S377 Chapter 16

Cell adhesion is a property of many cell types which position themselves by attaching to other cells or to the [blank_start]extracellular[blank_end] matrix using adhesion molecules in the [blank_start]plasma membrane.[blank_end]

Some adhesion molecules also [blank_start]transduce[blank_end] signals from the [blank_start]extracellular[blank_end] environment to the cell

Cell migration involves both the interaction of adhesion molecules with elements of the [blank_start]cytoskeleton[blank_end], and the coordinated attachment, [blank_start]movement[blank_end] and detachment of adhesion molecules from the extracellular matrix.

Cell [blank_start]migration[blank_end] is central to the development of eukaryotic organisms, but also occurs during tissue [blank_start]regeneration[blank_end] and repair.

Many cells have the potential for motility. The [blank_start]direction[blank_end] of cell migration is determined by chemotactic signalling molecules.

The slime mould Dictyostelium discoideum and mammalian [blank_start]leukocytes[blank_end] are the best-studied examples of mobile eukaryotic cells. The basic processes of motility are similar in all [blank_start]eukaryotes[blank_end].

If cells are not connected to the basal lamina or other cells as they should be (i.e. They are incorrectly positioned) , CAMs that also act as signalling molecules do not receive the survival signals. This leads to....

Cadherins are adhesion molecules important in

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[blank_start]Avidity[blank_end] is the overall strength of cellular [blank_start]adhesiveness[blank_end], which is determined by the [blank_start]density and distribution[blank_end] of adhesion molecules in a localized region of the plasma membrane, and by the affinity of [blank_start]individual[blank_end] adhesion molecules.

Adhesion molecules allow cells to attach to each other or the [blank_start]substratum[blank_end] or [blank_start]extracellular[blank_end] matrix.

[blank_start]Cadherins[blank_end] mediate cell–cell junctional adhesion via [blank_start]homophilic[blank_end] interactions, and are associated with the [blank_start]cytoskeleton[blank_end] via anchoring proteins called [blank_start]catenins[blank_end].

Cadherins interact with identical cadherins on other cells

[blank_start]Integrins[blank_end] bind to other [blank_start]molecules[blank_end], not other integrins. This is [blank_start]heterophilic[blank_end] binding.

Loss of [blank_start]cadherin[blank_end] function in tumours is associated with [blank_start]malignancy[blank_end], as it means a loss of [blank_start]homologous[blank_end] cell adhesion.

Which of these are integrins present in?

Cadherins bind to [blank_start]cadherins[blank_end]. Integrins bind to [blank_start]proteins[blank_end]. Lectins bind to [blank_start]carbohydrates on glycoproteins[blank_end]. [blank_start]Selectins[blank_end] are a type of lectin.

Adhesion molecules allow cells to attach to each other or the substratum or extracellular matrix.

Cadherins mediate cell–cell junctional adhesion via homophilic interactions, and are associated with the cytoskeleton via anchoring proteins called [blank_start]catenins[blank_end].

Integrins are very important in controlling cell [blank_start]adhesion[blank_end], as their affinity may be modulated by [blank_start]inside-out[blank_end] signalling. The [blank_start]metal ion[blank_end] dependent adhesion site on the [blank_start]I/A domain[blank_end] of integrins can be present in an open or closed form, which determines whether the integrin can bind to its substrate(s).

Different integrins can bind to components of the [blank_start]extracellular matrix[blank_end] or adhesion molecules on [blank_start]other cells[blank_end]. Some integrins also transduce [blank_start]survival signals[blank_end] for anchorage-dependent cells.

[blank_start]Ig superfamily[blank_end] CAMs contain several [blank_start]extracellular Ig[blank_end] domains. By contrast with i[blank_start]ntegrins[blank_end] and c[blank_start]adherins[blank_end], binding of Ig superfamily CAMs to their ligands is independent of [blank_start]Ca2+ (or Mg2+)[blank_end].

Which of these need Ca2+ (or Mg2+) to bind to their ligands?

C[blank_start]ollagen[blank_end], [blank_start]fibronectin[blank_end] and l[blank_start]aminin[blank_end] are important components of the ECM and [blank_start]basal laminae[blank_end], and bind to different [blank_start]β1 integrins[blank_end].

I[blank_start]ntegrins[blank_end], Ig superfamily cell adhesion molecules (Ig superfamily CAMs) and s[blank_start]electins[blank_end] are all involved in [blank_start]leukocyte migration[blank_end] into tissues, each type of molecule having a different function in the process. Selectins bind to [blank_start]carbohydrates on glycoproteins[blank_end] to tether migrating cells, whereas the interaction between integrins on the [blank_start]leukocytes[blank_end] and Ig superfamily CAMs on the [blank_start]endothelial cells[blank_end] allows the leukocyte to migrate through the [blank_start]endothelium[blank_end].

Label the ways cells can change their adhesive properties by changing the avidity of the adhesion molecules.

Cells can regulate the functional activity of their adhesion molecules by changing the surface [blank_start]density[blank_end] or distribution of the molecules ([blank_start]avidity[blank_end]), and/or by modulating their [blank_start]affinity[blank_end]. e.g. the [blank_start]allosteric[blank_end] modulation of [blank_start]integrin[blank_end] affinity

Adhesion molecules tend to cluster in high-[blank_start]avidity[blank_end] patches (which are called ‘[blank_start]focal adhesions[blank_end]’ in cell–matrix interactions).

Adhesion can be rapidly modulated by changing the [blank_start]affinity[blank_end] of the individual adhesion molecules. Alternatively, adhesion can be downregulated by [blank_start]internalizing[blank_end] or shedding adhesion molecules from the [blank_start]cell surface[blank_end].

