Platelet endothelial cell adhesion molecule (PECAM-1) also known as cluster of differentiation 31 (CD31) is a protein that in humans is encoded by the PECAM1 gene found on chromosome17q23.3. [5] [6] [7] [8] PECAM-1 plays a key role in removing aged neutrophils from the body.
PECAM-1 is a highly glycosylated protein with a mass of approximately 130 kDa. [9] The structure of this protein was determined by molecular cloning in 1990, when it was found out that PECAM-1 has an N-terminal domain with 574 amino acids, a transmembrane domain with 19 amino acids and a C-terminal cytoplasmic domain with 118 amino acids. The N-terminal domain consists of six extracellular Ig-like domains. [10]
PECAM-1 is a cell-cell adhesion protein [11] which interacts with other PECAM-1 molecules through homophilic interactions or with non-PECAM-1 molecules through heterophilic interactions. [12] Homophilic interactions between PECAM-1 molecules are mediated by antiparallel interactions between extracellular Ig-like domain 1 and Ig-like domain 2. These interactions are regulated by the level of PECAM-1 expression. Homophilic interactions occur, only when the surface expression of PECAM-1 is high. Otherwise, when expression is low, heterophilic interactions occur. [13]
CD31 is normally found on endothelial cells, platelets, macrophages and Kupffer cells, granulocytes, lymphocytes (T cells, B cells, and NK cells), megakaryocytes, and osteoclasts.
In immunohistochemistry, CD31 is used primarily to demonstrate the presence of endothelial cells in histological tissue sections. This can help to evaluate the degree of tumor angiogenesis, which can imply a rapidly growing tumor. Malignant endothelial cells also commonly retain the antigen, so that CD31 immunohistochemistry can also be used to demonstrate both angiomas and angiosarcomas. It can also be demonstrated in small lymphocytic and lymphoblastic lymphomas, although more specific markers are available for these conditions. [14]
PECAM-1 is found on the surface of platelets, monocytes, neutrophils, and some types of T-cells, and makes up a large portion of endothelial cell intercellular junctions. The encoded protein is a member of the immunoglobulin superfamily and is likely involved in leukocyte transmigration, angiogenesis, and integrin activation. [5] CD31 on endothelial cells binds to the CD38 receptor on natural killer cells for those cells to attach to the endothelium. [15] [16]
PECAM-1 plays a role in cell signaling. In the cytoplasmic domain of PECAM-1 are serine and tyrosine residues which are suitable for phosphorylation. After the tyrosine is phosphorylated, PECAM-1 recruits Src homology 2 (SH2) domain–containing signaling proteins. These proteins can then initiate signaling pathways. Of all these proteins, the protein most widely reported as interacting with the PECAM-1 cytoplasmic domain is SH2 domain–containing protein-tyrosine phosphatase SHP-2. [17] Signaling through PECAM-1 leads to the activation of neutrophils, monocytes and leukocytes. [18]
PECAM-1 is involved in migration of monocytes and neutrophils, [19] natural killer cells, [20] Vδ1+ γδ T lymphocytes [21] and CD34+ hematopoietic progenitor cells [22] through the endothelial cells. Moreover, PECAM-1 is involved in transendothelial migration of recent thymic emigrants to the secondary lymphoid organs. [23] Mechanism of leukocyte transmigration can be explained by creating a homophilic interaction. In this interaction migrating leukocytes express PECAM-1 on the surface and then they react with PECAM-1 on the surface of endothelial cell. [24]
PECAM-1 is also important for angiogenesis because it enables the formation of new blood vessels through the cell-cell adhesion. [25]
PECAM-1 is expressed by many solid tumor cell lines such as hemangioma, angiosarcoma, Kaposi’s sarcoma, breast carcinoma, glioblastoma, colon carcinoma, skin carcinoma and other tumor cell lines. [26] On the surface of these tumor cells PECAM-1 mediates the adhesion to endothelial cells. [27] PECAM-1 modulates tumor growth by the formation of new endothelial cell tubes. In mice, this process can be inhibited using an anti-PECAM-1 antibody. [28]
Recently, it was found out that elderly patients with gastric cancer have high concentration of PECAM-1 in the serum. That suggests that the use of a serum PECAM-1 level can be a good prognostic marker. [29]
Inhibition of PECAM-1 leads to a reduction of atherosclerotic lesions in mice. [30] That means that PECAM-1 is involved in atherosclerosis. The exact mechanism, how PECAM-1 contributes to atherosclerosis is not known, but there are some theories. PECAM-1 can act as a mechanoresponsive molecule. Or the pathogenesis can be caused by the infiltration of leukocytes mediated by PECAM-1. Finally, polymorphisms in the PECAM-1 gene can lead to the progression of atherosclerosis. [31]
Extensive microvascular thrombosis and increased microvascular permeability are main characteristics of disseminated intravascular coagulation, a fatal complication of sepsis. Patients with this devastating condition have high levels of PECAM-1 in the serum indicating PECAM-1 as a good diagnostic marker. Moreover, PECAM-1 can protect from the development of disseminated intravascular coagulation by inhibiting macrophage pyroptosis. [32]
