Cell adhesion molecules (CAMs) are a subset of cell surface proteins[1] that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion.[2] In essence, CAMs help cells stick to each other and to their surroundings. CAMs are crucial components in maintaining tissue structure and function. In fully developed animals, these molecules play an integral role in generating force and movement and consequently ensuring that organs are able to execute their functions normally.[3] In addition to serving as "molecular glue", CAMs play important roles in the cellular mechanisms of growth, contact inhibition, and apoptosis. Aberrant expression of CAMs may result in a wide range of pathologies, ranging from frostbite to cancer.[4]

Structure

CAMs are typically single-pass transmembrane receptors [5] and are composed of three conserved domains: an intracellular domain that interacts with the cytoskeleton, a transmembrane domain, and an extracellular domain. These proteins can interact in several different ways.[6] The first method is through homophilic binding, where CAMs bind with the same CAMs. They are also capable of heterophilic binding, meaning a CAM on one cell will bind with different CAMs on another cell.

Families of CAMs

There are four major superfamilies or groups of CAMs: the immunoglobulin super family of cell adhesion molecules (IgCAMs), Cadherins, Integrins, and the Superfamily of C-type of lectin-like domains proteins (CTLDs). Proteoglycans are also considered to be a class of CAMs.

One classification system involves the distinction between calcium-independent CAMs and calcium-dependent CAMs.[7] The Ig-superfamily CAMs do not depend on Ca2+ while integrins, cadherins and selectins depend on Ca2+. In addition, integrins participate in cell–matrix interactions, while other CAM families participate in cell–cell interactions.[8]

Calcium-independent

IgSF CAMs

Main article: IgSF CAM

Immunoglobulin superfamily CAMs (IgSF CAMs) is regarded as the most diverse superfamily of CAMs. This family is characterized by their extracellular domains containing Ig-like domains. The Ig domains are then followed by Fibronectin type III domain repeats and IgSFs are anchored to the membrane by a GPI moiety. This family is involved in both homophilic or heterophilic binding and has the ability to bind integrins or different IgSF CAMs.[citation needed]

Calcium-dependent

Integrins

Main article: Integrin

Integrins, one of the major classes of receptors within the ECM,[9] mediate cell–ECM interactions with collagen, fibrinogen, fibronectin, and vitronectin.[10] Integrins provide essential links between the extracellular environment and the intracellular signalling pathways, which can play roles in cell behaviours such as apoptosis, differentiation, survival, and transcription.[11]

Integrins are heterodimeric, as they consist of an alpha and beta subunit.[12] There are currently 18 alpha subunits and 8 beta subunits, which combine to make up 24 different integrin combinations.[10] Within each of the alpha and beta subunits there is a large extracellular domain, a transmembrane domain and a short cytoplasmic domain.[13] The extracellular domain is where the ligand binds through the use of divalent cations. The integrins contain multiple divalent cation binding sites in the extracellular domain [14]). The integrin cation binding sites can be occupied by Ca2+ or by Mn2+ ions. Cations are necessary but not sufficient for integrins to convert from the inactive bent conformation into the active extended conformation. Both the presence of cations bound to the multiple cation binding sites is required, along with the direct physical association with ECM ligands for integrins to attain the extended structure and concomitant activation.[15] Thus, rise in extracellular Ca2+ ions may serve to prime the integrin heterodimer. The release of intracellular Ca2+ have been shown to be important for integrin inside-out activation.[16] However, extracellular Ca2+ binding may exert different effects depending on the type of integrin and the cation concentration.[17] Integrins regulate their activity within the body by changing conformation. Most exist at rest in a low affinity state, which can be altered to high affinity through an external agonist which causes a conformational change within the integrin, increasing their affinity.[11]

An example of this is the aggregation of platelets;[11] Agonists such as thrombin or collagen trigger the integrin into its high affinity state, which causes increased fibrinogen binding, causing platelet aggregation.

Cadherins

Main article: Cadherin

The cadherins are homophilic Ca2+
-dependent glycoproteins.[18] The classic cadherins (E-, N- and P-) are concentrated at the intermediate cell junctions, which link to the actin filament network through specific linking proteins called catenins.[18]

Cadherins are notable in embryonic development. For example, cadherins are crucial in gastrulation for the formation of the mesoderm, endoderm, and ectoderm. Cadherins also contribute significantly to the development of the nervous system. The distinct temporal and spatial localization of cadherins implicates these molecules as major players in the process of synaptic stabilization. Each cadherin exhibits a unique pattern of tissue distribution that is carefully controlled by calcium. The diverse family of cadherins include epithelial (E-cadherins), placental (P-cadherins), neural (N-cadherins), retinal (R-cadherins), brain (B-cadherins and T-cadherins), and muscle (M-cadherins).[18] Many cell types express combinations of cadherin types.

