ICAM3 explained

Intercellular adhesion molecule 3 (ICAM3) also known as CD50 (Cluster of Differentiation 50), is a protein that in humans is encoded by the ICAM3 gene.^[1] The protein is constitutively expressed on the surface of leukocytes, which are also called white blood cells and are part of the immune system.^{[2] [3]} ICAM3 mediates adhesion between cells by binding to specific integrin receptors.^[4] It plays an important role in the immune cell response through its facilitation of interactions between T cells and dendritic cells, which allows for T cell activation.^[5] ICAM3 also mediates the clearance of cells undergoing apoptosis by attracting and binding macrophages, a type of cell that breaks down infected or dying cells through a process known as phagocytosis, to apoptotic cells.

Protein structure

ICAM3 is a 110–160 kDa protein that belongs to the intercellular adhesion molecule (ICAM) family. Like the other proteins in this family, ICAM3 is a type I transmembrane glycoprotein and consists in part of a hydrophobic transmembrane domain and a short domain that extends into the cytoplasm.^[6] ICAM3 also contains five extracellular immunoglobulin domains.

Function

ICAM3 is found on the surface of leukocytes, and the ICAM3 gene is constitutively expressed in these cells. Interactions between ICAM3 and specific integrin receptors facilitate adhesion between cells.

Dendritic and T cell binding

ICAM3 has an important function in the immune cell response, as it helps facilitate initial interactions between T cells and dendritic cells.^[7] Resting T cells show high levels of ICAM3 expression. ICAM3 on these T cells can bind to DC-SIGN, a transmembrane receptor present on dendritic cells, creating temporary contact between resting T cells and dendritic cells.^[5] This adhesion allows the T cell receptor (TCR) to interact with major histocompatibility complex (MHC) molecules on the surface of the dendritic cell, which, upon binding between the TCR, the MHC, and the peptide coupled to the MHC, facilitates T cell activation.^[5]

Apoptosis

ICAM3 plays a role in apoptotic cell clearance by promoting the movement of macrophages, which ingest and break down unhealthy cells via phagocytosis, to cells undergoing apoptosis. Apoptotic cells can release extracellular vesicles containing ICAM3, which acts as a chemoattractant to phagocytes such as macrophages, directing them toward apoptotic cells.^[8] Apoptotic cells also contain altered ICAM3 proteins on their surface. These altered proteins allow macrophages to specifically target and bind apoptotic cells. This process is believed to involve binding between ICAM3 and CD14 receptors, which are a type of cell surface receptor expressed on macrophages and other phagocytes.

Mast cells

ICAM3 is also found on mast cells, another type of leukocyte. Mast cells taken from human lungs and the HMC-1 line, a human mast cell line, both showed expression of ICAM3. ICAM3 helps mediate the adhesion of mast cells to the extracellular matrix.

Interactions

Dendritic and T cell binding

Binding between ICAM3 and DC-SIGN, which takes place during initial interactions between T cells and dendritic cells, occurs with high affinity.^{[5] [9]} This binding process is also calcium-dependent.^[5]

Apoptosis

CD14, a receptor expressed on the surface of phagocytes, can also bind ICAM3. Interactions between CD14 and altered ICAM3 molecules on apoptotic cells are believed to help promote phagocytosis of apoptotic cells.

Integrins

ICAM3 is a known ligand for LFA-1, an integrin expressed by leukocytes. To facilitate binding, the I domain of LFA-1 interacts with the ICAM3 protein’s first immunoglobulin domain. ICAM3 also binds the integrin αDβ2.

Additional interactions

ICAM3 has been shown to interact with activated ERM proteins, including ezrin (EZR) and moesin, in T cells.

