RARRES2

RARRES2 Full Name

retinoic acid receptor responder (tazarotene induced) 2

RARRES2 Introduction

RARRES2 (retinoic acid receptor responder 2, also known as tazarotene-induced gene 2 or TIG2) is a secreted protein that functions as the precursor of chemerin, a multifunctional adipokine and chemotactic factor. The gene is located on chromosome 7q36.1 and encodes a protein of approximately 18 kDa (163 amino acids) that is primarily expressed in adipose tissue, liver, lung, skin, and adrenal gland. RARRES2 was originally identified as a gene induced by the synthetic retinoid tazarotene in psoriatic skin lesions, linking it to skin biology and inflammation. The encoded protein is proteolytically cleaved at the C-terminus by serine proteases including plasmin, factor XIIa, and cathepsin G to generate the bioactive chemerin peptide (chemerin S157), which binds to and activates the G protein-coupled receptor chemokine-like receptor 1 (CMKLR1, also known as ChemR23). Through this receptor-ligand interaction, RARRES2/chemerin plays essential roles in adipocyte differentiation, energy metabolism, angiogenesis, and immune cell recruitment, particularly of macrophages, dendritic cells, and natural killer (NK) cells. Dysregulation of RARRES2 has been implicated in obesity, type 2 diabetes mellitus, cardiovascular disease, psoriasis, cancer, and reproductive disorders, making it a subject of intensive research in both metabolic and inflammatory diseases.

Figure 1. Schematic structure of RARRES2.

Gene Structure and Protein Architecture
The human RARRES2 gene spans approximately 7 kb and contains 6 exons. Alternative splicing generates multiple transcript variants, with the major isoform encoding a protein of 163 amino acids. The RARRES2 protein contains several structurally and functionally important features. The N-terminal region contains a hydrophobic signal peptide (amino acids 1-20) that targets the protein for secretion via the classical endoplasmic reticulum-Golgi pathway. The C-terminal region contains the bioactive chemerin peptide sequence, which is released upon proteolytic cleavage. This C-terminal domain contains nine conserved cysteine residues that form four disulfide bonds, creating a stable three-dimensional structure that is essential for receptor binding and activation. The mature secreted prochemerin (full-length RARRES2) is biologically inactive and requires C-terminal proteolytic processing for activation. Several serine proteases can activate prochemerin, but with different efficacies: plasmin and factor XIIa are potent activators that generate the most active chemerin isoform (chemerin S157), while cathepsin G and elastase generate less active or inactive isoforms depending on the cleavage site. The active chemerin peptide of approximately 14-16 kDa adopts a cystatin-fold structure, similar to cathelicidins and other antimicrobial peptides, despite no sequence homology. RARRES2 also contains potential N-linked glycosylation sites and phosphorylation sites that may regulate its secretion, stability, and activity.

Role in Inflammation, Immunity, and Cancer
RARRES2/chemerin is a potent chemoattractant for immune cells expressing its receptor CMKLR1, including macrophages, immature dendritic cells, and natural killer (NK) cells. By recruiting these cells to sites of inflammation or tissue injury, chemerin plays important roles in both innate and adaptive immunity. In the skin, chemerin is constitutively expressed by keratinocytes and is upregulated by inflammatory stimuli including retinoids, UVB irradiation, and cytokines such as TNF-α and IL-1β. Chemerin recruits plasmacytoid dendritic cells (pDCs) to the skin, where they produce type I interferons, linking chemerin to antiviral defense. In psoriasis, chemerin expression is markedly increased in lesional skin, and chemerin contributes to the recruitment of macrophages and dendritic cells that drive the inflammatory response. Elevated chemerin levels are also observed in rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. In cancer, the role of RARRES2 is complex and context-dependent. In colorectal cancer, RARRES2 is frequently downregulated through promoter hypermethylation, and low RARRES2 expression correlates with poor prognosis and lymph node metastasis. RARRES2 suppresses colorectal cancer progression by inhibiting the NF-κB and MAPK signaling pathways, which drive proliferation and inflammation. In contrast, in breast cancer, ovarian cancer, and gastric cancer, RARRES2 is often upregulated and promotes tumor progression. Chemerin enhances the migration and invasion of cancer cells by activating CMKLR1, which induces epithelial-mesenchymal transition (EMT) through upregulation of Snail and Twist and downregulation of E-cadherin. Chemerin also promotes tumor angiogenesis by recruiting endothelial progenitor cells and inducing VEGF expression. Furthermore, chemerin can create an immunosuppressive tumor microenvironment by recruiting tumor-associated macrophages (TAMs) that suppress anti-tumor immune responses. These opposing roles reflect the complexity of RARRES2/chemerin biology and highlight the importance of cancer type-specific studies.

Alternate Names for RARRES2

RARRES2; retinoic acid receptor responder (tazarotene induced) 2; TIG2; HP10433; retinoic acid receptor responder protein 2; chemerin; RAR-responsive protein TIG2; tazarotene-induced gene 2 protein;