Cell adhesion molecule

CAMs are typically single-pass transmembrane receptors {{cite web |url=https://membranome.org/protein_classes/3 |title=Single-pass transmembrane adhesion and structural proteins |author= |website=membranome |publisher=College of Pharmacy, University of Michigan |access-date= October 20, 2018 }}in Membranome database 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.{{cite journal | vauthors = Chothia C, Jones EY | title = The molecular structure of cell adhesion molecules | journal = Annu. Rev. Biochem. | volume = 66 | pages = 823–62 | date = 1997 | pmid = 9242926 | doi = 10.1146/annurev.biochem.66.1.823 | s2cid = 6298053 }} 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.

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.{{cite journal |vauthors=Brackenbury R, Rutishauser U, Edelman GM |title=Distinct calcium-independent and calcium-dependent adhesion systems of chicken embryo cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=78 |issue=1 |pages=387–91 |date=January 1981 |pmid=6165990 |pmc=319058 |doi= 10.1073/pnas.78.1.387|bibcode=1981PNAS...78..387B |doi-access=free }} 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.{{Cite journal|last1=Lodish|first1=Harvey|last2=Berk|first2=Arnold|last3=Zipursky|first3=S. Lawrence|last4=Matsudaira|first4=Paul|last5=Baltimore|first5=David|last6=Darnell|first6=James|date=2000-01-01|title=Cell–Cell Adhesion and Communication|url=https://www.ncbi.nlm.nih.gov/books/NBK21599/|language=en}}

{{main|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|date=March 2021}}

{{main|Integrin}}

Integrins, one of the major classes of receptors within the ECM,{{Citation|title=The Role of Integrins during Vertebrae Development|year=1995|author1=Brown, K|author2=Yamada, K|journal=Developmental Biology|volume=6|issue=2|pages=69–77|doi=10.1016/s1044-5781(06)80016-2}} mediate cell–ECM interactions with collagen, fibrinogen, fibronectin, and vitronectin.{{cite journal|date=October 2006|title=Integrin ligands at a glance|journal=J. Cell Sci.|volume=119|issue=Pt 19|pages=3901–3|doi=10.1242/jcs.03098|pmc=3380273|pmid=16988024|vauthors=Humphries JD, Byron A, Humphries MJ}} 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.{{cite book|title=Integrin, Adhesion/cell-matrix|last=Schnapp|first=L|publisher=Elsevier|year=2006|location=Seattle}}

Integrins are heterodimeric, as they consist of an alpha and beta subunit.{{cite journal|date=December 2005|title=Get a grip: integrins in cell-biomaterial interactions|journal=Biomaterials|volume=26|issue=36|pages=7525–9|doi=10.1016/j.biomaterials.2005.05.029|pmid=16002137|author=García AJ}} There are currently 18 alpha subunits and 8 beta subunits, which combine to make up 24 different integrin combinations. Within each of the alpha and beta subunits there is a large extracellular domain, a transmembrane domain and a short cytoplasmic domain.{{cite journal|date=March 1995|title=Integrins and reproduction|journal=Eur J Obstet Gynecol Reprod Biol|volume=59|issue=1|pages=71–81|doi=10.1016/0028-2243(94)01987-I|pmid=7781865|author=Vinatier D|doi-access=free}} 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 {{Cite journal|last=Xiong|first=J.-P.|date=2002-04-05|title=Crystal Structure of the Extracellular Segment of Integrin alpha Vbeta 3 in Complex with an Arg-Gly-Asp Ligand|url=https://www.science.org/doi/10.1126/science.1069040|journal=Science|volume=296|issue=5565|pages=151–155|doi=10.1126/science.1069040|pmid=11884718|bibcode=2002Sci...296..151X|s2cid=24339086|url-access=subscription}}). 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.{{Cite journal|last1=Dai|first1=Aguang|last2=Ye|first2=Feng|last3=Taylor|first3=Dianne W.|last4=Hu|first4=Guiqing|last5=Ginsberg|first5=Mark H.|last6=Taylor|first6=Kenneth A.|date=November 2015|title=The Structure of a Full-length Membrane-embedded Integrin Bound to a Physiological Ligand|url= |journal=Journal of Biological Chemistry|language=en|volume=290|issue=45|pages=27168–27175|doi=10.1074/jbc.M115.682377|pmc=4646401|pmid=26391523|doi-access=free}} 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.{{Cite journal|last1=Tharmalingam|first1=Sujeenthar|last2=Hampson|first2=David R.|date=2016|title=The Calcium-Sensing Receptor and Integrins in Cellular Differentiation and Migration|journal=Frontiers in Physiology|language=English|volume=7|page=190|doi=10.3389/fphys.2016.00190|issn=1664-042X|pmc=4880553|pmid=27303307|doi-access=free}} However, extracellular Ca2+ binding may exert different effects depending on the type of integrin and the cation concentration.{{Cite journal|last1=Zhang|first1=Kun|last2=Chen|first2=JianFeng|date=January 2012|title=The regulation of integrin function by divalent cations|url= |journal=Cell Adhesion & Migration|language=en|volume=6|issue=1|pages=20–29|doi=10.4161/cam.18702|issn=1933-6918|pmc=3364134|pmid=22647937}}

