Investigation of phosphoproteome in RAGE signaling

Abstract

The receptor for advanced glycation end products (RAGE) is one of the most important proteins implicated in diabetes, cardiovascular diseases, neurodegenerative diseases, and cancer. It is a pattern recognition receptor by virtue of its ability to interact with multiple ligands, RAGE activates several signal transduction pathways through involvement of various kinases that phosphorylate their respective substrates. Only few substrates have been known to be phosphorylated in response to activation by RAGE (e.g., nuclear factor kappa B); however, it is possible that these kinases can phosphorylate multiple substrates depending upon their expression and localization, leading to altered cellular responses in different cell types and conditions. One such example is, glycogen synthase kinase 3 beta which is known to phosphorylate glycogen synthase, acts downstream to RAGE, and hyperphosphorylates microtubule-associated protein tau causing neuronal damage. Thus, it is important to understand the role of various RAGE-activated kinases and their substrates. Therefore, we have reviewed here the details of RAGE-activated kinases in response to different ligands and their respective phosphoproteome. Furthermore, we discuss the analysis of the data mined for known substrates of these kinases from the PhosphoSitePlus (http://www.phosphosite.org) database, and the role of some of the important substrates involved in cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In summary, this review provides information on RAGE-activated kinases and their phosphoproteome, which will be helpful in understanding the possible role of RAGE and its ligands in progression of diseases.

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

“…In addition to functional and structural alterations AGEs cause to cells, they also serve as activating ligands for AGE receptors that operate various transduction pathways (Alexiou et al, 2010;Batkulwar et al, 2015;Bierhaus et al, 2005;Curtis et al, 2012;Grimsrud et al, 2007;Jono et al, 2002;Neeper et al, 1992;Yan et al, 2010). Some of the proinflammatory interactions these receptors mediate include reactive radical formation by NOX enzymes and nitric oxide synthase (iNOS) (Barlovic et al, 2010;Herold et al, 2007;Koulis et al, 2015;Nienhuis et al, 2009;Yan et al, 2003).…”

HMGB1 regulates P-glycoprotein expression in status epilepticus rat brains via the RAGE/NF-κB signaling pathway

“…HMGB1 binds to RAGE to stimulate the biological effects of NF-κB. RAGE/NF-κB is known to be a regulator of inflammation ( 20 , 21 ). The present study investigated whether HMGB1 binds to RAGE, leading to activation of NF-κB and enhanced transcription of MDR1A/B and P-gp expression during brain seizures.…”

Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment

“…Although it was first described to be activated by advanced glycation end products (AGEs), RAGE can interact with a number of different classes of agonists, including S100 family proteins (e.g. S100B), high-mobility group box protein 1 (HMGB1), 70-kDa heatshock protein (HSP70), and N⑀-(carboxymethyl)lysine (CML) (21), among others. RAGE is expressed only by lungs and endothelial cells in a constitutive fashion and is generally repressed in other tissues; however, an increase in the concentration of circulating RAGE ligands induces the expression of this receptor in most cell types (20).…”