S100B and S100A6 Differentially Modulate Cell Survival by Interacting with Distinct RAGE (Receptor for Advanced Glycation End Products) Immunoglobulin Domains

Abstract

S100 proteins are EF-hand calcium-binding proteins with various intracellular functions including cell proliferation, differentiation, migration, and apoptosis. Some S100 proteins are also secreted and exert extracellular paracrine and autocrine functions. Experimental results suggest that the receptor for advanced glycation end products (RAGE) plays important roles in mediating S100 protein-induced cellular signaling. Here we compared the interaction of two S100 proteins, S100B and S100A6, with RAGE by in vitro assay and in culture of human SH-SY5Y neuroblastoma cells. Our in vitro binding data showed that S100B and S100A6, although structurally very similar, interact with different RAGE extracellular domains. Our cell assay data demonstrated that S100B and S100A6 differentially modulate cell survival. At micromolar concentration, S100B increased cellular proliferation, whereas at the same concentration, S100A6 triggered apoptosis. Although both S100 proteins induced the formation of reactive oxygen species, S100B recruited phosphatidylinositol 3-kinase/AKT and NF-B, whereas S100A6 activated JNK. More importantly, we showed that S100B and S100A6 modulate cell survival in a RAGE-dependent manner; S100B specifically interacted with the RAGE V and C 1 domains and S100A6 specifically interacted with the C 1 and C 2 RAGE domains. Altogether these results highlight the complexity of S100/RAGE cellular signaling.

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation

“…Low concentrations of ROS may even mimic the action of growth factors [44]. Interestingly, the increase in intracellular ROS levels by extracellular psoriasin was in the same range as that previously demonstrated for S100B [45].…”

Site-Specific Blockade of RAGE-VdPrevents Amyloid-β Oligomer Neurotoxicity

“…These include advanced glycation end products ( Schmidt et al, 1992), the chromatin-binding protein HMGB1 (Huttunen et al, 2000;Tian et al, 2007), as well as several members of the S100 family (Hofmann et al, 1999;Leclerc et al, 2007) leading to either a trophic or a toxic cellular effect. We recently showed that S100B and S100A6, two structurally closely related RAGE ligands, interact with distinct domains of the receptor and activate distinct signaling pathways suggesting that the cellular effects triggered by RAGE might be specific for each ligand .…”

In�vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system

“…RAGE ligands include S100/calgranulins (S100A4, S100A6, S100A7, S100A8/9, S100A14, S100B and S100P) (2,(25)(26)(27)(28)(29) and HMGB-1 protein, which have been demonstrated to be upregulated in glioma, melanoma, bladder, liver, pancreatic, prostate, colorectal, gastric and lung cancer (30)(31)(32)(33)(34). Ligand-RAGE signaling pathways enhance the properties associated with malignant tumor phenotypes (10,22,(35)(36)(37), including by activating members of the small GTPase family (Cdc42 and Rac1), members of the mitogen-activated protein kinase family (extracellular signal-regulated kinase, p38 and stress-activated protein kinases/c-Jun amino-terminal kinases), NF-κB and the formin homology 1 domain (10,22,35-37).…”