Adhesion and integration

As metazoans become more complex, they develop cells, tissues and organs that are more specialized.

These are often organized into complex three dimensional structures.

For example, this is a diagram of the filtering system, a gomerulus, of a human kidney.

It removes waste products from the blood, while retaining water and proteins.

To produce such structurally and functionally complex multicellular assemblies, cells must interact with one another, both mechanically and chemically.

The mechanical integration of cells into tissues involves cell-cell and cell-extracellular matrix interactions or adhesions.

  
 
 

Cell-cell junctions.

There are number of different cell-cell junctions.

The best understood are those that are distinct and discrete.

In vertebrates, there are four distinct types of cell-cell junctions

  • tight junction
  • adherens junctions
  • desmosomes
  • gap junctions.

Tight junction, also known as zonula occludens, are common in epithelia.

 

Epithelia are the sheets of cells that line various surfaces.

The form a barrier and boundary.

They control the movement of materials.

 

Epithelia are classified based on the shape of the cells that form them, these cells can be flattened as in squamous epithelia, cuboidal or columnar.

Simple epithelia are formed by a single layer of cells, stratified epithelia by multiple cell layers.

 

Epithelia always face either a fluid- or gas-filled space, and they lie on a layer of mesenchymal cells and connective tissue, a basal lamina.

Epithelia provide both mechanical definition and act to control the movement of molecules across the boundaries they defines.

Some epithelia, like the epidermis of the skin, are essentially impermeable.

Others, like the lumenal lining of the gut are selectively and asymmetrically permeable.

  

Tight junctions play a central role in the regulation of permeability in epithelia. A tight junction is composed of strands of integral membrane proteins that seal off the space between adjacent cells.

Tight junctions are localized toward the apical face of the cell, the side that faces the fluid or air.

The number of tight junction strands determines the tigthness of the epithelium, how leaky it is.

The presence of many strands blocks the movement of essentially all molecules through the space between cells, so molecular movements across the epithelium must pass through the cells themselves.

 

 

The strands of the tight junction proteins also restrict the movement of proteins within the plane of the membrane.

Normally, most membrane proteins are free to diffuse within the lipid layer.

Tight junction strands block this movement. Proteins that are localized to either the apical and basolateral domains remain in these domains.

This molecular segregation enables the cell to establish distinct membrane domains.

It establishes an asymmetry to the epithelium and the epithelial cell.

Adherens junctions are located below the region of the tight junctions.

They are based on cadherin-type cell-cell adhesion proteins and their cytoplasmic accessory molecules, the catenins.

Cadherins were identified based on their ability to interact in a homotypic manner.

Cells that express the same type of cadherin bind to one another

  
 

Different cell types express different cadherins . There are epidermal, neuronal, placental, liver, and endothelial cadherins, among others.

Cadherin expression leads to the sorting out of similar cells.

 
 

Adherens junctions are attached to a component of the cytoskeleton, the actin or microfilament system.

This attachment is mediate by the catenins, which means link.

Catenin-like polypeptides have been identified in simple, pre-metazoans such as the slime mold Dictyostelium.

This suggests that the cadherin-catenin cell-cell adhesion system was present in the common ancestor of slime molds and animals

Desmosomes are a second type of cadherin-based junction.

They are build around desmosomal cadherins, known as desmoglein and desmocollin.

Desmosomes anchor a second cytoskeletal filament network, intermediate filaments, to the plasma membrane
 

Intermediate filaments are strong, elastic polymers.

Coupled to the cytoplasmic surface of the desmosome, they form a supracellular network that strengthens tissues, protecting them against mechanical damage.

Mutations can disrupt the assembly or integrity of supracellular intermediate filament networks lead to the weakening of the tissue.

When subject to even mild mechanical stress, the cells within the tissue can be damaged or destroyed.

 
 

In the skin, this produces a particularly severe phenotype - chronic skin blistering.

The cells rip open in response to even mild stress, such as that produced by rubbing against clothing.

Cell-Matrix Junctions

The basal lamina is a network of extracellular molecules.

It can serve as a mechanical support and as a sieve that will exclude proteins but allow small molecules to pass through it.
 
Cells adhere to the basal lamina through junctions analogous to cell-cell junctions.
 

Cells attach to the extracellular matrix molecules through integrin-type membrane protein.

Integrins are heterodimers, composed of an alpha and a beta subunit.

In humans there are over 15 different subunits and over 8 different ß subunits.

Each subunit pair has its own distinctive affinity for particular extracellular matrix molecules.

  
 
 

Most integrin pairs are involved in linking the extracellular matrix to actin filaments at a junction known as a focal contact.

The 6ß4 pair links the extracellular matrix to intermediate filaments at junction known as a hemidesmosome.

 

In addition to their role in matrix adhesion and cytoskeletal anchorage, integrins are involved in two types of signal transduction processes, known as outside-in and inside-out signaling.

In outside-in signaling, the binding of integrins to matrix components leads to integrin clustering in the plasma membrane.

Clustering favors the association of cytoplasmic polypeptides with the integrin's cytoplasmic domain. This in turn leads to a series of intracellular events that include:

  • activation of protein kinases/phosphatases
  • changes in intracellular pH and
  • changes in intracellular [Ca2+]
 

Inside-out signaling signaling occurs when changes within the cell lead to changes in the affinity of the integrin pair for its extracellular targets.

 

Integrin signaling is critical in cellular survival.

When an epithelial cells looses contact with its basal lamina, it will begin the process of apoptosis.

 
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