AGER

Receptor for Advanced Glycosylation End Products (AGER, or AGER) is a member of the immunoglobulin super-family transmembrane proteins, as a signal transduction receptor which binds advanced glycation endproducts, certain members of the S100/calgranulin family of proteins, high mobility group box 1 (HMGB1), advanced oxidation protein products, and amyloid (beta-sheet fibrils). Initial studies investigating the role of AGER in renal dysfunction focused on diabetes, neurodegenerative disorders, and inflammatory responses. However, AGER also has roles in the pathogenesis of renal disorders that are not associated with diabetes, such as obesity-related glomerulopathy, doxorubicin-induced nephropathy, hypertensive nephropathy, lupus nephritis, renal amyloidosis, and ischemic renal injuries. AGER represents an important factor in innate immunity against pathogens, but it also interacts with endogenous ligands, resulting in chronic inflammation. AGER signaling has been implicated in multiple human illnesses, including atherosclerosis, arthritis, Alzheimer's disease, atherosclerosis and aging associated diseases.

AGER Related Areas

 

AGER Alternative Names

AGER, AGER, DAMA-358M23.4, MGC22357 [Homo sapiens]
AGER, Ager [Mus musculus]

Summaries for AGER

Entrez Gene summary for AGER:

The advanced glycosylation end product (AGE) receptor encoded by this gene is a member of the immunoglobulin superfamily of cell surface receptors. It is a multiligand receptor, and besides AGE, interacts with other molecules implicated in homeostasis, development, and inflammation, and certain diseases, such as diabetes and Alzheimer's disease. Many alternatively spliced transcript variants encoding different isoforms, as well as non-protein-coding variants, have been described for this gene (PMID:18089847).

OMIM - description for AGER:

The alpha (HBA1, 141800; HBA2, 141850) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, HbA. Mutant beta globin that sickles causes sickle cell anemia (603903). Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. For clinical purposes, beta-thalassemia (613985) is divided into thalassemia major (transfusion dependent), thalassemia intermedia (of intermediate severity), and thalassemia minor (asymptomatic).

Wikipedia summary for AGER:

AGER, the Receptor for Advanced Glycation Endproducts is a 35kD transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al.[1] It is also called "AGER". Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common motif, AGER is often referred to as a pattern recognition receptor. AGER also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively and by active secretion from macrophages, natural killer (NK) cells and dendritic cells. The interaction between AGER and its ligands is thought to result in pro-inflammatory gene activation.[2] Due to an enhanced level of AGER ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors. Isoforms of the AGER protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble AGER or sAGER) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against AGER-associated diseases.

Human AGER Protein General Information

 

• Protein names: Recommended name: Advanced glycosylation end product-specific receptor
  Short name: AGER
• Sequence length: 404 AA
• Domain: Immunoglobulin domain Repeat Signal Transmembrane Transmembrane helix
• Sequence similarities: Contains 2 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 Ig-like V-type (immunoglobulin-like) domain.
• Subunit structure: Interacts with S100B, S100A1 and APP. Interacts with S100A12.
• Subcellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted.
• Tissue specificity: Endothelial cells.

General information above from UniProt

Function for AGER Protein

UniProtKB:

Mediates interactions of advanced glycosylation end products (AGE). These are nonenzymatically glycosylated proteins which accumulate in vascular tissue in aging and at an accelerated rate in diabetes. Acts as a mediator of both acute and chronic vascular inflammation in conditions such as atherosclerosis and in particular as a complication of diabetes. AGE/RAGE signaling plays an important role in regulating the production/expression of TNF-alpha, oxidative stress, and endothelial dysfunction in type 2 diabetes. Interaction with S100A12 on endothelium, mononuclear phagocytes, and lymphocytes triggers cellular activation, with generation of key proinflammatory mediators. Interaction with S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53/TP53 signaling By similarity. Receptor for amyloid beta peptide. Contributes to the translocation of amyloid-beta peptide (ABPP) across the cell membrane from the extracellular to the intracellular space in cortical neurons. ABPP-initiated RAGE signaling, especially stimulation of p38 mitogen-activated protein kinase (MAPK), has the capacity to drive a transport system delivering ABPP as a complex with RAGE to the intraneuronal space.

Genatlas:

• AGER 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
• AGER playing distinct functional roles in both the toxicity and disposal of advanced glycation end products (AGEs), substances that are linked to diabetes and aging
• AGER may play an important role in inflammatory processes and endothelial activation, likely to accelerate the processes of coronary atherosclerotic development, especially in diabetic patients
• AGER is implicated as a pro-inflammatory factor in chronic inflammatory conditions such as diabetes mellitus and rheumatoid arthritis (Pubmed 19591173)
• AGER plays an important role in the development and progression of vascular disease (Pubmed 19275767)
• RAGE activates programs responsible for acute and chronic inflammation, when bound by its many ligands (Pubmed 18603587)
• AGER play an important role in the internalization of Mycobacterium tuberculosis into macrophages (Pubmed 18279703)
• AGER contributes to the inflammatory response in many acute and chronic diseases (Pubmed 20407037)
• 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 (Pubmed 20407037)
• AGER together with caspase-3 activation and inhibition of NF-kappaB signaling pathways, might be involved in the pathogenesis of macrophage apoptosis induced by HMGB1 (Pubmed 19800306)
• AGER nduces the expression of thioredoxin interacting protein (TXNIP) in Schwann cells and the injured sciatic nerve) (Pubmed 21098642)

Phenotype Information for AGER

• Gene/Locus: HBB,AGER
• Phenotype: Delta-beta thalassemia
  Erythremias, beta-
  Heinz body anemias, beta-
  Hereditary persistence of fetal hemoglobin
  Methemoglobinemias, beta-
  Sickle cell anemia
  Thalassemia-beta, dominant
  inclusion-body

Phenotype Information for AGER from OMIM (Online Mendelian Inheritance in Man)

Drugs for AGER

Target	Drug Name	Disease	Drug Status
AGER	Labetalol	Hypertension	Approved
AGER	Tamsulosin	Benign prostatic hyperplasia	Approved
AGER	Carvedilol	Congestive Heart Failure	Approved
AGER	Ergotamine	Ergotamine	Approved
AGER	Midodrine	Symptomatic orthostatic hypotension	Approved
AGER	Prazosin	Hypertension	Approved

Drugs for AGER from TTD (Therapeutic Targets Database)