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FLASH GENE

Symbol

AGER

contributors: mct - updated : 18-06-2015

HGNC name	advanced glycosylation end product-specific receptor
HGNC id	320

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001136 11 - 1414 NP_001127 - 404 - 2009 19061941 plasma membrane NM_172197 10 - 1259 NP_751947 - 342 - 2009 19061941 extracellular variant CC 8 - 665 isoform CC - 133 - 2009 19061941 Deletion: 80 bp exon2, exon3, exon 4, exon 5, 120 bp exon6 variant AA 11 - 1398 isoform AA - 303 - 2009 19061941 Insertion: intron 1 variant BB 10 - 1371 isoform BB - 294 - 2009 19061941 insertion: intron 1/deletion: exon 9

EXPRESSION

Type	restricted

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         Homo sapiens   vessel         Homo sapiens Hearing/Equilibrium ear inner cochlea Corti highly Homo sapiens Respiratory lung         Homo sapiens Visual eye

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Homo sapiens Hearing / Equilibrium cochlea cell Homo sapiens Lymphoid/Immune T cell Homo sapiens Adult not specific fibroblast Homo sapiens Adult Skin/Tegument keratinocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text

eye

PROTEIN

PHYSICAL PROPERTIES		fibrous ,globular
STRUCTURE

motifs/domains	one immunoglobulin-like V-type domain
	two immunoglobulin-like C2-type domains
	a extracellular domain (322AAs), ex-RAGE functioning as a "decoy" to RAGE-ligand interaction and thus potentially dampening inflammatory conditions
	a transmembrane domain (19AAs)
	a cytosol domain (41AAs)
	the behavior of the cytoplasmic tail is strongly affected by its being part of the whole receptor

conjugated

GlycoP

HOMOLOGY

Homologene

FAMILY

immunoglobulin superfamily of cell surface molecules

CATEGORY

signaling , receptor

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,endoplasmic reticulum
text	one membrane anchored, one secreted form
	cell surface-located type I membrane protein
	AGER dimerization occurs in the endoplasmic reticulum (ER) (

basic FUNCTION	mediating amyloid beta peptide effect on neurons and microglia and mediating the amyloid -beta peptide transport across the blood -brain barrier and accumulation in brain
	playing distinct functional roles in both the toxicity and disposal of advanced glycation end products (AGEs), substances that are linked to diabetes and aging
	may play an important role in inflammatory processes and endothelial activation, likely to accelerate the processes of coronary atherosclerotic development, especially in diabetic patients
	play an important role in the internalization of Mycobacterium tuberculosis into macrophages
	mediates responses to cell danger and stress
	RAGE activates programs responsible for acute and chronic inflammation, when bound by its many ligands
	implicated as a pro-inflammatory factor in chronic inflammatory conditions such as diabetes mellitus and rheumatoid arthritis
	plays an important role in the development and progression of vascular disease
	together with caspase-3 activation and inhibition of NF-kappaB signaling pathways, might be involved in the pathogenesis of macrophage apoptosis induced by HMGB1
	contributes to the inflammatory response in many acute and chronic diseases
	AGER and ICAM1 are a new set of functionally linked adhesion molecules, which closely cooperate in mediating leukocyte adhesion during the acute trauma-induced inflammatory response
	induces the expression of thioredoxin interacting protein (TXNIP) in Schwann cells and the injured sciatic nerve)
	AGER and ICAM1 differentially regulate leukocyte adhesion in a stimulus-dependent manner
	prominent role in the survival and development of prostate tumor growth
	is required for the activation of interleukin 6 (IL6)–mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis
	is required for the mitochondrial localization of STAT3 in pancreatic cancer cells
	AGER-mediated autophagy is required for enhanced ATP production and proliferation in pancreatic cancer cells, mostly via regulation of mitochondrial STAT3
	expression of AGER on adaptive immune cells and a role for this receptor and its ligands in modulating human immune responses
	RETN, S100A12 and AGER are involved in the pathophysiology of Kawasaki disease (KD)
	novel roles for AGER as a conduit for LPA (phospholipid lysophosphatidic acid) signaling
	key molecule in the onset and sustainment of the inflammatory response
	expression in keratinocytes is critically involved in the perpetuation of acute inflammation, supporting the central role of AGER in paracrine communication between keratinocytes and stromal immune cells
	major receptor that mediates vascular inflammation
	AGER-heparan sulfate oligomeric complexes are essential for signaling and interfering with AGER oligomerization might be of therapeutic value
	is an inflammation perpetuating multi-ligand receptor and participates actively in various vascular and inflammatory diseases even in normoglycaemic conditions
	is a multifunctional receptor implicated in diverse processes including inflammation and cancer
	functional role for AGER/S100A7 signaling in linking inflammation to aggressive breast cancer development

