CD93 (Cluster ofDifferentiation 93) is aprotein that in humans is encoded by theCD93gene.[5][6][7] CD93 is aC-type lectintransmembrane receptor which plays a role not only in cell–cell adhesion processes but also in host defense.[7]
CD93 belongs to the Group XIV C-Typelectin family,[8] a group containing three other members, endosialin (CD248), CLEC14A[9] andthrombomodulin, a well characterized anticoagulant. All of them contain a C-type lectin domain, a series ofepidermal growth factor like domains, a highly glycosylated mucin-like domain, a unique transmembrane domain and a short cytoplasmic tail. Due to their strong homology and their close proximity on chromosome 20, CD93 has been suggested to have arisen from the thrombomodulin gene through aduplication event.
CD93 was originally identified in mice as an earlyB cell marker through the use of AA4.1 monoclonal antibody.[10][11] Then this molecule was shown to be expressed on an early population ofhematopoietic stem cells, which give rise to the entire spectrum of mature cells in the blood. Now CD93 is known to be expressed by a wide variety of cells such asplatelets,monocytes,microglia andendothelial cells. In the immune system CD93 is also expressed onneutrophils, activatedmacrophages, B cell precursors until the T2 stage in the spleen, a subset of dendritic cells and of natural killer cells. Molecular characterization of CD93 revealed that this protein is identical with C1qRp, a human protein identified as a putativeC1q receptor.[12] C1q belongs to thecomplement activation proteins and plays a major role in the activation of the classical pathway of the complement, which leads to the formation of the membrane attack complex. C1q is also involved in other immunological processes such as enhancement of bacterial phagocytosis, clearance ofapoptotic cells or neutralisation of virus. Strikingly, it has been shown that anti-C1qRp significantly reduced C1q enhanced phagocytosis. A more recent study confirmed that C1qRp is identical to CD93 protein, but failed to demonstrate a direct interaction between CD93 and C1q under physiological conditions. Recently it has been shown that CD93 is re-expressed during the late B cell differentiation and CD93 can be used in this context as a plasma cell maturation marker. CD93 has been found to be differentially expressed in grade IV glioma vasculature when compared to low grade glioma or normal brain and its high expression correlated with the poor survival of the patients.[13][14]
CD93 was initially thought to be a receptor for C1q, but now is thought to instead be involved in intercellularadhesion and in the clearance of apoptotic cells. The intracellular cytoplasmic tail of this protein contains two highly conserved domains which may be involved in CD93 function. Indeed, the highly charged juxtamembrane domain has been found to interact withmoesin, a protein known to play a role in linking transmembrane proteins to thecytoskeleton and in the remodelling of the cytoskeleton. This process appears crucial for both adhesion,migration andphagocytosis, three functions in which CD93 may be involved.
In the context of late B cell differentiation, CD93 has been shown to be important for the maintenance of high antibody titres after immunization and in the survival oflong-lived plasma cells in the bone marrow. Indeed, CD93 deficient mice failed to maintain high antibody level upon immunization and present a lower amount of antigen specific plasma cells in the bone marrow.
In the context of the endothelial cells, CD93 is involved in endothelial cell-cell adhesion, cell spreading, cell migration, cell polarization as well as tubular morphogenesis.[14] Recently it has been found that CD93 is able to control endothelial cell dynamics through its interaction with an extracellular matrix glycoprotein MMRN2.[15] Absence of CD93 or its interacting partner MMRN2 in the endothelial cells lead to disruption of extracellular matrix proteinfibronectin fibrillogenesis and decreasedintegrin B1 activation.[15]
CD93 plays a significant role in the glioma development. CD93 knockout mice with glioma show smaller tumor size and improved survival.[14] The tumors also show disrupted fibronectin fibrillogenesis and decreasedintegrin B1 activation.[15]
^Webster SD, Park M, Fonseca MI, Tenner AJ (January 2000). "Structural and functional evidence for microglial expression of C1qR(P), the C1q receptor that enhances phagocytosis".Journal of Leukocyte Biology.67 (1):109–16.doi:10.1002/jlb.67.1.109.PMID10648005.S2CID14982216.
^Dieterich LC, Mellberg S, Langenkamp E, Zhang L, Zieba A, Salomäki H, Teichert M, Huang H, Edqvist PH, Kraus T, Augustin HG, Olofsson T, Larsson E, Söderberg O, Molema G, Pontén F, Georgii-Hemming P, Alafuzoff I, Dimberg A (November 2012). "Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization".The Journal of Pathology.228 (3):378–90.doi:10.1002/path.4072.PMID22786655.S2CID31223309.
Ghebrehiwet B, Peerschke EI, Hong Y, Munoz P, Gorevic PD (June 1992). "Short amino acid sequences derived from C1q receptor (C1q-R) show homology with the alpha chains of fibronectin and vitronectin receptors and collagen type IV".Journal of Leukocyte Biology.51 (6):546–56.doi:10.1002/jlb.51.6.546.PMID1377218.S2CID1214598.
Stuart GR, Lynch NJ, Day AJ, Schwaeble WJ, Sim RB (December 1997). "The C1q and collectin binding site within C1q receptor (cell surface calreticulin)".Immunopharmacology.38 (1–2):73–80.doi:10.1016/S0162-3109(97)00076-3.PMID9476117.
Norsworthy PJ, Taylor PR, Walport MJ, Botto M (August 1999). "Cloning of the mouse homolog of the 126-kDa human C1q/MBL/SP-A receptor, C1qR(p)".Mammalian Genome.10 (8):789–93.doi:10.1007/s003359901093.PMID10430665.S2CID2160211.
Joseph K, Shibayama Y, Ghebrehiwet B, Kaplan AP (January 2001). "Factor XII-dependent contact activation on endothelial cells and binding proteins gC1qR and cytokeratin 1".Thrombosis and Haemostasis.85 (1):119–24.doi:10.1055/s-0037-1612914.PMID11204562.S2CID35432595.
Steinberger P, Szekeres A, Wille S, Stöckl J, Selenko N, Prager E, Staffler G, Madic O, Stockinger H, Knapp W (January 2002). "Identification of human CD93 as the phagocytic C1q receptor (C1qRp) by expression cloning".Journal of Leukocyte Biology.71 (1):133–40.doi:10.1189/jlb.71.1.133.PMID11781389.S2CID31767877.
