PECAM1 - platelet and endothelial cell adhesion molecule 1 |Elisa - Clia - Antibody - Protein

Background

PECAM-1 (Platelet and Endothelial Cell Adhesion Molecule 1), also known as CD31, is an integral member of the immunoglobulin (Ig) superfamily and functions primarily as a cell adhesion molecule. It plays critical roles in various physiological and pathological processes, including leukocyte transmigration, angiogenesis, vascular integrity, and immune response regulation. PECAM-1 is highly expressed on the surface of endothelial cells lining blood vessels, platelets, monocytes, neutrophils, and some subsets of T cells. Its pivotal role in mediating cell-cell interactions makes it central to maintaining vascular homeostasis and coordinating immune responses.

PECAM-1 is widely recognized for its involvement in processes like leukocyte extravasation, where it facilitates the migration of immune cells across the endothelium during inflammation. Additionally, it serves as an essential player in maintaining the structural integrity of the vascular endothelium and modulating signaling pathways linked to cell survival and inflammation. Given its broad expression and functional diversity, PECAM-1 has been a focal point of research in vascular biology, inflammation, and cardiovascular diseases.

Protein Structure

PECAM-1 is a type I transmembrane glycoprotein composed of 738 amino acids. Its structure is characteristic of the immunoglobulin (Ig) superfamily, featuring six extracellular Ig-like domains, a single transmembrane domain, and a cytoplasmic tail that mediates intracellular signaling. Each structural component plays a distinct role in the adhesion and signaling functions of the protein.

Extracellular Domain:

• The extracellular portion of PECAM-1 consists of six Ig-like domains (D1-D6), which are crucial for homophilic and heterophilic interactions. This domain allows PECAM-1 to mediate cell-cell adhesion through homophilic binding (PECAM-1 molecules on adjacent cells binding to one another), primarily between endothelial cells and leukocytes.
• The Ig-like domains contribute to its role in leukocyte transmigration, as they enable interactions with other adhesion molecules or receptors on leukocytes, endothelial cells, and platelets.
• This domain also has several N-linked glycosylation sites which are essential for its proper folding, stability, and surface localization.

Transmembrane Domain:

• The transmembrane region of PECAM-1 spans approximately 19 hydrophobic amino acids, anchoring the molecule to the plasma membrane. This domain is relatively conserved across species and does not directly contribute to ligand binding but is essential for localizing the protein within the plasma membrane.

Cytoplasmic Domain:

• The cytoplasmic tail of PECAM-1 is highly conserved and contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Upon phosphorylation, these ITIM motifs recruit tyrosine phosphatases, such as SHP-1 and SHP-2, which mediate intracellular signaling processes.
• This domain is integral to PECAM-1's role in modulating signaling pathways that influence cell survival, inflammation, and vascular permeability. It acts as a regulator of outside-in signaling, where extracellular interactions trigger intracellular signaling cascades that affect cell behavior.

Classification and Subtypes

PECAM-1 belongs to the immunoglobulin superfamily (IgSF), which includes proteins involved in cell adhesion, immune responses, and signal transduction. Although PECAM-1 does not have distinct subtypes, it can engage in various interactions that define its functional diversity. PECAM-1 primarily functions through:

Homophilic Binding:

• This occurs when PECAM-1 molecules on adjacent cells bind to each other. This type of interaction is critical for maintaining endothelial junctions and mediating immune cell migration across endothelial barriers during inflammation.

Heterophilic Binding:

• PECAM-1 can also bind to non-PECAM molecules, such as leukocyte integrins, allowing it to mediate interactions between endothelial cells and circulating immune cells. These interactions are vital in regulating immune cell trafficking and vascular functions.

PECAM-1 is a single gene product with alternative splicing variants that can result in proteins with slightly different cytoplasmic domains, which may modify its signaling properties, but these variants are not typically considered separate subtypes.

Function and Biological Significance

PECAM-1 has multifaceted roles in various biological processes, most notably in vascular biology, immune cell trafficking, and inflammatory responses.

Leukocyte Transmigration:

• One of the hallmark functions of PECAM-1 is its involvement in the transmigration (diapedesis) of leukocytes across the endothelial barrier. PECAM-1 is expressed both on leukocytes and endothelial cells, facilitating their interaction at junctions. Through homophilic binding, PECAM-1 forms a bridge that allows leukocytes to migrate through the endothelial monolayer during inflammation.
• This process is crucial for the body’s immune response, enabling neutrophils, monocytes, and lymphocytes to reach sites of infection or injury.

