes; without Cdk5-dependent phosphorylation, CASK is not recruited to developing synapses, fails to interact with presynaptic components, and calcium influx is altered; Cdk5 regulates the CASK-liprin-alpha interaction. In vitro kinase assay, subcellular fractionation, co-immunoprecipitation, calcium imaging in neurons with Cdk5 manipulation Neuron High 18054859
2008 CASK functions as an active Mg2+-independent protein kinase; crystal structures reveal the CaM-kinase domain adopts a constitutively active conformation binding ATP and catalyzing phosphotransfer without Mg2+; CASK phosphorylates itself and neurexin-1, recruited via its PDZ domain. X-ray crystallography, in vitro kinase assay, site-directed mutagenesis Cell High 18423203
2008 CASK is SUMOylated; SUMO1 conjugation to CASK reduces its interaction with protein 4.1; overexpression of a CASK-SUMO1 fusion (mimicking SUMOylation) impairs dendritic spine formation; knockdown of CASK reduces spine density and shrinks dendritic spines. RNA interference, SUMO fusion overexpression, co-immunoprecipitation, immunofluorescence in hippocampal neurons The Journal of Cell Biology High 18606847
2009 NMDA receptors are sorted from the ER into a specialized ER subcompartment bypassing somatic Golgi and merging with dendritic Golgi outposts; this compartment contains CASK and SAP97, and retention/trafficking of NMDARs in this compartment requires both CASK and SAP97. Live imaging, immunofluorescence, dominant-negative interference in rat hippocampal neurons Nature Neuroscience High 19620977
2010 CASK is phosphorylated by PKA at S562 (PDZ domain) and T724 (guanylate kinase domain); T724 phosphorylation up-regulates the CASK-Tbr-1 interaction and stimulates NR2b promoter activity; this links cAMP signaling to CASK's nuclear transcriptional function. In vitro PKA kinase assay, site-directed mutagenesis, co-immunoprecipitation, reporter gene assay in cortical neurons Journal of Neurochemistry High 20067577
2010 CASK CaM-kinase activity is inhibited by Mg2+ (and other divalent ions); substituting four residues in the ATP-binding pocket converts CASK to a Mg2+-stimulated kinase; crystal structures show Mg2+ accelerates catalysis by stabilizing the transition state; phylogenetic analysis shows this Mg2+ inhibition evolved during early animal evolution. X-ray crystallography, site-directed mutagenesis, kinetic analysis Science Signaling High 20424264
2011 Liprin-α2 is required for presynaptic recruitment and dynamic turnover of CASK at presynaptic terminals; depletion of liprin-α2 reduces FRAP-measured turnover of CASK, impairing synaptic vesicle pool size and synaptic output. FRAP, immunofluorescence, shRNA knockdown, electrophysiology The Journal of Cell Biology High 23751498
2011 Crystal structure of the liprin-α2/CASK complex reveals that three SAM domains of liprin-α form an integrated supramodule binding the CASK kinase-like domain; X-linked mental retardation mutations of CASK are defective in binding liprin-α; the CASK/liprin-α/liprin-β ternary complex enables large signaling assemblies. X-ray crystallography, biochemical binding assays, cellular co-localization Molecular Cell High 21855798
2011 The molecular basis of Caskin1 and Mint1 binding to CASK was determined: a short linear ExIWVxR peptide motif from Caskin1/Mint1 is necessary and sufficient to bind the CASK CaM kinase domain; TIAM1 contains a related motif that also binds CASK in vitro. Peptide binding assays, mutagenesis, structural mapping Journal of Molecular Biology High 21763699
2012 CASK directly interacts with connexin-43 (Cx43), predominantly with its hypophosphorylated form; coexpression of CASK and Cx43 abrogates the individual inhibitory effects of each protein on cell migration in scratch wound assay; CASK is mobilized to the plasma membrane upon wounding where it colocalizes with Cx43. Co-immunoprecipitation, in vitro binding, far western, cell migration assay, immunofluorescence Journal of Cell Science Medium 22389404
2013 CASK regulates SAP97 conformation (compact vs. extended) through L27 domain interaction; CASK binding stabilizes SAP97 in an extended conformation that preferentially associates with GluN2B-containing NMDARs, while unbound compact SAP97 preferentially associates with GluA1-containing AMPARs, providing a sorting mechanism. Intramolecular FRET sensors, co-immunoprecipitation, colocalization in hippocampal neurons The Journal of Neuroscience High 23864692