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.

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

{{main|Cadherin}}

The cadherins are homophilic {{chem|link=Calcium in biology|Ca|2+}}-dependent glycoproteins.{{cite journal |vauthors=Buxton RS, Magee AI |title=Structure and interactions of desmosomal and other cadherins |journal=Semin. Cell Biol. |volume=3 |issue=3 |pages=157–67 |date=June 1992 |pmid=1623205 |doi=10.1016/s1043-4682(10)80012-1}} 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.

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). Many cell types express combinations of cadherin types.

The extracellular domain has major repeats called extracellular cadherin domains (ECD). Sequences involved in {{chem|Ca|2+}} binding between the ECDs are necessary for cell adhesion. The cytoplasmic domain has specific regions where catenin proteins bind.{{Cite journal | title = The Function of E-Cadherin in Stem Cell Pluripotency and Self-Renewal | year = 2011 | journal = Genes | pages = 229–259 | volume = 2 | issue = 1 | doi = 10.3390/genes2010229 | pmid = 24710147 | pmc = 3924836 | last1 = Soncin | first1 = F. | first2 = M.C. |last2=Ward | doi-access = free }}

{{main|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.{{cite journal | vauthors = Cavallaro U, Christofori G | title = Cell adhesion and signalling by cadherins and Ig-CAMs in cancer | journal = Nat. Rev. Cancer | volume = 4 | issue = 2 | pages = 118–32 | date = February 2004 | pmid = 14964308 | doi = 10.1038/nrc1276 | s2cid = 18383054 |issn = 1474-1768 }}

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.{{cite journal|last1=Berg|first1=Ellen Lakey|last2=Goldstein|first2=Leslie A.|last3=Jimla|first3=Mark A.|last4=Nakache|first4=Maurice|last5=Picker|first5=Louis J.|last6=Streeter|first6=Philip R.|last7=Wu|first7=Nora W.|last8=Zhou|first8=David|last9=Butcher|first9=Eugene C.|title=Homing Receptors and Vascular Addressins: Cell Adhesion Molecules that Direct Lymphocyte Traffic|journal=Immunological Reviews|date=1 April 1989|volume=108|issue=1|pages=5–18|doi=10.1111/j.1600-065X.1989.tb00010.x|pmid=2670744|s2cid=37831094|language=en|issn=1600-065X}} 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.{{cite journal|last1=Picker|first1=Louis|title=Control of lymphocyte homing|journal=Current Opinion in Immunology|date=1 June 1994|volume=6|issue=3|pages=394–406|doi=10.1016/0952-7915(94)90118-X|pmid=7917107|language=en|issn=0952-7915}} 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.{{cite journal | vauthors = Gorfu G, Rivera-Nieves J, Ley K | title = Role of beta7 integrins in intestinal lymphocyte homing and retention | journal = Curr. Mol. Med. | volume = 9 | issue = 7 | pages = 836–50 | date = September 2009 | pmid = 19860663 | pmc = 2770881 | issn = 1566-5240| doi = 10.2174/156652409789105525 }} 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.{{cite book|last1=Andreoli|first1=Thomas E.|last2=Brown|first2=A. M.|last3=Fambrough|first3=D. M.|last4=Hoffman|first4=Joseph F.|last5=Schultz|first5=Stanley G.|last6=Welsh|first6=Michael J.|title = Molecular Biology of Membrane Transport Disorders|date=2013|publisher=Springer Science & Business Media|isbn = 978-1-4613-1143-0|url = https://books.google.com/books?id=GvTjBwAAQBAJ&pg=PA34|language=en}}

{{Portal|Biology}}

{{Commons category|Cell adhesion molecules}}

• Cell membrane
• Cell migration
• Immunological synapse
• Trogocytosis

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{{Cell adhesion molecules}}

Category:Cell adhesion molecules

Category:Single-pass transmembrane proteins