Adhesion Molecules

("Eschew Obfuscation")

Introduction

Adhesion molecules - one of the fastest growing and most confusing topics in cell biology today. Their clinical relevance is immense, especially concerning the body's local immune response to what it sees as an attack. This can be summarised by saying that the vascular endothelium largely determines the nature and magnitude of the local immune response! Adhesion molecules are however much more important than this. They appear to play a role in cellular interactions throughout the body, and are even more important in development of the organism.

Basic ideas

Nomenclature of cellular adhesion molecules (CAM) is varied and confusing. The following points may clear things up a bit:

CAMs are fascinating for several reasons. One is the relatively low affinity they have for their ligands. Initially one wonders why the 'glue' is so 'unsticky', until you realise that this weak binding is actually an advantage - the degree of stickiness can be regulated by the number of CAMs expressed (or the density of CAM ligands on the target), and CAMs also do not have to grab hold of the target like grim death - they can be used (for example) to slow down a moving leukocyte! Very cunning.

The four main types of cell-surface adhesion molecules

CAMs fall into two broad groups, the integrins which can bind molecules in the intercellular matrix as well as sometimes binding to other cells, and a second group that binds to other cells more-or less exclusively. There are three categories in the latter group, the cadherins, the immunoglobulin superfamily, and the selectins. The cadherins and the selectins need calcium ions to bind their targets, while the immunoglobulin superfamily don't.

integrins

cadherins

Ig-superfamily

selectins

(bind matrix or cells) (bind cells)
over 20, heterodimers,
alpha & beta subunits
(16[+?] alpha, 8 beta)		 homophilic, Ca++ required, common progenitor No Ca++ needed lectins
e.g. alpha1-beta1 integrin binds type IV collagen e.g. cadherin-E
acts as a universal intercellular epithelial 'glue'		 e.g. NCAMs in neural tissue (homophilic)
also VCAM1 (heterophilic)		 e.g. P-selectin (heterophilic)

The integrins

There are numerous integrins, each composed of an alpha and beta subunit. Traditionally, they have been classified according to the type of beta subunit (beta 1 to beta 8) but it has now been realised that the alpha subunit is just as important in some instances. For example, alpha-4 integrins bind VCAM-1 and fibronectin, whether they are alpha-4 beta-1 or alpha-4 beta-7. Monoclonal antibodies that block the alpha-4 subunit interfere with this binding, and have been shown to interfere with recruitment of eosinophils and T-cells in the inflamed lung. [ Lobb et al, Eur Respir J Suppl Aug 1996 22 104S-108Spp, also Foster CA, J Allergy Clin Immunol Dec 1996 98(6.2) S270-7pp ]

Classifying in the traditional way (by beta subunit) we get the following families

Integrins on cell surfaces often need to be activated before they will bind their ligand. The alpha IIb beta 3 integrin on platelets, for example, is only able to bind fibrinogen, Von Willebrand factor and other blood components when the platelet itself is activated.

What do integrins bind to? Initially it was thought that a particular sequence of amino acids is present in the ligand that binds the integrin. The first one identified was Arg-Gly-Asp, abbreviated to "RGD". Later, a similar sequence called LDV was discovered, and recently it has been established that all of the immunoglobulin superfamily that bind integrins use LDV-like sequences. For the record these are:
Integrins do not only bind the cell to their ligands, but serve to transduce the passage of information between the cell and its environment in both directions. Integrin binding probably alters the mechanical structure of the cytoskeleton. Cross-linking and/or clustering of integrins on the cell membrane is also apparently vital for a full biological response to integrin binding! Integrins are probably also vital in permitting the cell to sense its shape, linking the cytoskeleton to the exterior of the cell!

Cadherins

Cadherins are vital for tissue differentiation. E-, P- and N-cadherins are most widely expressed, although there are over thirty, with a wide variety being expressed in the brain in particular. Cadherins are generally homophilic. All cadherins appear to have evolved from the same predecessor. E-cadherin is the intercellular glue that holds together most epithelia. It is also known as uvomorulin. During embryonic development, there is a complex sequence of expression and loss of various cadherins, as cells migrate to their rightful places. N-cadherins are found not only in nervous tissue, but also in the lungs, the heart and the eye lens, and P-cadherins are found in trophoblast.

The Immunoglobulin superfamily

This comprises a vast array of molecules, including:

The role of some of these molecules is discussed below in the section on leukocyte migration.

Selectins

These are also intimately involved in leukocyte margination and movement into the tissues. P-selectin is particularly important here. It too is discussed below. The ligand for P-selectin is a specific oligosaccharide sequence prevalent on leukocytes, called the sialyl Lewis-x anigen. P-selectin is found on platelets and endothelium, L-selectin on lymphocytes, and E-selectin on endothelium.

A practical example: Leukocyte movement into tissues

Leukocyte extravasation is intimately associated with adhesion molecule interactions. This movement occurs in several phases:

A List of Synonyms

CAM Binds to..
alpha4beta1 integrin = VLA-4 = CD49d/CD29 VCAM, FN=CS-1, PP-HEV
alpha5beta1 integrin = VLA-5 = CD49e/CD29 FN(RGD)
alpha6beta1 integrin = VLA-6 = CD49f/CD29 LM
alphaLbeta2 integrin = LFA-1 = CD11a/CD18 ICAM-1, ICAM-2
alphaMbeta2 integrin = MAC-1 = CR3 = CD11b/CD18)ICAM-1, C3bi, FN, FX
alphaXbeta2 integrin = p150,95 = CR14receptor FN, ?C3bi
alpha4beta7 integrin = LPAM-1 = CD49d/CD-MadCAM-1, VCAM

LFA-2 = CD2 LFA-3
LFA-3 = CD58 LFA-2
VCAM = CD106 VLA-4 / alpha 4 beta 1
ICAM-1 = CD54 CD II ,CD18 / alpha L beta 2 , alpha M beta 2
ICAM-2 = CD102 alpha L beta 2
PE-CAM-1 = CD31
CD36 = "leukocyte differentiation antigen"oxidised LDL, long chain fatty acids,..
MAdCAM-1

E-selectin = CD62E = ELAM-1 sialyated mucinlike molecules
P-selectin = CD62P = GMP-140 = PADGEM P-selectin glycoprotein ligand1=PSGL-1
L-selectin = CD62L = LAM-1 = Mel-14 Glycosylated mucinlike molecules: Glycam-1,CD34,MadCAM-1

Cadherin E = uvomorulin homophilic
Cadherin P homophilic
Cadherin N homophilic



References

The molecular biological and medical literature is replete with references. Some are mentioned above in the text. We liked:

Date of First Publication: 1999 Date of Last Update: 2006/10/28Web page author: Click here