Alternative titles; symbols
HGNC Approved Gene Symbol: AGER
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:32,180,969-32,184,253 (from NCBI)
Sugaya et al. (1994) identified 3 genes, AGER, PBX2 (176311), and NOTCH4 (164951), located 90 to 140 kb centromeric to the tenascin-like gene (600985) in the MHC class III region near the junction with class II. AGER is a member of the immunoglobulin superfamily.
Yan et al. (1996) reported that the AGER protein, which they called RAGE, is an important receptor for the amyloid beta peptide (104760) and that expression of this receptor increases in Alzheimer disease (AD; 104300). They noted that expression of RAGE is particularly increased in neurons close to deposits of amyloid beta peptide and to neurofibrillary tangles.
In mice, Deane et al. (2003) showed that RAGE mediated the transport of human beta-amyloid-40 and -42 across the blood-brain barrier and resulted in the expression of proinflammatory cytokines and endothelin-1 (EDN1; 131240), the latter causing cerebral vasoconstriction. Inhibition of the RAGE-ligand interaction, either by RAGE IgG or soluble RAGE, which is not transported across the blood-brain barrier, suppressed the accumulation of beta-amyloid in brain parenchyma in a mouse model of AD. Deane et al. (2003) suggested that RAGE could be a target for inhibiting the development of cerebral amyloidosis and its pathogenic consequences.
Hofmann et al. (1999) reported that RAGE is a central cell surface receptor for S100A12 (603112), which they referred to as ENRAGE (extracellular newly identified RAGE-binding protein), and related members of the S100/calgranulin superfamily. Interaction of ENRAGE with cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggered cellular activation, with generation of key proinflammatory mediators. In murine models, blockade of ENRAGE/RAGE quenched delayed-type hypersensitivity and inflammatory colitis by arresting activation of central signaling pathways and expression of inflammatory gene mediators.
RAGE, a multiligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development, and inflammation, and certain diseases such as diabetes (see 125853, 222100) and Alzheimer disease. Engagement of RAGE by a ligand triggers activation of key cell signaling pathways, such as p21(ras) (see 139150), MAP kinases (see 176948), NF-kappa-B (NFKB; see 164011), and cdc42 (602590)/rac (602048), thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin (HMG1; 163905), a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the colocalization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumor invasion. Taguchi et al. (2000) demonstrated that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumors and tumors developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44 (601795)/p42 (603441), p38 (600289), and SAP/JNK (601158) MAP kinases, molecular effector mechanisms importantly linked to tumor proliferation, invasion, and expression of matrix metalloproteinases.
Chavakis et al. (2003) found that Rage-deficient mice had impaired leukocyte recruitment in a thioglycollate-induced acute peritonitis model. Leukocyte recruitment to inflamed peritoneum was enhanced in diabetic wildtype mice compared with nondiabetic wildtype mice, and this phenomenon was abrogated in the presence of soluble Rage and did not occur in Rage -/- mice. Human neutrophils strongly adhered to RAGE in vitro in a divalent cation-dependent manner, but not in the presence of monoclonal antibodies to MAC1 (ITGAM; 120980). Antibodies against ICAM1 (147840) or soluble RAGE partially blocked MAC1-dependent adhesion of neutrophils to endothelial cells and, when used in combination, nearly abolished adhesion. Addition of S100B (176990) augmented the RAGE-MAC1 interaction. Chavakis et al. (2003) concluded that RAGE acts as a counterreceptor for beta-2 integrin (ITGB2; 600065)-dependent leukocyte-endothelial cell interactions.
Bierhaus et al. (2004) examined sural nerve biopsies of patients with diabetic neuropathy (see 603933) and found that RAGE, ligands of RAGE, activated NFKB1 (164011), and interleukin 6 (IL6; 147620) colocalized in the microvasculature. Activation of NFKB1 and NFKB1-dependent gene expression was upregulated in peripheral nerves of mice with streptozotocin-induced diabetes, induced by advanced glycation end products, and prevented by RAGE blockade. Loss of pain perception in diabetic mice was reversed by treatment with soluble RAGE. In Rage -/- diabetic mice, NFKB1 activation was blunted and loss of pain perception was largely prevented, although the loss of plantar nerve fibers was similar to that of controls. Bierhaus et al. (2004) concluded that the RAGE-NFKB1 axis operates in diabetic neuropathy by mediating functional sensory deficits.
