RANK

Receptor for Advanced Glycation End-products (RAGE)

The Receptor for Advanced Glycation End-products (RAGE) is a multi-ligand cell surface receptor of the immunoglobulin superfamily. It is implicated in various physiological and pathological processes, including inflammation, diabetes, cancer, and neurodegenerative diseases.

Structure

RAGE is a transmembrane receptor composed of three extracellular immunoglobulin-like domains (V, C1, and C2), a single transmembrane domain, and a short cytoplasmic tail. The extracellular domains are responsible for ligand binding, while the cytoplasmic tail is essential for signal transduction.

Ligands

RAGE is known to bind a diverse array of ligands, including:

• Advanced Glycation End-products (AGEs)
• S100 proteins
• High Mobility Group Box 1 (HMGB1)
• Amyloid beta

These ligands are associated with various pathological conditions, and their interaction with RAGE can lead to the activation of multiple signaling pathways.

Signaling Pathways

Upon ligand binding, RAGE activates several intracellular signaling cascades, including:

• Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB)
• Mitogen-activated protein kinase (MAPK)
• Janus kinase/signal transducers and activators of transcription (JAK/STAT)

These pathways contribute to the regulation of gene expression, inflammation, and cell proliferation.

Role in Disease

RAGE is implicated in the pathogenesis of several diseases:

Diabetes

In diabetes, the accumulation of AGEs and their interaction with RAGE contribute to vascular complications, including atherosclerosis and nephropathy.

Cancer

RAGE is involved in tumor growth and metastasis. It promotes cell survival, proliferation, and migration through its interaction with various ligands.

Neurodegenerative Diseases

In conditions such as Alzheimer's disease, RAGE mediates the effects of amyloid beta, leading to neuronal dysfunction and inflammation.

Inflammatory Diseases

RAGE plays a critical role in chronic inflammatory diseases by perpetuating inflammatory responses through its interaction with pro-inflammatory ligands.

Therapeutic Target

Given its involvement in multiple diseases, RAGE is considered a potential therapeutic target. Strategies to inhibit RAGE include:

• Small molecule inhibitors
• Monoclonal antibodies
• Soluble RAGE (sRAGE), which acts as a decoy receptor

Research Directions

Ongoing research aims to better understand the structure-function relationship of RAGE, its role in disease progression, and the development of effective RAGE-targeted therapies.

Also see

• Advanced Glycation End-products
• S100 proteins
• High Mobility Group Box 1
• Amyloid beta
• Inflammation