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

PLCB1/CAMK4-NFKB1 is involved in AGER mediated signaling pathway in human endothelial cells

INTERACTION

DNA

RNA

small molecule

protein	many ligands, endo or exogenous
	interacting with EGFR
	interact with various ligands amphoterin also known as HMGB1, amyloid beta, proteins of the S100/calgranulin family and ITGAM(
	S100A12 is a small calcium binding protein that is a ligand of AGER
	agonist S100A4, fusion protein of RAGE encompassing the extracellular domain of RAGE (ex-RAGE), ex-RAGE followed by S100A4, or S100A4 followed by ex-RAGE
	interaction of HMGB1 and AGER is a key component initiating and sustaining the inflammatory response in inflammatory cardiomyopathy eventually leading to heart failure
	S100B receptor is AGER
	binding of S100B to AGER results in stimulation of AGER anti-mitogenic and promyogenic signaling
	functional interaction between AGER and TLRs coordinately regulates inflammation, immune response and other cellular functions
	AGER is a native C1QA, C1QB, C1QC globular domain receptor (C1q and AGER are linked to the recruitment of leukocytes and phagocytosis of C1q-coated material)
	HMGB1 is one of the important AGER ligands
	mediate its activity through modulation of the IL6/STAT3 pathway
	can proteolytically be converted by metalloproteinases ADAM10 and MMP9 into a soluble AGER form
	DOCK7 bound to the AGER cytoplasmic domain and transduced a signal to CDC42, resulting in the formation of abundant highly branched filopodia-like protrusions, dendritic pseudopodia
	HMGB1 promotes an inflammatory response by inducing the expression of ICAM1 and P-selectin via AGER-mediated stimulation of the endoplasmic reticulum stress pathway
	in ERMS cells, AGER upregulates myogenin which upregulates MYOD1 and downregulates PAX7, with consequent inhibition of proliferation and stimulation of differentiation

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in cerebral vasculature of Alzheimer's disease patients constitutional     --over   increased in preeclampsia (Fasshauer 2008) constitutional     --over   in patients with pulmonary tuberculosis as well as in diabetics constitutional       gain of function implicated in numerous pathological states including vascular disease, diabetes, cancer, and neurodegeneration

Susceptibility

to type 1 diabetes

Variant & Polymorphism SNP , other	-374 T/A polymorphism associated to type 1 diabetes

Candidate gene
Marker	CCNB2, AGER, CDK5RAP3, may be used as a very reliable biomarker of lung adenocarcinoma
	mRNA expression of S100A12 and AGER might be as a useful biomarker for Transitional cell carcinoma (TCC)
Therapy target
	System Type Disorder Pubmed miscelleaneous vascular   therapeutic intervention targeted at the AGER gene may be a useful means of treating pathologies of the vasculature neurology neurodegenerative alzheimer pharmacological stimulation of AGER shedding might open alternative treatment strategies for Alzheimer disease diabete     pharmacological stimulation of AGER shedding might open alternative treatment strategies for diabetes-induced inflammation cardiovascular aquired   therapeutic antagonism of RAGE might be a unique target for therapeutic intervention in heart failure

ANIMAL & CELL MODELS

Rage-deficient mice displayed a reduced propensity for breast tumor growth