PLAUR - plasminogen activator, urokinase receptor |Elisa - Clia - Antibody - Protein

Background

The plasminogen activator, urokinase receptor (PLAUR), also known as urokinase plasminogen activator receptor (uPAR), is a cell surface receptor that plays a pivotal role in modulating extracellular matrix degradation, cell adhesion, and migration. PLAUR is mainly expressed on various cell types, including immune cells (like monocytes and neutrophils), endothelial cells, and cancer cells, and it orchestrates processes crucial for tissue remodeling, inflammation, and metastasis. PLAUR facilitates these processes by binding to urokinase-type plasminogen activator (uPA) and concentrating proteolytic activity on the cell surface, contributing to localized extracellular proteolysis and influencing signal transduction pathways that mediate cell movement and adhesion. This receptor is encoded by the PLAUR gene, located on chromosome 19q13, and belongs to the Ly6/uPAR/α-neurotoxin receptor family, a superfamily of proteins involved in signal transduction.

Protein Structure

PLAUR is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein composed of three distinct domains that enable it to interact with various ligands and initiate downstream signaling.

Domain Organization:

• PLAUR consists of three homologous domains (D1, D2, and D3), each classified within the Ly6/uPAR/α-neurotoxin family due to their structural characteristics. These domains are organized in a tandem fashion.
• Each domain contains disulfide bridges that stabilize its tertiary structure, essential for maintaining the protein's conformation and function.
• The three-domain arrangement allows for specific ligand binding sites within D1, where uPA (urokinase) binds, and distinct functional interactions with other molecules across D2 and D3.

Binding and Activation Sites:

• The D1 domain contains the primary binding site for uPA, the ligand that initiates PLAUR’s role in extracellular proteolysis and signaling. Binding of uPA to PLAUR triggers plasminogen conversion to plasmin, activating a cascade for proteolytic degradation.
• PLAUR can also bind other molecules, such as vitronectin, integrins, and receptors like GPCRs, enabling cross-talk with different cell signaling pathways, especially those involving cell adhesion and migration.

Membrane Anchoring:

• PLAUR is anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor, which allows it to be freely mobile within the membrane. This flexibility is key for its role in cell signaling and migration, as it enables PLAUR to form complexes with other membrane receptors and initiate intracellular signaling cascades.
• The GPI anchor allows PLAUR to be shed from the cell surface in a soluble form, known as suPAR, which can circulate in the blood and has independent biological roles.

Soluble Forms (suPAR):

• The cleaved form of PLAUR, known as soluble uPAR (suPAR), retains the D1 domain and is found in various biological fluids. Elevated suPAR levels are associated with several diseases, including cancers, autoimmune diseases, and chronic infections.

Classification and Subtypes

PLAUR is classified as a member of the Ly6/uPAR/α-neurotoxin receptor family and is primarily a GPI-anchored protein with proteolytic and signaling functions. While no distinct subtypes of PLAUR have been identified, its cleaved form, suPAR, is an important biologically active form with systemic effects and is commonly detected in plasma or other bodily fluids, where it serves as a biomarker for disease severity in various conditions.

Function and Biological Significance

PLAUR functions as a key mediator in processes involving tissue remodeling, inflammation, immune responses, and cellular communication. Its biological significance is closely tied to its ability to localize proteolytic activity at the cell surface and mediate cell signaling pathways, influencing cellular behavior in various physiological and pathological processes.

Proteolytic Activation and Tissue Remodeling:

• PLAUR’s primary role is to localize uPA activity to the cell surface. Upon binding to uPA, PLAUR facilitates the conversion of plasminogen to plasmin, a broad-spectrum protease that degrades components of the extracellular matrix (ECM) and basement membrane. This activity is critical in tissue remodeling, wound healing, and cell migration.
• By concentrating plasminogen activation at the cell surface, PLAUR enables highly localized degradation of ECM components, which is essential for cell migration, especially in immune cells moving to sites of infection or injury and in cancer cells during metastasis.