2013 Drosophila CASK controls CaMKII autophosphorylation state: loss of dCASK increases activity-dependent autophosphorylation of CaMKII T287 by reducing T306 phosphorylation in the CaM-binding domain, which normally blocks CaM binding and prevents T287 phosphorylation; this regulates calcium signaling and memory. Genetic loss-of-function in Drosophila, phospho-specific antibodies, calcium imaging, behavioral assays Frontiers in Neural Circuits High 16880127 23543616
2016 CASK localizes at the lateral membrane of cardiac myocytes in association with dystrophin; CASK directly binds the C-terminus of NaV1.5 via pull-down; CASK silencing increases NaV1.5 surface expression at the lateral membrane (but not intercalated disc) by promoting its trafficking, increasing sodium current. Pull-down assay, whole-cell patch clamp, TIRF microscopy, biotinylation surface expression assay, shRNA knockdown Circulation Research High 27364017
2016 CASK stabilizes neurexin1β and links it to liprin-α; neurexin1β eliminates competition between liprin-α and Mint1 for CASK binding, allowing all four proteins to form a complex; CASK phosphorylates neurexin, modulating liprin-α interaction with the CASK-neurexin1β-Mint1 complex. Co-immunoprecipitation, in vitro kinase assay, competition binding assays in neuronal culture Cellular and Molecular Life Sciences Medium 27015872
2016 In C. elegans, LIN-2 (CASK) interacts with kinesin-3 UNC-104 via L27 and GUK domains and with SYD-2 (liprin-α) via SAM domains; LIN-2 loss severely reduces UNC-104 motor motility and SNB-1 cargo transport in axons and increases motor clustering along axons. Yeast two-hybrid, co-immunoprecipitation, bimolecular fluorescence complementation, live imaging of motor motility Traffic Medium 27172328
2018 CNTNAP2 stabilizes interneuron dendritic arbors through interaction with CASK; CNTNAP2 C-terminus interacts with CASK at the membrane; Cntnap2 KO reduces interneuron dendritic arborization and decreases CASK levels in the cortical membrane fraction; knockdown of CNTNAP2 or CASK similarly alters GluA1 levels and localization in interneurons. Yeast two-hybrid, co-immunoprecipitation, proximity ligation assay, super-resolution microscopy, shRNA knockdown, phenotype rescue Molecular Psychiatry High 29610457
2018 Missense mutations M519T (PDZ domain) and G659D (SH3 domain) in CASK specifically disrupt the CASK-neurexin interaction; G659D also disrupts the PDZ-SH3 interface and increases protein aggregation; patients with these mutations exhibit microcephaly and cerebellar hypoplasia, suggesting the CASK-neurexin interaction is critical for normal brain development. Co-immunoprecipitation with disease mutants, protein solubility assay, mutagenesis Human Genetics Medium 29426960
2019 CASK directly interacts with Dlg1 and is required for Dlg1 membrane localization during mitotic spindle orientation; depletion of CASK or blocking the CASK-Dlg1 interaction disrupts spindle orientation and causes multilumen formation in 3D epithelial cultures; the CASK-Dlg1 interaction is required for localization of the LGN-NuMA spindle orientation complex. shRNA knockdown, interfering peptides, 3D organoid culture, immunofluorescence, domain deletion Journal of Cell Science High 31289196
2020 Neurexin induces oligomerization of CASK; PDZ and GK domain mutations interfere with neurexin binding and neurexin-induced CASK oligomerization; GK domain mutations reduce CINAP and Tbr1 binding; an L27 domain mutation reduces SAP97 binding; pre-synaptic localization of CASK does not require neurexin binding. Co-immunoprecipitation, bimolecular fluorescence complementation, molecular modeling Journal of Neurochemistry Medium 33090494
2020 High-resolution crystal structure of CASK CaM kinase domain in complex with a Mint1 fragment shows the C-lobe of CASK-CaMK binds a short sequence common to CaMK targets and the N-lobe engages a Mint1-specific α-helix; the interaction is not regulated by Ca2+/CaM; Kd ~7.5 nM. X-ray crystallography, isothermal titration calorimetry, mutagenesis Structure High 32348748
