Receptor for advanced glycation endproducts: a multiligand receptor magnifying cell stress in diverse pathologic settings
Introduction
Multiligand receptors are an intriguing group of cell surface structures whose broad repertoire of ligands defies simple classification with respect to structural or functional properties. Examples of such receptors include Receptor for Advanced Glycation Endproducts (RAGE) [1], CD36 [2], scavenger receptor-B1 (SR-B1) [3], type A scavenger receptor [4], [5], [6] and Low Density Lipoprotein Receptor-Related protein (LRP) [7]. RAGE, an immunoglobulin superfamily molecule, is a particularly striking member of this family [8]. Its ligands include products of nonenzymatic glycoxidation (advanced glycation endproducts or AGEs) [9], the amyloid-β (Aβ) peptide cleavage product of β-amyloid precursor protein [10], the S100/calgranulin family of proinflammatory cytokine-like mediators [11], and the high mobility group 1 DNA binding protein amphoterin [12], [13]. RAGE biology is largely dictated by the expression or accumulation of its ligands. Thus, in mature animals, there is little expression of RAGE in most tissues, whereas deposition of ligands triggers receptor expression [10], [14], [15], [16]. For example, there are few cortical neurons which express RAGE in the central nervous system of mature animals under homeostatic conditions [14]. However, during development, when high levels of amphoterin are present in the central nervous system, RAGE is increased in a wide range of cortical neurons [12]. Similarly, when pathogenic Aβ species accumulate in Alzheimer’s disease, RAGE expression increases in neurons, microglia and affected cerebral vasculature. In contrast to the suppression of receptor expression observed with the Low Density Lipoprotein (LDL) receptor in a lipoprotein-rich environment [17], RAGE is upregulated by its ligands. This mechanism provides the potential for exacerbating cellular dysfunction due to RAGE–ligand interaction, as increasing expression of the receptor allows for more profound RAGE-mediated induction of cellular dysfunction.
This review of RAGE biology will summarize progress in understanding the contribution of the receptor to the biology of tumors, inflammatory disorders, amyloidoses and diabetic complications. In each case, the relevant ligands/disorders include S100 proteins (tumors), S100 proteins, amphoterin and AGEs (inflammation), amyloid fibrils and S100 proteins (amyloidoses), and AGEs and S100 proteins (diabetic complications).
Section snippets
RAGE-amphoterin interaction: implications for tumor biology
Amphoterin is a molecule associated with heparan sulfate-rich proteoglycans in the extracellular matrix recognized for its ability to support neurite outgrowth and to function as a nonhistone chromosomal DNA binding protein of the high mobility group (HMG) 1 family [18]. The identification of RAGE as a receptor for amphoterin followed a somewhat indirect route. Some years after we had discovered the receptor and had recognized its capacity to bind Aβ and AGEs [10], [19], we sought endogenous
RAGE–S100 interactions: implications for the inflammatory response
In our initial experiments which identified lung-derived natural ligands for RAGE, an ≈12 kDa polypeptide was found whose N-terminal amino acid sequence corresponded to that of a member of the S100/calgranulin family, S100A12 [11]. In view of the close structural relationship between the >15 members of the S100/calgranulin family [26], [27], [28], these data suggested the possibility that RAGE might serve as the mediator of cellular effects of these polypeptides. Consistent with this
RAGE–amyloid interaction: implications for the host response to amyloid
Our initial studies leading to identification of RAGE were motivated by a search to elucidate mechanisms underlying chronic vascular dysfunction. Two prominent examples of such chronic vascular dysregulation occur in amyloid and diabetic angiopathies. In amyloid-associated disorders, amyloid fibrils have been found in the vessel wall, especially in the extracellular matrix contiguous to endothelium and smooth muscle cells [35], [36], [37], [38], [39], [40]. In diabetes, advanced glycation
RAGE–AGE interaction: implications for the complications of diabetes
Diabetes results in elevation of plasma glucose, causing multiple direct and indirect effects on cellular elements. Increased levels of glucose have been shown to activate protein kinase C [41], to induce cellular generation of free radicals by a mitochondrial pathway [60], and to stimulate the polyol pathway [41], as well as multiple other effects. One pathway for mediating indirect effects of high glucose is through AGEs, whose formation is brought about by nonenzymatic glycoxidation of
Conclusion
RAGE is a multiligand receptor whose wide spectrum of ligands includes AGEs, S100/calgranulins, amyloid, and amphoterin. The biology of the receptor is largely dictated by situations resulting from the accumulation of these ligands. Such situations are expectedly diverse and include diabetes (AGEs), inflammatory disorders (S100/calgranulins), amyloidoses (amyloid fibrils) and tumors (amphoterin). RAGE–ligand interaction appears to function as a propagation factor driving a destructive host
Acknowledgements
This work was supported by funds from the Juvenile Diabetes Research Foundation, USPHS (HL60901, AG17490, AG12807), and the Surgical Research Fund.
