MRC2 - mannose receptor C-type 2 |Elisa - Clia - Antibody - Protein

Background

Mannose receptor C-type 2 (MRC2), also known as endocytic mannose receptor or uPARAP/Endo180, is a transmembrane glycoprotein receptor and a member of the C-type lectin family. MRC2 plays a significant role in the cellular processes of endocytosis and extracellular matrix (ECM) remodeling, particularly through binding and internalizing glycoproteins and matrix components. MRC2 is predominantly expressed in cells with endocytic functions, including fibroblasts, macrophages, and endothelial cells, and contributes to tissue homeostasis, immune response, and wound healing by modulating cellular uptake of glycosylated and collagenous materials.

MRC2 is one of several mannose receptors, structurally distinct from others such as MRC1. Unlike MRC1, which is primarily involved in antigen capture and immune surveillance, MRC2 is most notable for its role in collagen uptake and degradation, positioning it as a unique player in matrix remodeling and turnover. The receptor's collagen-binding capacity has been linked to its role in tumor progression and metastasis in cancer as well as in fibrosis, where excessive ECM accumulation disrupts normal tissue function.

Protein Structure

MRC2 is a type I transmembrane protein with a complex extracellular domain arrangement suited for binding a variety of ligands, including collagen. The protein consists of approximately 1500 amino acids and is composed of distinct structural domains critical for its multifunctional activity:

Extracellular Domain:

• The extracellular portion of MRC2 is organized into four major structural domains: an N-terminal cysteine-rich (CR) domain, a fibronectin type II (FNII) domain, and a series of eight C-type lectin-like domains (CTLDs). These CTLDs are responsible for recognizing and binding glycosylated ligands.
• The CR domain plays a role in ligand binding, especially sulfated sugars, and is similar to domains seen in other lectin receptors, suggesting a conserved function in binding specific glycosylation patterns.
• The FNII domain is primarily responsible for collagen binding and is a unique feature of MRC2 compared to other mannose receptors. This domain binds collagen types I, IV, and V, facilitating the receptor’s role in endocytosis and degradation of collagenous materials. Structural studies have shown that the FNII domain recognizes the triple-helical structure of collagen, which is crucial for its effective uptake and remodeling.
• The CTLDs contribute to MRC2’s ability to recognize a broad range of ligands beyond collagen. These CTLDs bind carbohydrate molecules in a calcium-dependent manner, typical of the C-type lectin family, enabling MRC2 to act as a versatile receptor for glycoproteins in addition to collagen.

Transmembrane Domain:

• The transmembrane domain is a single-pass hydrophobic α-helix that anchors MRC2 in the cell membrane. This domain is essential for the receptor’s stability on the cell surface and contributes to the spatial organization required for efficient ligand binding.

Cytoplasmic Tail:

• The short cytoplasmic tail contains signaling motifs that enable clathrin-mediated endocytosis. This tail includes internalization signals that facilitate the uptake of bound ligands through coated pits, allowing MRC2 to participate in continuous ligand internalization and recycling processes.
• It is notable for its tyrosine-based motifs and dileucine motifs, which are necessary for directing the receptor into endocytic pathways and modulating downstream signaling processes relevant to ECM degradation.

Classification and Subtypes

MRC2 belongs to the C-type lectin superfamily, known for their carbohydrate recognition domains that facilitate glycoprotein binding. Within this family, MRC2 is most closely related to MRC1 but is unique in its FNII domain, which enables specific collagen-binding properties. MRC2 does not have subtypes but is considered part of a broader functional group of mannose receptor-like proteins involved in ECM remodeling and cellular uptake of glycoproteins.

Other similar proteins, such as DEC-205 and phospholipase A2 receptors, share structural characteristics with MRC2 but differ in ligand specificity and tissue distribution, highlighting MRC2’s specialized role in collagen binding and turnover.