2006 Drosophila CASK (Camguk) controls CaMKII autophosphorylation at T306 (CaM-binding domain), which prevents subsequent T287 phosphorylation; loss of dCASK increases synapse-specific, activity-dependent T287 phosphorylation and reduces the dynamic range for activity-dependent CaMKII regulation. Drosophila genetics, phospho-specific antibody immunostaining, circuit-level electrophysiology Neuron High 16880127
2005 Drosophila Camguk (CASK ortholog) co-immunoprecipitates with Ether-à-go-go (EAG) potassium channels via a noncanonical SH3-binding site on EAG; Camguk coexpression increases EAG surface expression and whole-cell conductance by more than 2-fold in a manner dependent on EAG-T787 (the CaMKII phosphorylation site). Co-immunoprecipitation in COS-7 cells, Xenopus oocyte electrophysiology, surface expression assay The Journal of Neuroscience Medium 15901771
2002 L27 domains in CASK and Lin-7 function as obligate heterodimers; individually the L27 domains are largely unfolded, but association produces cooperative folding with increased helicity and a cooperative unfolding transition, identifying a structural basis for CASK-Lin-7 complex assembly. Circular dichroism, biophysical analysis, co-expression and purification The Journal of Biological Chemistry High 12110687
2010 CASK interaction with Tbr-1 (CASK T740A mutation reducing CASK-Tbr-1 interaction in brain) impairs extinction of associative memory without affecting acquisition; brain morphology is normal in these knock-in mice, indicating the CASK-Tbr-1 interaction specifically modulates cognitive flexibility. Gene targeting (knock-in mouse), co-immunoprecipitation from brain, behavioral assays Journal of Psychiatry & Neuroscience Medium 28234597
2012 CASK interacts with both PMCA4b and JAM-A on the sperm flagellum via its single PDZ domain in an alternating, non-synergistic manner; CASK-JAM-A interaction promotes PMCA4b-mediated Ca2+ efflux, while CASK-PMCA4b interaction inhibits its enzymatic activity, regulating Ca2+ homeostasis in sperm. Co-immunoprecipitation, colocalization, Ca2+ measurement, motility assay in Jam-A null sperm Journal of Cellular Physiology Medium 22020416
2003 The C-terminus of PMCA4b binds CASK; both proteins co-immunoprecipitate from brain and kidney; PMCA4b expression reduces T-element-dependent transcriptional activity by ~80%, dependent on its Ca2+ pumping activity, linking Ca2+ efflux via PMCA4b to CASK-mediated nuclear transcription. Co-immunoprecipitation from tissue, reporter gene assay, Ca2+-pump point mutant The Journal of Biological Chemistry Medium 12511555
2016 Neuron-specific deletion of CASK in mice does not cause perinatal lethality but induces severe recurrent epileptic seizures and growth retardation; CASK heterozygous knockout females (CASK+/-) replicate human MICPCH phenotypes including microcephaly and cerebellar hypoplasia; CASK knockdown in human cell lines causes reduced cellular respiration, suggesting a novel metabolic function. Cre-LoxP conditional KO, CASK+/- mouse phenotyping, cellular respiration assay (Seahorse), affinity chromatography with metabolic proteins Acta Neuropathologica Communications Medium 27036546

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 444 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 313 9660868
2000 Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature 304 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 220 18423203
2008 Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nature genetics 219 19165920
2009 SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nature neuroscience 179 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 175 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 162 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 151 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 129 14960569
2004 Transcriptional modification by a CASK-interacting nucleosome assembly protein. Neuron 128 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 105 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 92 23751498
2007 Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK. Neuron 91 18054859
2009 CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes. European journal of human genetics : EJHG 89 20029458
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 84 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 79 21855798
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