PECAM-1 contributes to at least two of the nervous system diseases, multiple sclerosis and cerebral ischaemia. First signs of multiple sclerosis are defects in the blood brain barrier and leukocyte migration mediated by adhesion molecules such as PECAM-1. Moreover, monocytes in patients with multiple sclerosis express high level of PECAM-1. Cerebral ischaemia is caused by the accumulation of leukocytes, which then infiltrate brain parenchyma and release toxic compounds such as oxygen radicals. Interactions between leukocyte and endothelium are mediated by PECAM-1. High levels of soluble PECAM-1 can be used to diagnose both diseases. Increased PECAM-1 levels indicate damage in the blood brain barrier in patients with multiple sclerosis and high PECAM-1 levels can be used as a short-term prediction of a stroke in patients with cerebral ischaemia. [33]
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indirect interaction, where cells attach to surrounding extracellular matrix, a gel-like structure containing molecules released by cells into spaces between them. Cells adhesion occurs from the interactions between cell-adhesion molecules (CAMs), transmembrane proteins located on the cell surface. Cell adhesion links cells in different ways and can be involved in signal transduction for cells to detect and respond to changes in the surroundings. Other cellular processes regulated by cell adhesion include cell migration and tissue development in multicellular organisms. Alterations in cell adhesion can disrupt important cellular processes and lead to a variety of diseases, including cancer and arthritis. Cell adhesion is also essential for infectious organisms, such as bacteria or viruses, to cause diseases.
L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.
The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.
P-selectin is a type-1 transmembrane protein that in humans is encoded by the SELP gene.
ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.
E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.
Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106) is a protein that in humans is encoded by the VCAM1 gene. VCAM-1 functions as a cell adhesion molecule.
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.
CD146 also known as the melanoma cell adhesion molecule (MCAM) or cell surface glycoprotein MUC18, is a 113kDa cell adhesion molecule currently used as a marker for endothelial cell lineage. In humans, the CD146 protein is encoded by the MCAM gene.
Leukocyte extravasation is the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.
Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.
Junctional adhesion molecule A is a protein that in humans is encoded by the F11R gene. It has also been designated as CD321.
CD93 is a protein that in humans is encoded by the CD93 gene. CD93 is a C-type lectin transmembrane receptor which plays a role not only in cell–cell adhesion processes but also in host defense.
Junctional adhesion molecule C is a protein that in humans is encoded by the JAM3 gene.
Receptor-type tyrosine-protein phosphatase beta or VE-PTP is an enzyme specifically expressed in endothelial cells that in humans is encoded by the PTPRB gene.
Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.
CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.
Tyrosine kinase with immunoglobulin-like and EGF-like domains 1 also known as TIE1 is an angiopoietin receptor which in humans is encoded by the TIE1 gene.
Fermitin family homolog 3) (FERMT3), also known as kindlin-3 (KIND3), MIG2-like protein (MIG2B), or unc-112-related protein 2 (URP2) is a protein that in humans is encoded by the FERMT3 gene. The kindlin family of proteins, member of the B4.1 superfamily, comprises three conserved protein homologues, kindlin 1, 2, and 3. They each contain a bipartite FERM domain comprising four subdomains F0, F1, F2, and F3 that show homology with the FERM head (H) domain of the cytoskeletal Talin protein. Kindlins have been linked to Kindler syndrome, leukocyte adhesion deficiency, cancer and other acquired human diseases. They are essential in the organisation of focal adhesions that mediate cell-extracellular matrix junctions and are involved in other cellular compartments that control cell-cell contacts and nucleus functioning. Therefore, they are responsible for cell to cell crosstalk via cell-cell contacts and integrin mediated cell adhesion through focal adhesion proteins and as specialised adhesion structures of hematopoietic cells they are also present in podosome's F actin surrounding ring structure. Isoform 2 may act as a repressor of NF-kappa-B and apoptosis
Endothelial cell anergy is a condition during the process of angiogenesis, where endothelial cells, the cells that line the inside of blood vessels, can no longer respond to inflammatory cytokines. These cytokines are necessary to induce the expression of cell adhesion molecules to allow leukocyte infiltration from the blood into the tissue at places of inflammation, such as a tumor. This condition, which protects the tumor from the immune system, is the result of exposure to angiogenic growth factors.