Function and Biological Significance

The primary functions of MRC2 are endocytosis and extracellular matrix degradation. Its main biological roles include:

Collagen Uptake and ECM Remodeling:

• MRC2 is central to the endocytosis and degradation of collagen, which is crucial for ECM turnover. Through binding and internalizing collagen fibrils, MRC2 aids in tissue remodeling, particularly in fibroblasts and macrophages. This function is vital for maintaining tissue integrity, facilitating wound healing, and enabling normal tissue remodeling processes.

Immune Response Modulation:

• Although less involved in direct immune surveillance than MRC1, MRC2 can influence immune responses by regulating ECM composition, which impacts cellular migration, antigen presentation, and cytokine release.
• The receptor has been shown to impact macrophage activation and differentiation, indirectly influencing inflammation and immune cell recruitment by modifying the local ECM environment.

Role in Fibrosis and Tumor Progression:

• MRC2’s role in collagen degradation links it to fibrotic diseases. Dysregulated MRC2 expression or activity can lead to abnormal collagen accumulation, contributing to tissue fibrosis in organs like the liver, kidneys, and lungs.
• In cancer, MRC2 expression is associated with tumor-associated fibroblasts (TAFs), where it facilitates ECM remodeling conducive to tumor invasion and metastasis. Increased MRC2 levels have been observed in various cancers, including breast and pancreatic cancers, where it correlates with enhanced tumor aggressiveness.

Cell Migration and Adhesion:

• MRC2 influences cell adhesion and migration by modulating the ECM. Through collagen turnover, MRC2 impacts the structural integrity of the ECM, thereby influencing processes such as angiogenesis, wound healing, and tissue repair.
• The receptor has been implicated in the migration of fibroblasts and endothelial cells, contributing to its role in tissue repair and remodeling.

Clinical Issues

Given its role in collagen metabolism and tissue remodeling, MRC2 has been implicated in a variety of clinical conditions, particularly fibrotic diseases and cancer:

Fibrosis:

• Excessive MRC2 activity can contribute to pathological fibrosis, where abnormal ECM deposition occurs. Overexpression or hyperactivation of MRC2 has been linked to liver fibrosis, pulmonary fibrosis, and renal fibrosis. This suggests that MRC2 could be a potential therapeutic target for inhibiting collagen deposition in fibrotic diseases.

Cancer:

• In the context of cancer, MRC2 expression on tumor-associated fibroblasts supports the ECM remodeling necessary for tumor cell invasion. Higher MRC2 levels have been observed in various solid tumors, where its presence often correlates with a poor prognosis due to enhanced tumor progression and metastasis. Blocking MRC2 activity could thus provide therapeutic benefits by limiting ECM degradation and tumor spread.

Vascular Diseases:

• MRC2’s expression in endothelial cells suggests potential implications in vascular diseases, particularly those involving ECM remodeling or endothelial dysfunction. The receptor’s involvement in tissue repair and fibrosis may have indirect impacts on vascular health, although this area requires further research.

Potential as a Biomarker:

• MRC2 expression levels could serve as a biomarker for certain cancers and fibrotic conditions, aiding in diagnosis or prognosis. Measuring MRC2 expression in tissue biopsies may provide insight into the extent of ECM remodeling and disease progression.

Summary

MRC2, or mannose receptor C-type 2, is a multifunctional transmembrane receptor with a specialized role in ECM remodeling, primarily through collagen uptake and degradation. Structurally, it consists of an extracellular region with a unique combination of CR, FNII, and CTLD domains, a transmembrane domain, and a cytoplasmic tail that mediates endocytic activity. MRC2 is expressed primarily in fibroblasts, macrophages, and endothelial cells, where it contributes to tissue homeostasis, immune modulation, and wound healing.

Biologically, MRC2 is vital for collagen turnover and ECM integrity, influencing tissue repair, fibrosis, and cancer progression. In pathological contexts, MRC2 is associated with fibrotic diseases and cancer metastasis, making it a potential therapeutic target and biomarker for these conditions. Further studies of MRC2 could yield insights into its roles in disease and potential applications in therapeutic intervention and diagnostics.