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FLASH GENE

Symbol

CAST

contributors: mct/npt - updated : 24-03-2015

HGNC name	calpastatin
HGNC id	1515

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	PLCS PLACK syndrome
Location	5q15      Physical location : 95.997.740 - 96.110.383
Synonym name	heart-type calpastatin
	sperm BS-17 component
	calpain inhibitor
Synonym symbol(s)	BS-17, MGC9402
EC.number	3.4.22.17

DNA

TYPE	functioning gene
SPECIAL FEATURE	head to head
STRUCTURE	112.65 kb     30 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed variant 1 32 - 4629 - 791 - Niapour (2008) NM_173060 29 - 4304 - 686 - 2005 15820218 variant 2 variant 3 - - 3447 - 430 - Niapour (2008) variant 5 30 - 4524 - 756 - Niapour (2008) NM_001042440 30 - 4550 - 750 - 2005 15820218 variant 6 variant 7 - - 4572 - 712 - Niapour (2008) variant 8 31 - 4563 - 769 - Niapour (2008) variant 9 - - 4357 - 708 - Niapour (2008) variant 10 - - 4234 - 667 - Niapour (2008) NM_001190442 31 - 4468 - 673 - 2005 15820218 variant 11 variant 12 - - 4195 - 654 - Niapour (2008) NM_001284212 28 - 4195 NP_001271141 - 666 - - NM_001284213 - - 4137 NP_001271142 - 636 - -

EXPRESSION

Type	ubiquitous

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 Digestive liver       highly Nervous brain         Reproductive female system uterus cervix   highly   female system breast mammary gland   highly   female system placenta     highly

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	unique N terminal domain (L domain) that suppressed the channel activating effect of CALM in a reversible and concentration-dependent manner , L-domain playing a crucial role in determining the formation of complexes with calpain in which calpain can be either inhibited or still active
	four inhibitory domains (domain 1 to 4)

HOMOLOGY

interspecies	homolog to murine Cast
	homolog to rattus Golgi associated protein GCP360

Homologene

FAMILY

protease inhibitor I27 (calpastatin) family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic

basic FUNCTION	calpain inhibitor, involved in muscle protein degradation in living tissue
	involved in the proteolysis of amyloid precursor protein
	may be affecting the expression levels of genes encoding structural or regulatory proteins
	when calcium is present, calpastatin and calpain attach to each other, inhibiting the protease
	is potentially a crucial regulator of calpain activity, the production of p25, and, hence, the deregulation of CDK5, and impairment of CAST expression may contribute to the pathogenesis of neurodegenerative disorders
	may play a role in regulating the initial metastatic dissemination of breast cancer
	through CSL competes with CALM as a partial agonist for the site in the IQ domain in the C-terminal region of the CACNA1C channel, which may be involved in activation of the channel
	CAST inhibit CAPN1 activity and thus prevent cell death

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	a complete calpain-calpastatin system is expressed in the oocyte and might play a role in the various calcium-mediated processes occurring during activation of oocytes
	calpastatin diffusion and formation of the calpain-calpastatin complex together with an increased synthesis of the inhibitor protein represent a cellular defense response to conditions of prolonged dysregulation in intracellular Ca(2+) homeostasis

INTERACTION

DNA

RNA

small molecule

protein	with CAPN
	with CACNA1C (modulates Ca2+-channel activity through interacting with the calmodulin-binding site on the C-terminal tail of the CACNA1C channel)
	Toll-like receptor-induced calpastatin expression not only inhibited SELK cleavage, but cleavage of another calpain target, talin
	PIN1 may act directly via phosphorylated serine/threonine–proline motifs in CAST, or indirectly via other PIN1 substrates that control CAST, and PIN1 reduces the ability of calpastatin to inhibit calpain in endothelial cells

cell & other

REGULATION

Other

diminishing transiently during myoblast differentiation

ASSOCIATED DISORDERS

corresponding disease(s)

PLCS

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in endometrial carcinoma tumoral     --low   in malignant ovarian tissue constitutional       loss of function in angiogenic endothelial cells (ECs) facilitates mu-calpain-induced SOCS3 degradation, which amplifies pathological angiogenesis through IL6/STAT3/VEGFC axis constitutional     --low   leads to activation of calpain in human lens epithelial cells constitutional     --over   protects axonal transport in a model of traumatic axonal injury constitutional     --over   muscle-specific overexpression of CAST, greatly reduced sarcopenia of ageing

Susceptibility

to Parkinson disease (PD) to Keratoconus (KC)

Variant & Polymorphism SNP	single nucleotide polymorphisms (SNPs) in a region containing the Calpastatin (CAST) gene were associated with Parkinson disease
	SNP rs4434401 to be associated with KC

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurosensorial visual retina use of CAST, a highly specific calpain inhibitor, to prevent or delay RP neurosensorial visual retina IGF1 maintains calpastatin expression and attenuates apoptosis in several models of photoreceptor cell death neurology ataxia   is an attractive target for developing therapeutic approaches in MJD

ANIMAL & CELL MODELS

	overexpression of Cast under the control of the calcium/calmodulin-dependent protein kinase II promoter in APP/PS1 mice caused a remarkable decrease of amyloid plaque burdens and prevented Tau phosphorylation and the loss of synapses
	calpain inhibitors may be partially effective to inhibit photoreceptor apoptosis in RCS rat retinal degeneration