Signal Transduction and Cell Migration:

• PLAUR lacks an intracellular signaling domain but interacts with integrins and other receptors to mediate signal transduction indirectly. Through these interactions, it activates downstream signaling pathways such as Ras-MAPK, PI3K-Akt, and NF-κB, which influence cell proliferation, survival, and motility.
• By engaging with integrins, PLAUR influences cell adhesion, spreading, and migration, making it a crucial player in processes like immune cell recruitment to inflammatory sites and the metastatic spread of tumor cells.

Role in Immune Response:

• In immune cells, PLAUR regulates migration and adhesion to ensure efficient trafficking to sites of infection or inflammation. It modulates the activity of leukocytes, contributing to both innate and adaptive immune responses.
• PLAUR also plays a role in regulating cytokine production, influencing the inflammatory response and aiding in immune cell activation and recruitment.

Biomarker Potential:

• The soluble form of PLAUR, suPAR, is a recognized biomarker for several diseases, including cancer, cardiovascular diseases, autoimmune disorders, and infectious diseases. Elevated suPAR levels correlate with disease severity and poorer prognosis, reflecting its systemic involvement in inflammation and immune activation.

Clinical Issues

Cancer:

• PLAUR is heavily implicated in cancer biology, where it supports tumor cell invasion, angiogenesis, and metastasis by facilitating ECM degradation and activating signal transduction pathways that promote cell migration. High levels of PLAUR are often found in aggressive cancers, and elevated suPAR levels in blood are associated with advanced disease and metastasis.
• PLAUR is a potential target for cancer therapy, with efforts focusing on inhibiting its interaction with uPA or interfering with its signaling functions to prevent tumor growth and spread.

Inflammatory and Autoimmune Diseases:

• PLAUR has been linked to various inflammatory diseases, including rheumatoid arthritis and chronic obstructive pulmonary disease (COPD), where its proteolytic and signaling functions contribute to tissue destruction and immune cell recruitment. In autoimmune diseases, abnormal PLAUR expression can exacerbate tissue damage by promoting inflammatory responses.
• Elevated suPAR levels are often observed in chronic inflammatory conditions, reflecting ongoing immune activation and tissue remodeling.

Cardiovascular Diseases:

• PLAUR plays a role in cardiovascular health, with elevated suPAR levels associated with an increased risk of cardiovascular events and mortality. It is believed to contribute to atherosclerosis by promoting immune cell infiltration and inflammation within vascular tissues.
• suPAR is used as a biomarker to assess cardiovascular disease risk and predict outcomes in patients with heart disease.

Infectious Diseases:

• In infections, PLAUR contributes to the recruitment of immune cells to the site of infection and modulates the immune response. High levels of suPAR are found in patients with chronic infections, such as HIV or hepatitis, and correlate with disease progression.
• suPAR is used as a prognostic biomarker in sepsis and other severe infections, where it helps predict mortality risk and guide treatment decisions.

Summary

PLAUR, also known as uPAR, is a GPI-anchored receptor that plays a central role in tissue remodeling, cell migration, and immune regulation. Structurally, it consists of three Ig-like domains that bind uPA and other ligands, facilitating proteolytic degradation at the cell surface. Through interactions with integrins and other cell surface receptors, PLAUR influences cell signaling pathways involved in proliferation, migration, and immune responses. Its cleaved soluble form, suPAR, circulates in the bloodstream and is used as a biomarker for various diseases.

Functionally, PLAUR contributes to processes such as tissue repair, immune cell migration, and cancer metastasis. Dysregulation or overexpression of PLAUR is associated with several pathological conditions, including cancers, autoimmune diseases, cardiovascular diseases, and infections. Its significance as a biomarker, particularly suPAR, is well-established in predicting disease severity and outcomes. Consequently, PLAUR and suPAR serve as valuable diagnostic and prognostic tools, as well as potential therapeutic targets in diseases characterized by abnormal cell migration, tissue remodeling, and immune dysregulation.