CD9 is a gene encoding a protein that is a member of the transmembrane 4 superfamily also known as the tetraspanin family. It is a cell surface glycoprotein that consists of four transmembrane regions and has two extracellular loops that contain disulfide bonds which are conserved throughout the tetraspanin family. [5] [6] [7] Also containing distinct palmitoylation sites that allows CD9 to interact with lipids and other proteins. [5] [8] [9]
Tetraspanin proteins are involved in a multitude of biological processes such as adhesion, motility, membrane fusion, signaling and protein trafficking. [5] [10] Tetraspanins play a role in many biological processes because of their ability to interact with many different proteins including interactions between each other. Their distinct palmitoylation sites allow them to organize on the membrane into tetraspanin-enriched microdomains (TEM). [11] [8] [10] These TEMs are thought to play a role in many cellular processes including exosome biogenesis. [12] CD9 is commonly used as a marker for exosomes as it is contained on their surface. [11] [10] [13] [14]
However, in some cases CD9 plays a larger role in the ability of exosomes to be more or less pathogenic. Shown in HIV-1 infection, exosomes are able to enhance HIV-1 entry through tetraspanin CD9 and CD81. [15] However, expression of CD9 on the cellular membrane seems to decrease the viral entry of HIV-1. [16] [17]
CD9 has a diverse role in cellular processes as it has also been shown to trigger platelet activation and aggregation. [18] It forms a alphaIIbbeta3-CD9-CD63 complex on the surface of platelets that interacts directly with other cells such as neutrophils which may assist in immune response. [11] [19] In addition, the protein appears to promote muscle cell fusion and support myotube maintenance. [20] [21] Also, playing a key role in egg-sperm fusion during mammalian fertilization. [9] While oocytes are ovulated, CD9-deficient oocytes do not properly fuse with sperm upon fertilization. [22] CD9 is located in the microvillar membrane of the oocytes and also appears to intervene in maintaining the normal shape of oocyte microvilli. [23]
CD9 can also modulate cell adhesion [24] and migration. [25] [26] This function makes CD9 of interest when studying cancer and cancer metastasis. However, it seems CD9 has a varying role in different types of cancers. Studies showed that CD9 expression levels have an inverse correlation to metastatic potential or patient survival. The over expression of CD9 was shown to decrease metastasis in certain types of melanoma, breast, lung, pancreas and colon carcinomas. [27] [28] [29] [30] [31] However in other studies, CD9 has been shown to increase migration or be highly expressed in metastatic cancers in various cell lines such as lung cancer, [25] scirrhous-type gastric cancer, [26] hepatocellular carcinoma, [32] acute lymphoblastic leukemia, [33] and breast cancer. Suggesting based on the cancer CD9 can be a tumor suppressor or promotor. [34] It has also been suggested that CD9 has an effect on the ability for cancer cells to develop chemoresistance.
Additionally, CD9 has been shown to block adhesion of Staphylococcus aureus to wounds. The adhesion is essential for infection of the wound. [35] This suggests that CD9 could be of possible use to as treatment for skin infection by Staphylococcus aureus.
CD9 has been shown to interact with:
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.
Integrin beta-1 (ITGB1), also known as CD29, is a cell surface receptor that in humans is encoded by the ITGB1 gene. This integrin associates with integrin alpha 1 and integrin alpha 2 to form integrin complexes which function as collagen receptors. It also forms dimers with integrin alpha 3 to form integrin receptors for netrin 1 and reelin. These and other integrin beta 1 complexes have been historically known as very late activation (VLA) antigens.
CD49d is an integrin alpha subunit. It makes up half of the α4β1 lymphocyte homing receptor.
Leukocyte antigen CD37 is a protein that in humans is encoded by the CD37 gene.
Leukocyte surface antigen CD53 is a protein that in humans is encoded by the CD53 gene.
CD63 antigen is a protein that, in humans, is encoded by the CD63 gene. CD63 is mainly associated with membranes of intracellular vesicles, although cell surface expression may be induced.
CD151 molecule, also known as CD151, is a human gene.
G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
CD81 molecule, also known as CD81, is a protein which in humans is encoded by the CD81 gene. It is also known as 26 kDa cell surface protein, TAPA-1, and Tetraspanin-28 (Tspan-28).
CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.
CD82, or KAI1, is a human protein encoded by the CD82 gene.
Tetraspanin-7 is a protein that in humans is encoded by the TSPAN7 gene.
CUB domain-containing protein 1 (CDCP1) is a protein that in humans is encoded by the CDCP1 gene. CDCP1 has also been designated as CD318 and Trask. Alternatively spliced transcript variants encoding distinct isoforms have been reported.
Uroplakin-1a (UP1a) is a protein that in humans is encoded by the UPK1A gene.
Tetraspanin-13 is a protein that in humans is encoded by the TSPAN13 gene.
Tetraspanin-4 is a protein that in humans is encoded by the TSPAN4 gene.
Prostaglandin F2 receptor negative regulator is a protein that in humans is encoded by the PTGFRN gene. PTGFRN has also been designated as CD315.
Tetraspanin-8 is a protein that in humans is encoded by the TSPAN8 gene.
Transmembrane 4 L6 family member 5 is a protein that in humans is encoded by the TM4SF5 gene.
Tetraspanin-12 (Tspan-12) also known as tetraspan NET-2 (NET2) or transmembrane 4 superfamily member 12 (TM4SF12) is a tetraspanin protein that in humans is encoded by the TSPAN12 gene. Tetraspanin-12 is found in the membrane of a variety of cells. It has an unusually long C-terminal intracellular tail of approximately 60 amino acids.