See also

• Cluster of differentiation

References

Further reading

• Simmons DL . The role of ICAM expression in immunity and disease . Cancer Surveys . 24 . 141–155 . 1995 . 7553659 .
• Hayflick JS, Kilgannon P, Gallatin WM . The intercellular adhesion molecule (ICAM) family of proteins. New members and novel functions . Immunologic Research . 17 . 3 . 313–327 . 1998 . 9638475 . 10.1007/BF02786454 . 19901365 .
• Fawcett J, Holness CL, Needham LA, Turley H, Gatter KC, Mason DY, Simmons DL . Molecular cloning of ICAM-3, a third ligand for LFA-1, constitutively expressed on resting leukocytes . Nature . 360 . 6403 . 481–484 . December 1992 . 1448173 . 10.1038/360481a0 . 4310468 . 1992Natur.360..481F .
• Vazeux R, Hoffman PA, Tomita JK, Dickinson ES, Jasman RL, St John T, Gallatin WM . Cloning and characterization of a new intercellular adhesion molecule ICAM-R . Nature . 360 . 6403 . 485–488 . December 1992 . 1448174 . 10.1038/360485a0 . 4315548 . 1992Natur.360..485V .
• Pino-Otín MR, Juan M, de la Fuente MA, Viñas O, Martínez-Cáceres E, Fernández MD, Miralles A, Vilella R, Yagüe J, Vives J . 6 . CD50 (intercellular adhesion molecule-3) is expressed at higher levels on memory than on naive human T cells but induces a similar calcium mobilization on both subsets . Tissue Antigens . 46 . 1 . 32–44 . July 1995 . 7482494 . 10.1111/j.1399-0039.1995.tb02473.x .
• Marazuela M, Postigo AA, Acevedo A, Díaz-González F, Sanchez-Madrid F, de Landázuri MO . Adhesion molecules from the LFA-1/ICAM-1,3 and VLA-4/VCAM-1 pathways on T lymphocytes and vascular endothelium in Graves' and Hashimoto's thyroid glands . European Journal of Immunology . 24 . 10 . 2483–2490 . October 1994 . 7523142 . 10.1002/eji.1830241034 . 25833828 .
• Holness CL, Bates PA, Little AJ, Buckley CD, McDowall A, Bossy D, Hogg N, Simmons DL . 6 . Analysis of the binding site on intercellular adhesion molecule 3 for the leukocyte integrin lymphocyte function-associated antigen 1 . The Journal of Biological Chemistry . 270 . 2 . 877–884 . January 1995 . 7822326 . 10.1074/jbc.270.2.877 . free .
• Martin S, Rieckmann P, Melchers I, Wagner R, Bertrams J, Voskuyl AE, Roep BO, Zielasek J, Heidenthal E, Weichselbraun I . 6 . Circulating forms of ICAM-3 (cICAM-3). Elevated levels in autoimmune diseases and lack of association with cICAM-1 . Journal of Immunology . 154 . 4 . 1951–1955 . February 1995 . 10.4049/jimmunol.154.4.1951 . 7836774 . free .
• Bossy D, Mattei MG, Simmons DL . The human intercellular adhesion molecule 3 (ICAM3) gene is located in the 19p13.2-p13.3 region, close to the ICAM1 gene . Genomics . 23 . 3 . 712–713 . October 1994 . 7851905 . 10.1006/geno.1994.1565 .
• Skubitz KM, Ahmed K, Campbell KD, Skubitz AP . CD50 (ICAM-3) is phosphorylated on tyrosine and is associated with tyrosine kinase activity in human neutrophils . Journal of Immunology . 154 . 6 . 2888–2895 . March 1995 . 10.4049/jimmunol.154.6.2888 . 7876557 . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–174 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Juan M, Vilella R, Mila J, Yagüe J, Miralles A, Campbell KS, Friedrich RJ, Cambier J, Vives J, De Fougerolles AR . 6 . CDw50 and ICAM-3: two names for the same molecule . European Journal of Immunology . 23 . 7 . 1508–1512 . July 1993 . 8325327 . 10.1002/eji.1830230717 . 23774801 .
• de Fougerolles AR, Klickstein LB, Springer TA . Cloning and expression of intercellular adhesion molecule 3 reveals strong homology to other immunoglobulin family counter-receptors for lymphocyte function-associated antigen 1 . The Journal of Experimental Medicine . 177 . 4 . 1187–1192 . April 1993 . 8459213 . 2190956 . 10.1084/jem.177.4.1187 .
• Hosaka S, Shah MR, Pope RM, Koch AE . Soluble forms of P-selectin and intercellular adhesion molecule-3 in synovial fluids . Clinical Immunology and Immunopathology . 78 . 3 . 276–282 . March 1996 . 8605703 . 10.1006/clin.1996.0039 .
• Van der Vieren M, Le Trong H, Wood CL, Moore PF, St John T, Staunton DE, Gallatin WM . A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3 . Immunity . 3 . 6 . 683–690 . December 1995 . 8777714 . 10.1016/1074-7613(95)90058-6 . free .
• Hayflick JS, Stine J, Fox R, Hoekstra D, Gallatin WM . Functional mapping of the cytoplasmic region of intercellular adhesion molecule-3 reveals important roles for serine residues . The Journal of Biological Chemistry . 272 . 35 . 22207–22214 . August 1997 . 9268366 . 10.1074/jbc.272.35.22207 . free .
• Serrador JM, Alonso-Lebrero JL, del Pozo MA, Furthmayr H, Schwartz-Albiez R, Calvo J, Lozano F, Sánchez-Madrid F . 6 . Moesin interacts with the cytoplasmic region of intercellular adhesion molecule-3 and is redistributed to the uropod of T lymphocytes during cell polarization . The Journal of Cell Biology . 138 . 6 . 1409–1423 . September 1997 . 9298994 . 2132557 . 10.1083/jcb.138.6.1409 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–156 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Bernstein CN, Sargent M, Gallatin WM . Beta2 integrin/ICAM expression in Crohn's disease . Clinical Immunology and Immunopathology . 86 . 2 . 147–160 . February 1998 . 9473377 . 10.1006/clin.1997.4462 .

