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FLASH GENE

Symbol

GAPDH

contributors: mct/shn - updated : 22-08-2017

HGNC name	glyceraldehyde-3-phosphate dehydrogenase
HGNC id	4141

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	3.88 kb     9 Exon(s)

regulatory sequence	Promoter (TATA box)
	Binding site   enhancer   HRE
text structure	containing a hypoxia responsive element (HRE) consisting of a hypoxia inducible factor-1 (HIF-1) consensus binding site plus adjacent sequence
	a gln-responsive element

MAPPING

cloned

Y

linked

N

status

confirmed

Map	pter - D12S356 - D12S374 - GAPDH - D12S1623 - D12S1625 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002046 9 - 1310 NP_002037 - 335 - 2002 11955624

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           salivary gland       highly Lymphoid/Immune tonsils       highly Reproductive female system ovary     highly   female system uterus cervix   highly Respiratory respiratory tract larynx     highly Skin/Tegument skin       highly Visual eye anterior segment cornea

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Muscular

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic erthrocyte

cell lineage
cell lines	lung cancer cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

a NAD-binding domain

conjugated

PhosphoP

mono polymer

homomer , tetramer

HOMOLOGY

interspecies	ortholog to gapdh, Danio rerio
	ortholog to Gapdh, Rattus norvegicus
	ortholog to Gapdh, Mus musculus

Homologene

FAMILY

glyceraldehyde 3-phosphate dehydrogenase family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	triggering apoptosis when translocated to the nucleus
	nuclear localization is regulated by ceramide in a cell cycle-dependent manner
	exact function of GAPDH in the nucleus is largely unknown but nuclear GAPDH seems to be involved in the regulation of TP53 activation
	nuclear translocation of GAPDH might be regulated by the PI3K signaling pathway acting mainly as a nuclear export signal and the AMPK signaling pathway acting as a nuclear import signal
	association between AIRE-induced apoptosis and GAPDH nuclear translocation

basic FUNCTION	catalyzing the reversible oxidative phosphorylation of G3P in the presence of Pi and NAD (glycolysis and gluconeogenesis)
	involved exclusively in cytosolic energy production
	involved in neuronal disease and in programmed cell death
	may play a role in P. gingivalis adherence and colonization of the oral cavity
	is required for membrane transport between the endoplasmic reticulum and the Golgi complex
	nuclear GAPDH isoform is involved in the maintenance and/or protection of telomeres
	is a target for insulin regulation
	general mediator initiating one or more apoptotic cascades, may be involved in the Lewy body formation and probably associated with the apoptotic death pathway
	accumulates in mitochondria during apoptosis, and induces the pro-apoptotic mitochondrial membrane permeabilization, a decisive event of the intrinsic pathway of apoptosis
	glycolytic enzyme playing an essential role in the phosphorelay signaling, where its redox-sensitive cysteine residue may provide additional input signals
	may participates in oxidative stress-induced cell death via an alternative mechanism in which aggregation but not nuclear translocation of GAPDH plays a role
	critical role of GAPDH aggregates in oxidative stress-induced brain damage
	exerts other functions beyond glycolysis, and oxidatively modified GAPDH regulates its cellular functions by changing its interacting proteins
	GAPDH-dependent phosphorylation of L1CAM is a novel mechanism in regulating L1CAM-mediated neurite outgrowth
	displays multiple functions, such as nuclear RNA export, DNA replication and repair, and apoptotic cell death
	Nitrosylated-GAPDH physiologically transnitrosylates nuclear proteins such as sirtuin-1, histone deacetylase-2 and DNA-activated protein kinase
	AIRE-induced cellular stress and apoptosis are associated with GAPDH translocation into the nuclei
	GAPDHS and GAPDH isozyme should facilitate the identification of selective GAPDHS inhibitors for contraceptive development

CELLULAR PROCESS	cell life, cell death/apoptosis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

carbohydrate , energetic

signaling

a component

INTERACTION

DNA

RNA

binding

small molecule	cofactor, nucleotide,
	Pi
	NAD
	ATP

protein	C-terminus of amyloid precursor protein
	Huntingtin and dentatorubral-pallidoluysian atrophy protein, DRPLA
	Spinocerebellar ataxia type1, SCA1 and androgen receptor, AR
	2,3-DPGM and 3-PGK
	protein disulfide isomerase, PDI
	phospholipase D2, PLD2
	muscle specific Ca(2)+/calmodulin-dependent protein kinase, CaMKIIbeta(M)
	N-myristoylated p22
	Rab2
	Ca(2+)/calmodulin-dependent protein kinase phosphatase, CaMKP
	even in absentia homolog 1 (Drosophila), SIAH1
	myocilin, MYOC
	protein SET
	TPPP/p25 protein
	FKBP6
	ISYNA1
	NLS-bearing SIAH1
	Nitrosylated GAPDH (SNO-GAPDH) binds to Siah1
	AIRE-induced apoptosis pathway is associated with GAPDH nuclear translocation and induction of NO-induced cellular stress in AIRE-expressing cells
	NPM1 physiologically bound to both SIAH1 and GAPDH, disrupting the SIAH1–GAPDH complex in the nucleus in response to nitrosative stress
	GAPDH–SIAH1 interaction is augmented by S-nitrosylation of GAPDH
	NPM1 did not compete with RILPL1 for GAPDH binding in the cytoplasm, although a small amount of NPM1 protein was able to reside in the cytoplasm
	MZF1 regulates GAPDH, indicating a role for GAPDH in calcitriol-mediated signaling
	MAP3K5 a representative stress kinase, interacts with both GAPDH and SIAH1 and is likely able to phosphorylate Siah1 at specific amino acid residues
	dissociation of the GAPDH/SIAH1 pro-apoptotic complex can block high glucose-induced pericyte apoptosis, widely considered a hallmark feature of Diabetic retinopathy (DR)
	GAPDH is a PRMT3-binding protein and GAPDH is methylated at R248 by PRMT3

cell & other

actin filaments

REGULATION

activated by

hypoxia

induced by	thioredoxin
		glutamine

inhibited by	binding to the cell membrane
	lipid peroxidation products such as HNE and HHE

Other	disulfide bonding due to oxidant exposure leads to a reduced enzymatic activity
	upregulated with proliferation, activation, and differentiation
	phosphorylated by protein kinase Ciota /lambda
	regulated by RILP1 (binds GAPDH, in competition with SIAH1, retaining GAPDH in the cytosol and preventing its nuclear translocation)

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional   amplification     in Huntington disease (high molecular weight protein) tumoral     --over   in gastric cancer tumoral   translocation     with BCL6 in primary diffuse large B-cell lymphomas of the central nervous system tumoral     --over   overexpressed in renal cell carcinoma constitutional     --over   in apoptosis and in several chronic pathologies

Susceptibility

to late-onset Alzheimer disease

Variant & Polymorphism SNP	SNP increasing the risk of late-onset Alzheimer disease

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed diabete     agents that can directly target modification of GAPDH have potential in inhibiting the development and in arresting the progression of diabetic retinopathy cancer digestive pancreas double blockade of GAPDH and mitochondrial respiration could be a novel strategy for the treatment of PRMT3-overexpressing pancreatic cancer

ANIMAL & CELL MODELS