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FLASH GENE
Symbol CASK contributors: shn - updated : 30-08-2013
HGNC name calcium/calmodulin-dependent serine protein kinase (MAGUK family)
HGNC id 1497
Corresponding disease
FGS4 FG syndrome 4
MICPCH microcephaly with pontine and cerebellar hypoplasia syndrome
Location Xp11.4      Physical location : 41.374.190 - 41.782.287
Synonym name
  • peripheral plasma membrane protein CASK
  • CAMGUK protein
  • protein lin-2 homolog
  • trinucleotide repeat containing 8
  • calcium/calmodulin-dependent serine protein kinase membrane-associated guanylate kinase
  • Synonym symbol(s) MAGUK, LIN2, CAGH39, TNRC8, CMG, CSNK, FLJ22219, FLJ31914, FGS4, MICPCH, MRXSNA,
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 408.10 kb     27 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map pter - DXS8012 - DXS993 - CASK - DXS1207 - DXS1201 - cen
    Physical map
    RPGR Xp21.1 retinitis pigmentosa GTPase regulator OTC Xp21.1 ornithine carbamoyltransferase LOC392442 X similar to BAG-family molecular chaperone regulator-1 (BCL-2 binding athanogene-1) (BAG-1) (Glucocorticoid receptor-associated protein RAP46) LOC392443 X similar to ferritin light chain LOC392444 X similar to Nucleolar transcription factor 1 (Upstream binding factor 1) (UBF-1) TM4SF2 Xp11.4-q11 transmembrane 4 superfamily member 2 LOC389845 X LOC389845 STRAIT11499 Xp11.4 hypothetical protein STRAIT11499 LOC389846 X hypothetical gene supported by BC043536 GAPDP1 Xp11.4-p11.23 glyceraldehyde-3-phosphate dehydrogenase pseudogene 1 LOC392445 X similar to 40S ribosomal protein S11 BCOR Xp11.4 BCL6 co-repressor LOC158624 Xp11.4 similar to IMP dehydrogenase (EC 1.1.1.205) I - human ATP6AP2 Xq21 ATPase, H+ transporting, lysosomal accessory protein 2 LOC347411 Xp11.4 similar to ENSANGP00000015797 MGC39350 Xp11.4 hypothetical protein MGC39350 CRSP2 Xp11.2-p11.4 cofactor required for Sp1 transcriptional activation, subunit 2, 150kDa LOC392446 X similar to claudin 7; Clostridium perfringens enterotoxin receptor-like 2; claudin 9 MKRN4 Xp21.1 makorin, ring finger protein, 4 LOC392447 X similar to 60S ribosomal protein L32 LOC286444 Xp11.4 similar to ribosomal protein S2; 40S ribosomal protein S2 LOC392448 X similar to Chloride intracellular channel protein 4 (mc3s5/mtCLIC) USP9X Xp11.4 ubiquitin specific protease 9, X chromosome (fat facets-like Drosophila) DDX3X Xp11.3-p11.23 DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked NYX Xp11.4 nyctalopin CASK Xp11.4 calcium/calmodulin-dependent serine protein kinase (MAGUK family) LOC158781 Xp11.4 tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta pseudogene GPR34 Xp11.4-p11.3 G protein-coupled receptor 34 GPR82 Xp11.4 G protein-coupled receptor 82 I-4 Xp11.4-Xp11.3 type 1 protein phosphatase inhibitor LOC139334 Xp11.4 similar to inosine monophosphate dehydrogenase 1 isoform b; sWSS2608 LOC392449 X similar to Nanog homeobox; homeobox transcription factor Nanog LOC389847 X similar to Amine oxidase [flavin-containing] A (Monoamine oxidase) (MAO-A) MAOA Xp11.23 monoamine oxidase A MAOB Xp11.23 monoamine oxidase B NDP Xp11.4 Norrie disease (pseudoglioma) LOC286398 Xp11.4 similar to RNA-binding region containing protein 2 (Hepatocellular carcinoma protein 1) (Splicing factor HCC1) FLJ22843 Xp11.4 hypothetical protein FLJ22843 RRM2P3 Xp21-p11 ribonucleotide reductase M2 polypeptide pseudogene 3 LOC139339 Xp11.4 similar to ubinuclein 1 LOC392450 X similar to Farnesyl pyrophosphate synthetase (FPP synthetase) (FPS) (Farnesyl diphosphate synthetase) MGC51029 Xp11.4 hypothetical protein MGC51029 LOC392451 X similar to hypothetical protein LOC389848 X similar to 40S ribosomal protein SA (P40) (34/67 kDa laminin receptor) (Colon carcinoma laminin-binding protein) (NEM/1CHD4) (Multidrug resistance-associated protein MGr1-Ag)
    RNA
    TRANSCRIPTS type messenger