The extracellular domain has major repeats called extracellular cadherin domains (ECD). Sequences involved in Ca2+
 binding between the ECDs are necessary for cell adhesion. The cytoplasmic domain has specific regions where catenin proteins bind.[19]

Selectins

Main article: Selectin

The selectins are a family of heterophilic CAMs that are dependent on fucosylated carbohydrates, e.g., mucins for binding. The three family members are E-selectin (endothelial), L-selectin (leukocyte), and P-selectin (platelet). The best-characterized ligand for the three selectins is P-selectin glycoprotein ligand-1 (PSGL-1), which is a mucin-type glycoprotein expressed on all white blood cells. Selectins have been implicated in several roles but they are especially important in the immune system by helping white blood cell homing and trafficking.[20]

Biological function of CAMs

The variety in CAMs leads to diverse functionality of these proteins in the biological setting. One of the CAMS that are particularly important in the lymphocyte homing is addressin.[21] Lymphocyte homing is a key process occurring in a strong immune system. It controls the process of circulating lymphocytes adhering to particular regions and organs of the body.[22] The process is highly regulated by cell adhesion molecules, particularly, the addressin also known as MADCAM1. This antigen is known for its role in tissue-specific adhesion of lymphocytes to high endothelium venules.[23] Through these interactions they play a crucial role in orchestrating circulating lymphocytes.

CAM function in cancer metastasis, inflammation, and thrombosis makes it a viable therapeutic target that is currently being considered. For example, they block the metastatic cancer cells' ability to extravasate and home to secondary sites. This has been successfully demonstrated in metastatic melanoma that hones to the lungs. In mice, when antibodies directed against CAMs in the lung endothelium were used as treatment there was a significant reduction in the number of metastatic sites.[24]

See also

Wikimedia Commons has media related to Cell adhesion molecules.

