The receptor for advanced glycation end‐products (RAGE) directly binds to ERK by a D‐domain‐like docking site

Abstract

The receptor for advanced glycation end-products (RAGE)-mediated cellular activation through the mitogen-activated protein kinase (MAPK) cascade, activation of NF-U UB and Rho family small G-proteins, cdc42/Rac, is implicated in the pathogenesis of in£ammatory disorders and tumor growth/metastasis. However, the precise molecular mechanisms for the initiation of cell signaling by RAGE remain to be elucidated. In this study, proteins which directly bind to the cytoplasmic C-terminus of RAGE were puri¢ed from rat lung extracts using an a⁄nity chromatography technique and identi¢ed to be extracellular signal-regulated protein kinase-1 and -2 (ERK-1/2). Their interactions were con¢rmed by immunoprecipitation of ERK-1/2 from RAGE-expressing HT1080 cell extracts with anti-RAGE antibody. Furthermore, the augmentation of kinase activity of RAGE-bound ERK upon the stimulation of cells with amphoterin was demonstrated by determining the phosphorylation level of myelin basic protein, an ERK substrate. In vitro binding studies using a series of C-terminal deletion mutants of human RAGE revealed the importance of the membrane-proximal cytoplasmic region of RAGE for the direct ERK^RAGE interaction. This region contained a sequence similar to the D-domain, a ERK docking site which is conserved in some ERK substrates including MAPK-interacting kinase-1/2, mitogen-and stress-activated protein kinase-1, and ribosomal S6 kinase. These data suggest that ERK may play a role in RAGE signaling through direct interaction with RAGE. ß

Trans-synaptic EphB2–ephrin–B3 interaction regulates excitatory synapse density by inhibition of postsynaptic MAPK signaling

“…Our experiments establish eB3 as a member of a small group of transmembrane proteins that can interact with Erk (19,20) and provide evidence for a biological function of the interaction. The Erk2-eB3 interaction appears to negatively regulate Erk signaling possibly by retaining Erk in the dendrites, or by virtue of eB3's selective interaction with Erk2.…”

Amphoterin Stimulates Myogenesis and Counteracts the Antimyogenic Factors Basic Fibroblast Growth Factor and S100B via RAGE Binding

“…Alternatively, amphoterin might have induced a larger extent of receptor clustering, thereby increasing RAGE transducing activity. Amphoterin-induced RAGE clustering with consequent RAGE hyperactivation has been recently proposed (24). Considering the much smaller extent of MCK induction in WT myoblasts under the same experimental conditions (Fig.…”

Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity

“…Serum levels of HMGB-1 and sRAGE in SSc 13 comparisons. Spearman's rank correlation coefficient was used to examine the relationship between 2 continuous variables.…”

“…RAGE, the first receptor that was identified for HMGB-1, is encoded in the MHC class III region, together with the genes encoding the receptors for several complement components, as well as the genes encoding TNF, lymphotoxin, and heat-shock protein 70 [9]. RAGE can be expressed as both a transmembrane molecule, which directly interacts with extracellular-signal-regulated kinases 1 and 2 and drives activation of the mitogen-activated protein kinase p38 and NFκB, and as a soluble molecule [9,13].…”