References (70)
- et al.
The biology of RAGE and its ligands
Biochim. Biophys. Acta
(2000) Scavenger receptors in innate immunity
Curr. Opin. Immunol.
(1996)- et al.
N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for RAGE that activate cell signalling pathways and modulate gene expression
J. Biol. Chem.
(1999) - et al.
RAGE mediates a novel proinflammatory axis: the cell surface receptor for S100/calgranulin polypeptides
Cell
(1999) - et al.
RAGE is a cellular binding site for amphoterin: mediation of neurite outgrowth and co-expression of RAGE and amphoterin in the developing nervous system
J. Biol. Chem.
(1995) - et al.
Isolation and some characteristics of an adhesive factor of brain that enhances neurite outgrowth in central neurons
J. Biol. Chem.
(1987) - et al.
Isolation and characterization of binding proteins for advanced glycosylation endproducts from lung tissue which are present on the endothelial cell surface
J. Biol. Chem.
(1992) - et al.
RAGE-mediated neurite outgrowth and activation of NF-kB require the cytoplasmic domain of the receptor but different downstream signaling pathways
J. Biol. Chem.
(1999) - et al.
The S100 family of EF-hand calcium-binding proteins: functions and pathology
TIBS
(1996) Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type
Biochim. Biophys. Acta
(1999)
Novel insights into structure and function of MRP8 and MRP14
Biochim. Biophys. Acta
Enhanced cellular oxidant stress by the interaction of AGEs with their receptors/binding proteins
J. Biol. Chem.
Blockade of RAGE restores effective wound healing in diabetic mice
Am. J. Pathol.
Cerebrovascular muscle atrophy is a feature of Alzheimer disease
Brain Res.
The cellular and molecular mechanisms of diabetic complications
Endocrin. Metabol. Clin. N. Am.
The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta peptide but not aggregated, cytotoxic amyloid-beta peptide
J. Biol. Chem.
Microglial cells internalize aggregates of the Alzheimer’s disease amyloid beta-protein via a scavenger receptor
Neuron
Aβ(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity
J. Biol. Chem.
Differential binding of vascular cell-derived proteoglycans (perlecan, biglycan, decorin, and versican) to the beta-amyloid protein of Alzheimer’s disease
Arch. Biochem. Biophys.
The HHQK domain of beta-amyloid provides a structural basis for the immunopathology of Alzheimer’s disease
J. Biol. Chem.
Activation of the Receptor for Advanced Glycation Endproducts triggers a p21ras-dependent mitogen-activated protein kinase pathway regulated by oxidant stress
J. Biol. Chem.
A redox-triggered Ras-effector interaction: recruitment of phosphatidylinositol 3′-kinase to Ras by redox stress
J. Biol. Chem.
CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism
J. Clin. Invest.
Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems
J. Clin. Invest.
Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein
Ann. Rev. Biochem.
Is the class A macrophage scavenger receptor multifunctional?—The mouse’s tale
J. Clin. Invest.
LRP: a multifunctional scavenger and signaling receptor
J. Clin. Invest.
The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses
J. Clin. Invest.
RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease
Nature
Blockade of RAGE/amphoterin suppresses tumor growth and metastases
Nature
Tissue distribution of the receptor for advanced glycation endproducts (RAGE): expression in smooth muscle, cardiac myocytes, and neural tissue in addition to vasculature
Am. J. Pathol.
Expression of RAGE in peripheral occlusive vascular disease
Am. J. Pathol.
Suppression of accelerated diabetic atherosclerosis by sRAGE
Nat. Med.
Lipoprotein and receptor interactions in vivo
Curr. Opin. Lipidol.
Regulation of cell migration by amphoterin
J. Cell Sci.
Cited by (252)
Essential autophagic protein Beclin 1 localizes to atherosclerotic lesions of human carotid and major intracranial arteries
2020, Journal of the Neurological SciencesBlood-brain barrier regulation in psychiatric disorders
2020, Neuroscience LettersNeuroprotective potential of formononetin, a naturally occurring isoflavone phytoestrogen
2024, Chemical Biology and Drug Design