At the leading edge of the [blank_start]pseudopod[blank_end], [blank_start]F-actin[blank_end] filaments form [blank_start]branched arrays[blank_end]. [blank_start]ARP complexes[blank_end] attach to the side of filaments and add new ones, forming branches. [blank_start]Thymosin[blank_end] inhibits this by [blank_start]sequestering actin[blank_end]. [blank_start]Profilin[blank_end] promotes it by adding actin to the forming branches. The balance between them determines [blank_start]rate of formation[blank_end]. Actin monomers are added to the plus end, as T-form (i.e. [blank_start]Actin-ATP[blank_end]), over time it hydrolyses to D-form (i.e. [blank_start]Actin-ADP[blank_end]). [blank_start]Cofilin[blank_end] binds to [blank_start]D-form[blank_end] and helps to degrade the [blank_start]minus end[blank_end] where most of the D-form is. Some [blank_start]plus ends[blank_end] are capped, which stops further growth. Most plus ends in [blank_start]stationary cells[blank_end] are capped.

Adhesion molecules interact with the cytoskeleton indirectly via anchoring proteins

Which of these is present in the uropod and important in the contraction of the trailing edge?

Extension of pseudopodia involves polymerization, extension and branching of [blank_start]actin[blank_end] filaments at the leading edge of the cell.

Many [blank_start]adhesion molecules[blank_end], including integrins and Ig superfamily CAMs interact with [blank_start]actin filaments[blank_end] via [blank_start]anchoring proteins[blank_end]. Engagement of adhesion molecules with the [blank_start]cytoskeleton[blank_end] depends on the arrangement of the cell and whether the cell has been activated by [blank_start]extracellular signals[blank_end].

The [blank_start]ERM family[blank_end] proteins –e[blank_start]zrin[blank_end], r[blank_start]adixin[blank_end] and m[blank_start]oesin[blank_end] –act as cytoskeletal anchoring proteins for several transmembrane proteins including [blank_start]Ig superfamily CAMs[blank_end]. Following activation, these proteins switch to an [blank_start]open conformation[blank_end], which cross-links the adhesion molecule to [blank_start]actin filaments[blank_end].

α -Actinin, [blank_start]vinculin[blank_end] and talin are involved in cross-linking [blank_start]integrins[blank_end] to [blank_start]filaments[blank_end].

[blank_start]Myosin II[blank_end] interacts with filaments, to maintain the [blank_start]shape[blank_end] of the cell, for moving the cell [blank_start]forward[blank_end] and to move [blank_start]organelles[blank_end].

[blank_start]Chemotactic[blank_end] molecules promote [blank_start]polarization[blank_end] of cells and [blank_start]directional[blank_end] migration. In multicellular animals, many chemotactic molecules act on [blank_start]7-helix[blank_end] transmembrane [blank_start]G protein-coupled[blank_end] receptors.

[blank_start]Chemokines[blank_end] are a large group of chemotactic molecules which control [blank_start]leukocyte[blank_end] migration. They have a [blank_start]glycosaminoglycan (GAG)[blank_end] binding site (GAGs may be located in the extracellular matrix or on the surface of cells), and a [blank_start]chemokine receptor[blank_end] binding site.

Binding of [blank_start]chemotactic[blank_end] molecules to their receptors can lead to the activation of [blank_start]PI 3-kinase[blank_end] and the [blank_start]phosphorylation[blank_end] of membrane lipids, which recruit proteins with [blank_start]pleckstrin homology[blank_end] (PH) domains to the leading edge of the cell and modulate interactions between the [blank_start]actin cytoskeleton[blank_end] and adhesion molecules.

Chemokines and their receptors are not very [blank_start]specific[blank_end]. Many of the receptors will bind several types of ligand and many chemokines will bind to several different receptors. This is called [blank_start]promiscuous binding[blank_end].

Activation of GTPases belonging to the [blank_start]Rho family[blank_end] has global effects on cell morphology, the arrangement of the [blank_start]cytoskeleton[blank_end], and cell adhesion properties. Prenylation of RhoA translocates it to the plasma membrane, where it can be activated by GTP binding and modulate the F-actin network by formation of focal adhesions.

Molecular interactions between the [blank_start]signalling pathways[blank_end] induced by different [blank_start]chemotactic receptors[blank_end] allow cells to regulate their overall patterns of [blank_start]migration[blank_end] within the complex gradients of chemotactic (or repellent) molecules that may be found in vivo .

[blank_start]Slit[blank_end] proteins expressed on the cell surface are [blank_start]repellent[blank_end] proteins that act on [blank_start]Robo receptors[blank_end] and can prevent [blank_start]cell movement[blank_end] into tissues expressing the Slit proteins. Slits and Robos are widely and transiently expressed during [blank_start]development[blank_end], and are still present in the adult in many tissues.

[blank_start]Matrix metalloproteases[blank_end] (MMPs) are secreted by [blank_start]migrating cells[blank_end], which allows them to move through tissues by [blank_start]cleaving molecules[blank_end] of the extracellular matrix.

[blank_start]Metalloprotease disintegrins[blank_end] (ADAMs) interfere with [blank_start]intercellular adhesion[blank_end], and also can facilitate leukocyte [blank_start]motility[blank_end].

MMPs and ADAMs are [blank_start]inhibited[blank_end] by tissue inhibitors of metalloproteases ([blank_start]TIMPs[blank_end]). The balance of the enzymes and inhibitors is important in controlling cell [blank_start]motility[blank_end] and tissue [blank_start]remodelling[blank_end].