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FLASH GENE
Symbol CASK contributors: shn - updated : 30-08-2018
HGNC name calcium/calmodulin-dependent serine protein kinase (MAGUK family)
HGNC id 1497
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)
  • formation of the CASK/liprin-alpha/liprin-beta ternary complex suggests that liprins can mediate assembly of target proteins into large protein complexes capable of regulating numerous cellular activities
    • 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)
  • Ca(2+) homeostasis in sperm is maintained by the relative ratios of CASK-ATP2B4 and CASK-F11R interactions
  • 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
  • interaction with CASK and disruption of the CASK and TBR1 interaction impairs extinction, suggesting the involvement of CASK in cognitive flexibility
  • CASK-PPFIA2 interaction may be involved in the pathophysiology of cerebellar hypoplasia in MICPCH syndrome
    • 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