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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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, CAMGUK, hCASK
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

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)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003688 27 splicing 8298 NP_003679 112 921 enriched in brain in synaptic plasma membranes 1998 9660868 including two alternate in-frame exons NM_001126054 26 splicing 8229 NP_001119526 112 898 liver, kidney, enriched in brain in synaptic plasma membranes 1998 9660868 including one alternate in-frame exon NM_001126055 25 splicing 8226 NP_001119527 112 897 enriched in brain in synaptic plasma membranes - omitting two alternate in-frame exons

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive liver       lowly Endocrine pancreas       highly Nervous brain       highly Homo sapiens Reproductive female system placenta     moderately Respiratory lung       lowly Urinary kidney       lowly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial         Muscular striatum skeletal   moderately Nervous central

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Homo sapiens not specific epithelial 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)
	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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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