References

  1. ^ Cell+Adhesion+Molecules at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  2. ^ Chothia, C.; Jones, E. Y. (1997). "The molecular structure of cell adhesion molecules". Annual Review of Biochemistry. 66: 823–862. doi:10.1146/annurev.biochem.66.1.823. ISSN 0066-4154. PMID 9242926.
  3. ^ Gumbiner, B. M. (1996-02-09). "Cell adhesion: the molecular basis of tissue architecture and morphogenesis". Cell. 84 (3): 345–357. doi:10.1016/s0092-8674(00)81279-9. ISSN 0092-8674. PMID 8608588.
  4. ^ Korthuis RJ, Anderson DC, Granger DN (March 1994). "Role of neutrophil-endothelial cell adhesion in inflammatory disorders". J Crit Care. 9 (1): 47–71. doi:10.1016/0883-9441(94)90032-9. ISSN 0883-9441. PMID 8199653.
  5. ^ "Single-pass transmembrane adhesion and structural proteins". membranome. College of Pharmacy, University of Michigan. Retrieved October 20, 2018.in Membranome database
  6. ^ Chothia C, Jones EY (1997). "The molecular structure of cell adhesion molecules". Annu. Rev. Biochem. 66: 823–62. doi:10.1146/annurev.biochem.66.1.823. PMID 9242926. S2CID 6298053.
  7. ^ Brackenbury R, Rutishauser U, Edelman GM (January 1981). "Distinct calcium-independent and calcium-dependent adhesion systems of chicken embryo cells". Proc. Natl. Acad. Sci. U.S.A. 78 (1): 387–91. Bibcode:1981PNAS...78..387B. doi:10.1073/pnas.78.1.387. PMC 319058. PMID 6165990.
  8. ^ Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James (2000-01-01). "Cell–Cell Adhesion and Communication". ((cite journal)): Cite journal requires |journal= (help)
  9. ^ Brown, K; Yamada, K (1995), "The Role of Integrins during Vertebrae Development", Developmental Biology, 6 (2): 69–77, doi:10.1016/s1044-5781(06)80016-2
  10. ^ a b Humphries JD, Byron A, Humphries MJ (October 2006). "Integrin ligands at a glance". J. Cell Sci. 119 (Pt 19): 3901–3. doi:10.1242/jcs.03098. PMC 3380273. PMID 16988024.
  11. ^ a b c Schnapp, L (2006). Integrin, Adhesion/cell-matrix. Seattle: Elsevier.
  12. ^ García AJ (December 2005). "Get a grip: integrins in cell-biomaterial interactions". Biomaterials. 26 (36): 7525–9. doi:10.1016/j.biomaterials.2005.05.029. PMID 16002137.
  13. ^ Vinatier D (March 1995). "Integrins and reproduction". Eur J Obstet Gynecol Reprod Biol. 59 (1): 71–81. doi:10.1016/0028-2243(94)01987-I. PMID 7781865.
  14. ^ Xiong, J.-P. (2002-04-05). "Crystal Structure of the Extracellular Segment of Integrin alpha Vbeta 3 in Complex with an Arg-Gly-Asp Ligand". Science. 296 (5565): 151–155. Bibcode:2002Sci...296..151X. doi:10.1126/science.1069040. PMID 11884718. S2CID 24339086.
  15. ^ Dai, Aguang; Ye, Feng; Taylor, Dianne W.; Hu, Guiqing; Ginsberg, Mark H.; Taylor, Kenneth A. (November 2015). "The Structure of a Full-length Membrane-embedded Integrin Bound to a Physiological Ligand". Journal of Biological Chemistry. 290 (45): 27168–27175. doi:10.1074/jbc.M115.682377. PMC 4646401. PMID 26391523.
  16. ^ Tharmalingam, Sujeenthar; Hampson, David R. (2016). "The Calcium-Sensing Receptor and Integrins in Cellular Differentiation and Migration". Frontiers in Physiology. 7: 190. doi:10.3389/fphys.2016.00190. ISSN 1664-042X. PMC 4880553. PMID 27303307.
  17. ^ Zhang, Kun; Chen, JianFeng (January 2012). "The regulation of integrin function by divalent cations". Cell Adhesion & Migration. 6 (1): 20–29. doi:10.4161/cam.18702. ISSN 1933-6918. PMC 3364134. PMID 22647937.
  18. ^ a b c Buxton RS, Magee AI (June 1992). "Structure and interactions of desmosomal and other cadherins". Semin. Cell Biol. 3 (3): 157–67. doi:10.1016/s1043-4682(10)80012-1. PMID 1623205.
  19. ^ Soncin, F.; Ward, M.C. (2011). "The Function of E-Cadherin in Stem Cell Pluripotency and Self-Renewal". Genes. 2 (1): 229–259. doi:10.3390/genes2010229. PMC 3924836. PMID 24710147.
  20. ^ Cavallaro U, Christofori G (February 2004). "Cell adhesion and signalling by cadherins and Ig-CAMs in cancer". Nat. Rev. Cancer. 4 (2): 118–32. doi:10.1038/nrc1276. ISSN 1474-1768. PMID 14964308. S2CID 18383054.
  21. ^ Berg, Ellen Lakey; Goldstein, Leslie A.; Jimla, Mark A.; Nakache, Maurice; Picker, Louis J.; Streeter, Philip R.; Wu, Nora W.; Zhou, David; Butcher, Eugene C. (1 April 1989). "Homing Receptors and Vascular Addressins: Cell Adhesion Molecules that Direct Lymphocyte Traffic". Immunological Reviews. 108 (1): 5–18. doi:10.1111/j.1600-065X.1989.tb00010.x. ISSN 1600-065X. PMID 2670744. S2CID 37831094.
  22. ^ Picker, Louis (1 June 1994). "Control of lymphocyte homing". Current Opinion in Immunology. 6 (3): 394–406. doi:10.1016/0952-7915(94)90118-X. ISSN 0952-7915. PMID 7917107.
  23. ^ Gorfu G, Rivera-Nieves J, Ley K (September 2009). "Role of beta7 integrins in intestinal lymphocyte homing and retention". Curr. Mol. Med. 9 (7): 836–50. doi:10.2174/156652409789105525. ISSN 1566-5240. PMC 2770881. PMID 19860663.
  24. ^ Andreoli, Thomas E.; Brown, A. M.; Fambrough, D. M.; Hoffman, Joseph F.; Schultz, Stanley G.; Welsh, Michael J. (2013). Molecular Biology of Membrane Transport Disorders. Springer Science & Business Media. ISBN 978-1-4613-1143-0.
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