    text exon (E24a) of the CASK gene, which encodes for a conserved peptide insertion in the guanylate kinase interaction domain, typically a skipped exon, which awakens during neuronal stimulation with the potential to diversify the protein interaction properties of the CASK polypeptide (PMID: 2308758)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    27 splicing 8298 112 921 enriched in brain in synaptic plasma membranes 1998 9660868
    including two alternate in-frame exons
    26 splicing 8229 112 898 liver, kidney, enriched in brain in synaptic plasma membranes 1998 9660868
    including one alternate in-frame exon
    25 splicing 8226 112 897 enriched in brain in synaptic plasma membranes -
    omitting two alternate in-frame exons
    EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveliver   lowly
    Endocrinepancreas   highly
    Nervousbrain   highly Homo sapiens
    Reproductivefemale systemplacenta  moderately
    Respiratorylung   lowly
    Urinarykidney   lowly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelial    
    Muscularstriatumskeletal moderately
    Nervouscentral   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymphocyte Homo sapiens
    not specificepithelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N-terminal calcium/calmodulin-dependent protein (CaM) kinase domain
  • a central PSD-95, Dlg, and ZO-1/2 domain (PDZ)
  • a Src homology 3 (SH3) domains
  • a C-terminal guanylate kinase sequence
  • HOMOLOGY
    interspecies ortholog to Cask, Mus musculus
    ortholog to Cask, Rattus norvegicus
    Homologene
    FAMILY
  • MAGUK family
  • CATEGORY adhesion , chaperone/stress , enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microfilament
    intracellular,nucleus,nucleolus
    text
  • lateral and/or basal membrane of epithelial cells
  • translocates to the nucleus where it interacts with the brain- specific T-box family transcription factor TBR1
  • actin cytoskeleton
  • resides at basolateral membranes in polarized epithelia
  • specific localization to the synapses, where it forms large signaling complexes regulating neurotransmission
  • basic FUNCTION
  • acting as a calcium/calmodulin-dependent serine protein kinase
  • acting as a serine/threonine protein kinase
  • being a cytoskeletal membrane scaffold that coordinates signal transduction pathways within the polarized cell structures and the cortical cytoskeleton
  • playing a role in synaptic transmembrane protein anchoring and ion channel trafficking
  • contributing to neural development and regulation of gene expression via interaction with the transcription factor TRB1
  • may mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1
  • acting as a coactivator for Tbr-1
  • implicated in synaptic protein targeting, synaptic organization, and transcriptional regulation
  • not only functions as a scaffold but also recruits signaling molecules and may contribute to signal transduction
  • has a role in embryonic brain development, and has an important function during neuronal development
  • having a crucial role during synaptogenesis and a possible involvement of CASK in stereocilia and retinal function
  • contributes to spinogenesis and which is controlled by SUMOylation, and stabilizes or maintains spine morphology
  • regulating the expression of CDKN1A via the TCF3 transcription factor
  • multidomain scaffold protein, having a key role in regulating mammalian development, given its high level of expression during embryogenesis
  • calcium/calmodulin-dependent serine protein kinase that targets to neuronal synapses to regulate the trafficking, targeting, and signaling of ion channels
  • required for the retention and trafficking of NMDARs in this endoplasmic reticulum subcompartment
  • CASK and CASKIN1 may work together to organize the cytomatrix in active zones
  • represents an intracellular gateway to regulate purinergic nociceptive signaling
  • DLG1 and CASK play critical cooperative roles in maintaining the nephron progenitor population, potentially via a mechanism involving effects on FGF signaling
