Integrin beta 2

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In molecular biology, CD18 (Integrin beta chain-2) is an integrin beta chain protein that is encoded by the ITGB2 gene in humans.[1] Upon binding with one of a number of alpha chains, CD18 is capable of forming multiple heterodimers, which play significant roles in cellular adhesion and cell surface signaling, as well as important roles in immune responses.[1][2] CD18 also exists in soluble, ligand binding forms. Deficiencies in CD18 expression can lead to adhesion defects in circulating white blood cells in humans, reducing the immune system's ability to fight off foreign invaders.

Structure and function

The ITGB2 protein product is CD18. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain, and are crucial for cells to be able to efficiently bind to the extracellular matrix.[1] This is especially important for neutrophils, as cellular adhesion plays a large role in extravasation from the blood vessels. A given chain may combine with multiple partners resulting in different integrins.

The known binding partners of CD18 are CD11a,[3] CD11b,[4] CD11c and CD11d.[1] Binding of CD18 and CD11 results in the formation of Lymphocyte Functions Associated Antigen 1 (LFA-1),[3] a protein found on B cells, all T cells, macrophages, neutrophils and NK cells. LFA-1 is involved in adhesion and binding to antigen presenting cells through interactions with the surface protein ICAM-1

Binding of CD18 and CD11b-d results in the formation of complement receptors (e.g. Macrophage-1 antigen receptor, Mac-1, when bound to CD11b),[4] which are proteins found largely on neutrophils, macrophages and NK cells. These complement receptors participate in the innate immune response by recognizing foreign antigen peptides and phagocytizing them, thus destroying the antigen.

Clinical significance

In humans, lack of functional CD18 causes Leukocyte Adhesion Deficiency, a disease defined by a lack of leukocyte extravasation from blood into tissues, which is the inability of circulating leukocytes to respond to foreign bodies present in the tissue.[5] This subsequently reduces the ability of the individual's immune system to fight off infection, making them more susceptible to foreign infection than those with functional CD18 proteins. The beta 2 integrins have also been found in a soluble form, meaning they are not anchored into the plasma membrane of the cell, but rather exist outside of the cell in the plasma, and are capable of ligand binding.[6] The soluble beta 2 integrins are ligand binding and plasma levels are inversely associated with disease activity in the autoimmune disease spondyloarthritis.[7]

Interactions

CD18 has been shown to interact with:

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Amin Aanout, M. (March 1, 1990). "Structure and Function of the Leukocyte Adhesion Molecules CD11/CD18". Blood. 75 (5): 1037–1050.
  2. ↑ "ITGB2 integrin subunit beta 2 [ Homo sapiens (human) ]".
  3. ↑ 3.0 3.1 Verma NK, Kelleher D (August 2017). "Not Just an Adhesion Molecule: LFA-1 Contact Tunes the T Lymphocyte Program". Journal of Immunology. 199 (4): 1213–1221. doi:10.4049/jimmunol.1700495. PMID 28784685.
  4. ↑ 4.0 4.1 Todd, R (1996). "The continuing saga of complement receptor type 3 (CR3)". Journal of Clinical Investigation. 98 (1): 1–2.
  5. ↑ Kishimoto TK, Hollander N, Roberts TM, Anderson DC, Springer TA (July 1987). "Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency". Cell. 50 (2): 193–202. PMID 3594570.
  6. ↑ Gjelstrup LC, Boesen T, Kragstrup TW, Jørgensen A, Klein NJ, Thiel S, Deleuran BW, Vorup-Jensen T (October 2010). "Shedding of large functionally active CD11/CD18 Integrin complexes from leukocyte membranes during synovial inflammation distinguishes three types of arthritis through differential epitope exposure". Journal of Immunology. 185 (7): 4154–68. doi:10.4049/jimmunol.1000952. PMID 20826754.
  7. ↑ Kragstrup TW, Jalilian B, Hvid M, Kjærgaard A, Østgård R, Schiøttz-Christensen B, Jurik AG, Robinson WH, Vorup-Jensen T, Deleuran B (February 2014). "Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis". Arthritis Research & Therapy. 16 (1): R42. doi:10.1186/ar4471. PMID 24490631.
  8. ↑ Wixler V, Geerts D, Laplantine E, Westhoff D, Smyth N, Aumailley M, Sonnenberg A, Paulsson M (October 2000). "The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes". The Journal of Biological Chemistry. 275 (43): 33669–78. doi:10.1074/jbc.M002519200. PMID 10906324.
  9. ↑ Liliental J, Chang DD (January 1998). "Rack1, a receptor for activated protein kinase C, interacts with integrin beta subunit". The Journal of Biological Chemistry. 273 (4): 2379–83. doi:10.1074/jbc.273.4.2379. PMID 9442085.
  10. ↑ Kotovuori A, Pessa-Morikawa T, Kotovuori P, Nortamo P, Gahmberg CG (June 1999). "ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity". Journal of Immunology. 162 (11): 6613–20. PMID 10352278.
  11. ↑ Lu C, Takagi J, Springer TA (May 2001). "Association of the membrane proximal regions of the alpha and beta subunit cytoplasmic domains constrains an integrin in the inactive state". The Journal of Biological Chemistry. 276 (18): 14642–8. doi:10.1074/jbc.M100600200. PMID 11279101.
  12. ↑ Huang C, Springer TA (August 1995). "A binding interface on the I domain of lymphocyte function-associated antigen-1 (LFA-1) required for specific interaction with intercellular adhesion molecule 1 (ICAM-1)". The Journal of Biological Chemistry. 270 (32): 19008–16. doi:10.1074/jbc.270.32.19008. PMID 7642561.
  13. ↑ Rietzler M, Bittner M, Kolanus W, Schuster A, Holzmann B (October 1998). "The human WD repeat protein WAIT-1 specifically interacts with the cytoplasmic tails of beta7-integrins". The Journal of Biological Chemistry. 273 (42): 27459–66. doi:10.1074/jbc.273.42.27459. PMID 9765275.
  14. ↑ Geiger C, Nagel W, Boehm T, van Kooyk Y, Figdor CG, Kremmer E, Hogg N, Zeitlmann L, Dierks H, Weber KS, Kolanus W (June 2000). "Cytohesin-1 regulates beta-2 integrin-mediated adhesion through both ARF-GEF function and interaction with LFA-1". The EMBO Journal. 19 (11): 2525–36. doi:10.1093/emboj/19.11.2525. PMC 212768. PMID 10835351.

Further reading

  • Bunting M, Harris ES, McIntyre TM, Prescott SM, Zimmerman GA (January 2002). "Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands". Current Opinion in Hematology. 9 (1): 30–5. doi:10.1097/00062752-200201000-00006. PMID 11753075.
  • Roos D, Law SK (2003). "Hematologically important mutations: leukocyte adhesion deficiency". Blood Cells, Molecules & Diseases. 27 (6): 1000–4. doi:10.1006/bcmd.2001.0473. PMID 11831866.
  • Gahmberg CG, Fagerholm S (August 2002). "Activation of leukocyte beta2-integrins". Vox Sanguinis. 83 Suppl 1: 355–8. doi:10.1111/j.1423-0410.2002.tb05333.x. PMID 12617168.
  • Schymeinsky J, Mócsai A, Walzog B (August 2007). "Neutrophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications". Thrombosis and Haemostasis. 98 (2): 262–73. doi:10.1160/th07-02-0156. PMID 17721605.

External links

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