As in figure 2. The MIDAS (metal-ion-dependent adhesive site)

As heterodimeric transmembrane receptor proteins present
on the cell membrane, integrins have key regulatory roles in cellular motility
and invasion. Integrins are present on all cells of the body with the exception
of erythrocytes (Arnaout, 2016). Mammalian integrins include the ?2 subfamily;
?L (CD11a), ?D (CD11d), ?X (CD11c), ?M (CD11b)
which are integrins that have an essential role in the immune system
(Arnaout, 2016).

A
total of 24 structures made of different combinations of 18 ? and 8 ? subunits
form integrins that are able to attach cells to cell ligands and the
extracellular matrix (Das et al., 2018).
Integrins are the main receptor proteins on cells used to respond and bind to
the extracellular matrix and other cells (Alberts et al., 2002). The glycoprotein subunits ? and ? are noncovalently
associated; shown in figure 1 (Alberts et
al., 2002).

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The structure of the ?2?L
or LFA1 integrin expressed in leukocytes is demonstrated in figure 2. The
extracellular binding site for ligands is the aI domain; indicated in red in
figure 2. The MIDAS (metal-ion-dependent adhesive site) found in the ?1 domain
indicated in purple on figure 2 is important for the ligand binding of protein
and metal ions (Das et al., 2018).

Plasma proteins or
counter transmembrane receptors such as intercellular adhesion molecules (ICAMS)
are ligands for ?2?L. These are found on the surface of other cells have
a role in facilitating processes such as migration within tissues and the
innate and adaptive immune responses (Das et
al., 2018). This importance is demonstrated in studies where the impairment
of the ? subunit, dramatically influences leukocyte recruitment. Similarly,
with a compromised ? subunit leukocyte adhesion deficiency results, leading to compromised
inflammatory responses and so, life-threatening recurrent infections.

As a constituent of complement
factors CD11c and CD18, the ?2?X integrin has a role as a
receptor for heparin oligomers. This is Mg2+ dependant. Leukocyte mediated
responses enabled by this integrin family permit the release of heparin from
granular storage molecules within connective tissue where mast cells reside.
The ?2?X heparin interaction has a role in inflammation. For example,
heparin produced is able to interfere with the binding of IC3b complement
fragment and ?XI (Das et al., 2018). Different
conformations are implemented upon interaction with the ligand. This includes when
interacting with heparin which results in further communication between the
integrin and KIM127 antibody which in turn promotes CD18-dependant adhesion
(Stephans et al., 1995). The location
of this change of the ?2?X integrin is at the calf-1 shown on figure
1.

The integrin ?2?D has a role in promoting
inflammatory macrophages (Yakubenko et
al., 2009). When in low quantities this integrin is thought to play a role
in supporting cell migration. Similarly, the ?2?M integrin
has a role in inflammation and mediating leukocyte adhesion as the ?M
manages fibrinogen binding. The MIDAS element present is made up of 5 sites,
assigning sites to the divalent cation and ligands that bind. There is also
recognition of ?-glucan carbohydrate structures and mannose by this particular
integrin (Forsyth et al., 2001).

?2
integrins are activated by phosphorylation. Integrin molecules are switched to
an active composition from a folded inactive composition upon binding. This is
triggered through extracellular matrix-integrin binding. Activation can also
occur as a result of intracellular proteins connecting the integrin to the
cytoskeleton. (Alberts et al., 2002).

Following these changes, a cascade of
events is activated; shown in figure 4. The proteins talin and kindlins are
essential in the activation of integrins. Interaction of talin-H with the
cytoplasmic tails, for example (Das et al.,
2014). Talin binding can also depend on other factors. For instance, in the
presence of phospholipids some integrins binding affinity greatly increases
indicating the important role of appropriate talin-integrin binding (Kalli et al., 2010). Higher affinity of talin-H
is seen in integrin groups such as the ?2 family indicating the need for quick
and effective activation, particularly important considering their influence in
the immune system in the production of adaptive and innate immune responses,
for example (Das et al., 2014). Binding
of the talin-F3 occurs when this domain identifies two areas of the ?
cytoplasmic tails, one of which is on the NPxY/F motif. These motifs are found
in the middle of most ? cytoplasmic tails. This reaction results in disjoining
of the ? and ? subunits throughout, and extends into the membrane. This binding
is vital as it leads to the recruitment of further molecules until for
instance, the eventual step of Arp 2/3 and resulting effects on the actin
cytoskeleton with actin. This stimulates and enables cellular motility (Das et al., 2014). Cellular motility
enabling epithelial-mesenchymal transitions (EMT) for instance. For example, expression
of the ?V?6 integrin is associated with EMT. This particular integrin is found
in epithelial tissues suffering inflammation or undergoing the process of wound
healing but also invasive edge carcinomas. The EMT process is a key step in
cancer progression, with movement through the basal membrane, invasion and
intravasation enabling change from a cancer in-situ to metastasis.

Integrins are crucial components with an influence in
cancer progression. Tumour interactions with leukocytes which involve these
integrins contribute to the formation of metastatic lesions and cancer cell
adhesion, such an interaction is demonstrated in figure 5. For example, heparin
which interacts with the ?2?X integrins has been shown to have a
good impact on patient survival. Also, there are some studies to suggest
heparin can interfere with leukocyte recruitment and binding to the endothelium.
Preclinical studies have demonstrated heparin’s anti-metastatic actions in
various animal models and its role as a cell adhesion inhibitor. Also noted is
the role of integrins within the metastatic cascade (Bendas & Borsig,
2012).

In conclusion, although not always directly,
integrins have a key place in the invasion and motility abilities of cells and
underpin various systems including the adaptive and innate immune system. A
link is also present between integrin actions and cancer and metastasis.