Notes and References

1. Web site: ICAM3 intercellular adhesion molecule 3 [Homo sapiens (human)] - Gene - NCBI ]. 2022-03-10 . www.ncbi.nlm.nih.gov.
2. Xiao X, Mruk DD, Cheng CY . Intercellular adhesion molecules (ICAMs) and spermatogenesis . Human Reproduction Update . 19 . 2 . 167–186 . March 2013 . 23287428 . 3576004 . 10.1093/humupd/dms049 .
3. Pastwińska J, Żelechowska P, Walczak-Drzewiecka A, Brzezińska-Błaszczyk E, Dastych J . The Art of Mast Cell Adhesion . Cells . 9 . 12 . 2664 . December 2020 . 33322506 . 10.3390/cells9122664 . 7764012 . free .
4. Cockram . Tom O. J. . Dundee . Jacob M. . Popescu . Alma S. . Brown . Guy C. . 2021 . The Phagocytic Code Regulating Phagocytosis of Mammalian Cells . Frontiers in Immunology . 12 . 629979 . 10.3389/fimmu.2021.629979 . 34177884 . 8220072 . 1664-3224. free .
5. Svajger U, Anderluh M, Jeras M, Obermajer N . C-type lectin DC-SIGN: an adhesion, signalling and antigen-uptake molecule that guides dendritic cells in immunity . Cellular Signalling . 22 . 10 . 1397–1405 . October 2010 . 20363321 . 7127357 . 10.1016/j.cellsig.2010.03.018 .
6. Smith CW . 3. Adhesion molecules and receptors . The Journal of Allergy and Clinical Immunology . 121 . 2 Suppl . S375-9; quiz S414 . February 2008 . 18241685 . 10.1016/j.jaci.2007.07.030 . 2008 Mini-Primer on Allergic and Immunologic Diseases . free .
7. van Kooyk Y, Geijtenbeek TB . A novel adhesion pathway that regulates dendritic cell trafficking and T cell interactions . Immunological Reviews . 186 . 47–56 . August 2002 . 12234361 . 10.1034/j.1600-065x.2002.18605.x . 23267228 .
8. Hawkins LA, Devitt A . Current understanding of the mechanisms for clearance of apoptotic cells-a fine balance . Journal of Cell Death . 6 . 57–68 . January 2013 . 25278779 . 4147779 . 10.4137/jcd.s11037 .
9. Rahimi . Nader . 2020-12-22 . C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell Adhesion Molecules Turned to Pathogen Recognition Receptors . Biology . 10 . 1 . 1 . 10.3390/biology10010001 . 2079-7737 . 7822156 . 33375175. free .