The importance of Ca2+/Zn2+ signaling S100 proteins and RAGE in translational medicine

Abstract

The Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand receptor involved in a large number of human disorders. Identified first as the receptor for the Advanced Glycation Endproducts (AGEs), RAGE has emerged in recent years as a major receptor for many members of the S100 calcium and zinc binding protein family. The interaction with and the signaling triggered by several S100 proteins such as S100B and S100A12 have been studied in details and have shown concentration and cell type dependent signaling cascades. The S100 protein family consists of more than 20 members which present high amino-acid sequence and structural similarities. These small EF-hand calcium binding proteins interact with a large number of protein targets and are almost all been shown to be involved in cancer. In this review we discuss the recent knowledge about the role of S100 proteins and RAGE in human disorders.

Hornerin, an S100 family protein, is functional in breast cells and aberrantly expressed in breast cancer

“…Proteins containing this motif are involved in virtually all normal and pathological cell functions including gene transcription, inflammatory and immune responses, regulation of protein phosphorylation, transcription factors, anti-microbial responses, Ca 2+ homeostasis, the dynamics of cytoskeleton constituents, as well as cell proliferation, differentiation, and death [1-3]. Given the global importance of these proteins, inhibitors of specific S100 proteins are currently being developed as therapeutics for diseases including diabetes mellitus, heart failure, neurological diseases, and several types of cancer [2,4]. …”

In Vivo Screening of S100B Inhibitors for Melanoma Therapy

“…This is particularly important for S100 inhibitors since there are over 20 structurally similar proteins in the S100 protein family, and they each regulate several physiologically important pathways in a cell-specific manner (14, 15). Thus, an S100 inhibitor could have multiple phenotypes depending on the number of S100 proteins it blocked and the S100 status of the cell-type targeted.…”

S100 proteins in cancer

“…This term alludes to the solubility of these approximately 10,000 Da proteins in 100% saturated ammonium sulphate. Although S100 family members exhibit a high degree of sequence and structural similarity, they are not functionally interchangeable and they participate in a wide range of biological processes such as proliferation, migration and/or invasion, inflammation and differentiation 2–4 . The structure and function of the S100 proteins are regulated by Ca 2+ binding, which allows them to act as Ca 2+ sensors that can translate fluctuations in intracellular Ca 2+ levels into a cellular response 5,6 .…”

“…Individual family members show unique affinities for divalent metal ions, oligomerization properties, post-translational modifications and spatiotemporal expression patterns. Intracellular S100 proteins bind to and regulate the activity of many targets; in some cases, multiple S100 family members may regulate one target 2–4 . Several S100 proteins are present in the extracellular space where they can participate in local intercellular communication (autocrine and paracrine), enter the systemic circulation and coordinate biological events over long distances.…”

“…Several S100 proteins are present in the extracellular space where they can participate in local intercellular communication (autocrine and paracrine), enter the systemic circulation and coordinate biological events over long distances. S100 proteins lack a signal peptide for secretion via the conventional Golgimediated pathway, and whether extracellular S100 proteins are actively secreted from living cells or passively released is still debated 2,4 . Extracellular S100 proteins interact with a variety of cell-surface receptors including receptor for advanced glycosylation end products (RAGE; also known as AGER), G protein-coupled receptors, Toll-like receptor 4 (TLR4), scavenger receptors, fibroblast growth factor receptor 1 (FGFR1), CD166 antigen (also known as ALCAM), interleukin-10 receptor (IL-10R), extracellular matrix metalloproteinase inducer (EMMPRIN; also known as basigin) and the bioactive sphingolipid ceramide 1-phosphate 4,7–10 .…”