Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the
binding of cells with other cells or with the
extracellular matrix (ECM), in a process called cell adhesion. 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. 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.
Structure
CAMs are typically single-pass
transmembrane receptors 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.
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
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
super family of cell adhesion molecules (
IgCAM
IgSF CAMs (Immunoglobulin-like Cell Adhesion Molecules) are cell adhesion molecules that belong to Immunoglobulin superfamily. It is regarded as the most diverse superfamily of CAMs. This family is characterized by their extracellular domains cont ...
s),
Cadherin
Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane protein ...
s,
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.
The Ig-superfamily CAMs and integrins do not depend on Ca
2+ while cadherins and selectins depend on Ca
2+. In addition, integrins participate in cell–matrix interactions, while other CAM families participate in cell–cell interactions.
Calcium-independent
IgSF CAMs
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.
Calcium-dependent
Integrins
Integrins, one of the major classes of receptors within the ECM,
mediates cell–ECM interactions with
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
,
fibrinogen,
fibronectin, and
vitronectin.
Integrins provide essential links between the
extracellular environment and the intracellular signalling pathways, which can play roles in cell behaviours such as
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...
,
differentiation,
survival, and
transcription.
Integrins are
heterodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
ic, as they consist of an alpha and beta subunit.
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.
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 ). 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. 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. However, extracellular Ca2+ binding may exert different effects depending on the type of integrin and the cation concentration.
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
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
;
Agonists such as
thrombin or
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
trigger the integrin into its high affinity state, which causes increased
fibrinogen binding, causing platelet aggregation.
Cadherins
The
cadherin
Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane protein ...
s are homophilic -dependent
glycoproteins.
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
Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. Be ...
for the formation of the
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical E ...
,
endoderm
Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gast ...
, and
ectoderm
The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from t ...
. 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 binding between the ECDs are necessary for
cell adhesion
Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indir ...
. The cytoplasmic domain has specific regions where catenin proteins bind.
Selectins
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
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
), 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.
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. 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. 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.
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.
See also
*
Cell membrane
*
Cell migration
*
Immunological synapse
*
Trogocytosis
Trogocytosis ( gr, trogo; ''gnaw'') is when a cell nibbles another cell. It is a process whereby lymphocytes (B cell, B, T cell, T and Natural killer cell, NK cell (biology), cells) conjugated to antigen-presenting cells extract Cell surface molec ...
References
{{Cell adhesion molecules
Cell adhesion molecules
Single-pass transmembrane proteins