2009 A missense mutation in CASK causes FG syndrome in an Italian family. American journal of human genetics 75 19200522
2004 Identification of Tbr-1/CASK complex target genes in neurons. Journal of neurochemistry 70 15584924
2015 Phenotypic and molecular insights into CASK-related disorders in males. Orphanet journal of rare diseases 65 25886057
2012 CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia. Epilepsia 65 22709267
2014 Down-regulation of miR-203 induced by Helicobacter pylori infection promotes the proliferation and invasion of gastric cancer by targeting CASK. Oncotarget 61 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 56 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 52 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 48 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
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
2010 Evolution of CASK into a Mg2+-sensitive kinase. Science signaling 43 20424264
2018 CNTNAP2 stabilizes interneuron dendritic arbors through CASK. Molecular psychiatry 41 29610457
2013 CASK regulates CaMKII autophosphorylation in neuronal growth, calcium signaling, and learning. Frontiers in molecular neuroscience 41 24062638
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 40 23864692
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
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 38 18629876
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
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
2018 Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction. Human genetics 31 29426960
2020 Presynaptic dysfunction in CASK-related neurodevelopmental disorders. Translational psychiatry 29 32929080
2012 CASK interacts with PMCA4b and JAM-A on the mouse sperm flagellum to regulate Ca2+ homeostasis and motility. Journal of cellular physiology 29 22020416
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
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
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 23 30549415
2006 Neural activity- and development-dependent expression and distribution of CASK interacting nucleosome assembly protein in mouse brain. The Journal of comparative neurology 23 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 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
2005 CASK inhibits ECV304 cell growth and interacts with Id1. Biochemical and biophysical research communications 21 15694377
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
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
2008 The MAGUK-family protein CASK is targeted to nuclei of the basal epidermis and controls keratinocyte proliferation. Journal of cell science 20 18664494
2019 The interaction between CASK and the tumour suppressor Dlg1 regulates mitotic spindle orientation in mammalian epithelia. Journal of cell science 19 31289196
2017 A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly. Intractable & rare diseases research 19 28944139
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
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 18 19726564
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
2020 Structural Basis for the High-Affinity Interaction between CASK and Mint1. Structure (London, England : 1993) 16 32348748
2019 The CNTNAP2-CASK complex modulates GluA1 subcellular distribution in interneurons. Neuroscience letters 16 30779956
2006 CASK associates with glutamate receptor interacting protein and signaling molecules. Biochemical and biophysical research communications 16 17084383
2021 Long Noncoding RNA AATBC Promotes the Proliferation and Migration of Prostate Cancer Cell Through miR-1245b-5p/CASK Axis. Cancer management and research 15 34234553
2020 Haploinsufficiency of X-linked intellectual disability gene CASK induces post-transcriptional changes in synaptic and cellular metabolic pathways. Experimental neurology 15 32305418
2017 A clinical series using intensive neurorehabilitation to promote functional motor and cognitive skills in three girls with CASK mutation. BMC research notes 15 29258560
2014 Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry. Frontiers in molecular neuroscience 15 25071438
2017 A de novo splice site mutation in CASK causes FG syndrome-4 and congenital nystagmus. American journal of medical genetics. Part A 14 28139025