Zhou et al. (2006) observed that Rage -/- mice had increased bone mass and bone mineral density and decreased bone resorptive capacity. Differentiated Rage-deficient osteoclasts exhibited disrupted actin ring and sealing zone structures, impaired maturation, and reduced bone resorptive activity in vitro. Signaling through integrin alpha-V-beta-3 (ITGAV, 193210; ITGB3, 173470) after vitronectin (VTN; 193190) stimulation was impaired in Rage -/- preosteoclasts and bone marrow macrophages. Zhou et al. (2006) concluded that RAGE has a role in osteoclast actin cytoskeletal reorganization, adhesion, maturation, and function.
Sugaya et al. (1994) mapped the AGER gene to chromosome 6p21.3 by mapping by contiguous cosmids and YAC clones and by fluorescence in situ hybridization. The PBX2 and AGER genes are immediately contiguous and are transcribed in the same direction.
Bierhaus, A., Haslbeck, K.-M., Humpert, P. M., Liliensiek, B., Dehmer, T., Morcos, M., Sayed, A. A. R., Andrassy, M., Schiekofer, S., Schneider, J. G., Schulz, J. B., Heuss, D., and 12 others. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J. Clin. Invest. 114: 1741-1751, 2004. [PubMed: 15599399] [Full Text: https://doi.org/10.1172/JCI18058]
Chavakis, T., Bierhaus, A., Al-Fakhri, N., Schneider, D., Witte, S., Linn, T., Nagashima, M., Morser, J., Arnold, B., Preissner, K. T., Nawroth, P. P. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J. Exp. Med. 198: 1507-1515, 2003. [PubMed: 14623906] [Full Text: https://doi.org/10.1084/jem.20030800]
Deane, R., Yan, S. D., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., Zhu, H., Ghiso, J., and 11 others. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nature Med. 9: 907-913, 2003. [PubMed: 12808450] [Full Text: https://doi.org/10.1038/nm890]
Hofmann, M. A., Drury, S., Fu, C., Qu, W., Taguchi, A., Lu, Y., Avila, C., Kambham, N., Bierhaus, A., Nawroth, P., Neurath, M. F., Slattery, T., Beach, D., McClary, J., Nagashima, M., Morser, J., Stern, D., Schmidt, A. M. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97: 889-901, 1999. [PubMed: 10399917] [Full Text: https://doi.org/10.1016/s0092-8674(00)80801-6]
Sugaya, K., Fukagawa, T., Matsumoto, K., Mita, K., Takahashi, E., Ando, A., Inoko, H., Ikemura, T. Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a Notch homolog, human counterpart of mouse mammary tumor gene int-3. Genomics 23: 408-419, 1994. [PubMed: 7835890] [Full Text: https://doi.org/10.1006/geno.1994.1517]
Taguchi, A., Blood, D. C., del Toro, G., Canet, A., Lee, D. C., Qu, W., Tanji, N., Lu, Y., Lalla, E., Fu, C., Hofmann, M. A., Kislinger, T., Ingram, M., Lu, A., Tanaka, H., Hori, O., Ogawa, S., Stern, D. M., Schmidt, A. M. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405: 354-360, 2000. [PubMed: 10830965] [Full Text: https://doi.org/10.1038/35012626]
Yan, S. D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., Migheli, A., Nawroth, P., Stern, D., Schmidt, A. M. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 382: 685-691, 1996. [PubMed: 8751438] [Full Text: https://doi.org/10.1038/382685a0]
Zhou, Z., Immel, D., Xi, C.-X., Bierhaus, A., Feng, X., Mei, L., Nawroth, P., Stern, D. M., Xiong, W.-C. Regulation of osteoclast function and bone mass by RAGE. J. Exp. Med. 203: 1067-1080, 2006. [PubMed: 16606672] [Full Text: https://doi.org/10.1084/jem.20051947]