Maintenance of Vascular Integrity:

• PECAM-1 contributes to the stability of endothelial junctions by mediating cell-cell adhesion between adjacent endothelial cells. This function is vital for maintaining the integrity and selective permeability of the endothelial barrier, especially during inflammation, when the barrier can become more permeable to allow immune cell migration.
• PECAM-1 also regulates endothelial cell survival by modulating apoptotic signaling pathways, thereby promoting endothelial cell longevity and contributing to vascular homeostasis.

Angiogenesis:

• PECAM-1 is involved in the formation of new blood vessels, a process known as angiogenesis. It plays a role in the migration and organization of endothelial cells during vessel formation, contributing to wound healing, tissue repair, and tumor growth.

Signal Transduction:

• PECAM-1 is a signaling receptor. The ITIM motifs in its cytoplasmic domain, when phosphorylated, recruit phosphatases such as SHP-1 and SHP-2. These phosphatases downregulate immune responses by dephosphorylating key signaling molecules involved in inflammatory signaling, thereby acting as negative regulators of inflammation.
• PECAM-1 also participates in anti-apoptotic signaling by activating survival pathways, further underscoring its role in vascular biology and endothelial cell function.

Inflammatory Response Regulation:

• PECAM-1 modulates inflammation by reducing excessive immune cell activation and cytokine production. By acting as a “checkpoint” in leukocyte migration and by negatively regulating pro-inflammatory signaling cascades, PECAM-1 helps resolve inflammation and prevents tissue damage due to chronic inflammation.

Clinical Issues

PECAM-1 is implicated in various vascular and immune-related pathologies, including:

Cardiovascular Diseases:

• PECAM-1 is linked to the development of atherosclerosis due to its role in regulating endothelial cell function and leukocyte transmigration. Dysfunctional PECAM-1 signaling can contribute to endothelial activation, a critical step in plaque formation.
• Altered PECAM-1 expression or signaling has been associated with ischemia-reperfusion injury, where the restoration of blood flow to tissues causes inflammation and damage, exacerbated by immune cell infiltration.

Inflammatory Diseases:

• PECAM-1’s role in modulating immune cell migration and endothelial permeability makes it relevant in chronic inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and multiple sclerosis (MS). In these conditions, abnormal PECAM-1 signaling can either promote excessive immune cell infiltration or impair proper resolution of inflammation.

Cancer:

• PECAM-1 is involved in the process of tumor angiogenesis, where new blood vessels are formed to supply tumors with nutrients and oxygen. Targeting PECAM-1 could be a strategy for inhibiting tumor growth by preventing the formation of these vessels.
• Additionally, PECAM-1’s role in immune cell trafficking might influence the tumor microenvironment and impact immune evasion by tumors.

Transplantation:

• PECAM-1 has been implicated in transplant rejection, particularly in cases of solid organ transplantation. Its expression on endothelial cells of grafted organs and circulating leukocytes plays a role in graft inflammation and rejection, making it a potential therapeutic target to reduce immune-mediated transplant rejection.

Autoimmune Diseases:

• PECAM-1 polymorphisms have been associated with increased susceptibility to autoimmune diseases, including systemic lupus erythematosus (SLE). Dysregulation of PECAM-1 signaling in these diseases contributes to aberrant immune cell migration and inflammation, exacerbating the disease.

Summary

PECAM-1 (CD31) is a type I transmembrane glycoprotein that belongs to the immunoglobulin superfamily and is widely expressed on endothelial cells, platelets, and leukocytes. Structurally, PECAM-1 consists of an extracellular domain with six Ig-like domains that mediate cell-cell adhesion, a transmembrane domain that anchors it in the membrane, and a cytoplasmic tail that modulates intracellular signaling pathways through ITIM motifs. Functionally, PECAM-1 is critical in regulating leukocyte transmigration, maintaining vascular integrity, and modulating immune responses. Clinically, PECAM-1 is implicated in a variety of vascular disorders, inflammatory diseases, cancers, and autoimmune conditions. Its role as a mediator of endothelial and immune cell interactions underscores its significance in both health and disease, making it a potential target for therapeutic interventions.