  • CELLULAR PROCESS cell organization/biogenesis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • component of a complex CASK, VELI1 (LIN7A) and GRIN2B subunit
  • forming with LIN7, two mutually exclusive tripartite complexes with APBA1 or CASKIN1
  • involved in a complex containing CASK, TBR1 and TSPYL2
  • LIN7-CASK-PPFIA2 complex recruits components of the synaptic release machinery to adhesive proteins of the active zone
  • binding to WHRN and NRXN1 cytosolic tail
  • interacting with CASKIN1, APBA1, LIN7(A/B/C) and L27 domain of DLG1 and isoform 2 of DLG4
  • part of CASK-TBR1-RELN signaling cascade
  • TBR1–CASK–TAF9 complex regulates expression of the NMDA receptor subunit 2b (GRIN2B)
  • INTERACTION
    DNA
  • acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical developmen
  • RNA
    small molecule metal binding, nucleotide,
  • ATP
  • Mg2+
  • protein
  • neurexin 1, 2 and 3, NRXN1-3
  • amyloid beta (A4) precursor protein-binding, family A, member 1, APBA1
  • syndecan 2, SDC2 and actin-binding protein 4.1
  • calcium channel, voltage-dependent, N type, alpha 1B subunit, CACNA1B
  • syndecan 1, SDC1
  • discs, large homolog 1, DLG1
  • mediates the interaction between rabphilin3a and beta-neurexins
  • junctional adhesion molecule (JAM),
  • CASK interacting protein 1, CASKIN1 (Tabuchi et al, 2002)
  • contactin associated protein-like 3, CNTNAP3 and contactin associated protein-like 4, CNTNAP4
  • parkin, PARK
  • ATPase Ca++ transporting plasma membrane 4, ATP2B4
  • FCH and double SH3 domains 2, FCHSD2
  • CASK-interacting protein CIP98, CIP98
  • potassium inwardly-rectifying channel subfamily J member 12, KCNJ12
  • TAF9 RNA polymerase II TATA box binding protein (TBP)-associated factor 32kDa , TAF9 also known as CINAP
  • inhibitor of DNA binding 1, dominant negative helix-loop-helix protein, ID1
  • syndecan 2 ,SDC2
  • translocates to the nucleus and interacts with the brain-specific T-box family member TBR1
  • FCHSD2
  • TSPYL2
  • binding to calmodulin
  • GRIP1, PRKCE, and RGS4
  • in the nuclei of neurons, CASK interacts with CINAP (CASK-interacting nucleosome assembly protein)/CDA1/DENTT
  • targeting RELN (associates with TBR1, a transcription factor that activates the expression of RELN, an extracellular matrix protein required for proper neuronal migration and lamination)
  • interacting with DLG1 and LIN7C (subcellular distributions of DLG1 and LIN7C are independent of CASK in the stomach)
  • CASK binds to a region of CASKIN1 called the CASK interaction domain (CID)(PMID;
  • CASK directly interacts with GJA1
  • CASK, is a FRMD7 interactor (CASK promotes FRMD7 co-localization at the plasma membrane, where it enhances CASK-induced neurite length)
  • neuronal CASK/P2RX3 interaction was up-regulated by nerve growth factor (NGF) signaling and down-regulated by P2RX3 agonist-induced desensitization
  • PPFIA2 promotes the presynaptic recruitment and turnover of RIMS1/CASK to facilitate synaptic transmission
  • CASK binding regulates DLG1 conformation and its subsequent sorting and synaptic targeting of AMPARs and NMDARs during trafficking to synapses
  • cell & other
    REGULATION
    Other developmentally regulated by unknown signals
    autophosphorylated
    ASSOCIATED DISORDERS
    corresponding disease(s) FGS4 , MICPCH
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    coordinate overexpression of CASK and RELN in carcinoma of esophagus
    constitutional   deletion    
    results in haploinsufficiency, which might be causative for developmental delay or mental retardation
    constitutional germinal mutation      
    associated to congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia, and severe mental retardation
    constitutional germinal mutation      
    XLMR
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • CASK knockdown mice are viable but smaller than WT mice, whereas CASK KO mice die at first day after birth without major developmental abnormalities except a partially penetrant cleft palate syndrome