PHCL 582

Adhesion Molecules

Jan 23, 2006

Adhesion Molecules
.
Contents

Introduction
Ig superfamily CAMs
Integrins
Cadherins
Selectins
References

Introduction
Cell surface adhesion molecules play vital roles in numerous cellular processes. Some of these
include: cell growth, differentiation, embryogenesis, immune cell transmigration and response,
and cancer metastasis. Adhesion molecules are also capable of transmitting information from the
extracellular matrix to the cell. There are four major families of cell adhesion molecules. These
are the immunoglobulin (Ig) superfamily cell adhesion molecules (CAMs), integrins, cadherins,
and selectins.1-4

Ig superfamily CAMs
The Ig superfamily CAMs are calcium-independent transmembrane glycoproteins. 2-4 Members of
the Ig superfamily include the intercellular adhesion molecules (ICAMs), vascular-cell adhesion
molecule (VCAM-1), platelet-endothelial-cell adhesion molecule (PECAM-1), and neural-cell
adhesion molecule (NCAM). Each Ig superfamily CAM has an extracellular domain, which
contains several Ig-like intrachain disulfide-bonded loops with conserved cysteine residues, a
transmembrane domain, and an intracellular domain that interacts with the cytoskeleton.
Typically, they bind integrins or other Ig superfamily CAMs. The neuronal CAMs have been
implicated in neuronal patterning. Endothelial CAMs play an important role in immune response
and inflammation.

Integrins
Integrins are non-covalently linked heterodimers of alpha () and beta () subunits.1, 2, 4-8 They are
transmembrane proteins that are constitutively expressed, but require activation in order to bind
their ligand. To date, 15 subunits and 8 subunits have been identified. These can combine in
various ways to form different types of integrin receptors. The associations between and
subunits are restricted (see Table 1 below for major integrin pairings). For example, not every
and combination will be observed. In most cases, one subunit combines with several different
subunits to form a subfamily of integrin receptors.1, 4, 6, 7

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Adhesion Molecules

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Integrins exhibit both outside-in and inside-out signaling properties. 1, 4, 5, 9, 10 An example of

inside-out signaling occurs when a cell stimulus, for example, triggering of the TCR/CD3
complex on an immune cell, activates the integrin receptor. This can activate it to bind its ligand.
Inside-out signaling may also down-regulate integrin activation. Outside-in signaling occurs
after the integrin receptor binds its ligand and a signal is transmitted from the integrin receptor
into the cell. Integrins appear to have three activation states: basal avidity, low avidity, and high
avidity. Additionally, cells will alter their expression of various integrin receptors depending on
activation state, maturity, or lineage. Integrins are capable of binding divalent cations such as
calcium, magnesium, and manganese. Magnesium and manganese alone are capable of
activating integrins.

Cadherins
The cadherins are calcium-dependent adhesion molecules. 2, 4, 11, 12 The three most common
cadherins are neural (N)-cadherin, placental (P)-cadherin, and epithelial (E)-cadherin. All three
belong to the classical cadherin subfamily. There are also desmosomal cadherins and protocadherins. Cadherins are intimately involved in embryonic development and tissue organization.
They exhibit homophilic adhesion. The extracellular domain consists of several cadherin repeats,
each is capable of binding a calcium ion. When calcium is bound, the extracellular domain has a
rigid, rod-like structure. Following the transmembrane domain, the intracellular domain is highly
conserved. The intracellular domain is capable of binding the , , and catenins. The adhesive
properties of the cadherins have been shown to be dependent upon the ability of the intracellular
domain to interact with cytoplasmic proteins such as the catenins.

Selectins
The selectins are a family of divalent cation dependent glycoproteins. 1, 2, 4, 8 They are carbohydratebinding proteins, binding fucosylated carbohydrates, especially, sialylated Lewis x, and mucins.1, 2, 4, 8,
13, 14
The three family members include: Endothelial (E)-selectin, leukocyte (L)-selectin, and
platelet (P)-selectin. The extracellular domain of each consists of a carbohydrate recognition
motif, an epidermal growth factor (EGF)-like motif, and varying numbers of a short repeated
domain related to complement-regulatory proteins (CRP).

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Adhesion Molecules

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Following the transmembrane region, each has a short cytoplasmic domain. The selectins play an
important role in the initial steps of leukocyte trafficking. One selectin receptor, P-selectin
glycoprotein ligand-1 (PSGL-1), requires specific carbohydrate decoration for full bioactivity.
CAMs are critical to numerous cellular processes and responses. Additionally, they also play a
role in various disease states. Transendothelial migration of leukocytes is an example of one of
the many roles of adhesion molecules.1, 4, 8, 15This type of leukocyte trafficking consists of four
distinct steps. The first is rolling of the circulating leukocyte along endothelial cells (i.e., leukocyte
rolling on a blood vessel wall). This step is selectin-mediated. The second step involves the
triggering or activation of cell surface adhesion molecules, namely, the integrins. This can be
accomplished through contact with specific ECM proteins, inflammatory cytokines, or
chemokines. The third step involves firm adhesion; the leukocyte firmly attaches to an endothelial
cell. This involves arrest of the rolling process and spreading over the endothelial surface,
typically a vessel wall. The integrins and their ligands play crucial roles in this step. The fourth
step is transmigration of the leukocyte through adjacent endothelial cells in a process called
diapedesis. This allows the leukocyte to enter the subendothelial space. PECAM-1 is a crucial
player in this step. Transendothelial migration demonstrates cooperativity between leukocyte and
endothelial cell adhesion molecules. An extremely complicated process can be broken down into
distinct steps, each controlled by specific cell adhesion molecules.
Tumorigenesis is another process that involves cell adhesion molecules. 2, 4, 16-20 For successful
tumorigenesis, there must be changes in cellular adhesivity which facilitate the disruption of
normal tissue architecture. Additionally, angiogenesis must occur to provide the growing tumor
with a blood supply. During metastasis, cells must be able to detach from the primary tumor, enter
the blood stream through attachment to a blood vessel wall, travel through the bloodstream, and
attach to a vessel wall at a secondary site in order to establish a new tumor.
Defects in cell adhesion molecules are also associated with disease states. For example,
leukocyte adhesion deficiency (LAD) syndrome is associated with adhesion cascade defects.
LAD I is associated with mutations in the 2 integrin. There are two forms that have been
identified. The first is quite severe, with no LFA-1 (L2) expression. Patients with the second form
express low levels of 2 (i.e., about 2 - 5% of normal levels). Patients with the first form of LAD I
usually die within a few years of birth unless they receive a bone marrow transplantation. Patients
expressing the second form of LAD I have a moderate phenotype, but experience numerous
types of infections. LAD II results from a defect in the selectins. It is extremely rare and less
severe than LAD I. However, patients also exhibit severe mental and growth retardation believed
to be due to a generalized defect in fucose metabolism. 8
CAMs also play a role in establishment of the blood-brain barrier and facilitate its penetration by
immune cells. Selectins and integrins are the most important cell adhesion molecules in this
process.21 CAMs have also been used by pathogenic microorganisms to evade the immune
system.22

References
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8.
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Coppolino, M.G. & S. Dedhar (2000) Int. J. Biochem. Cell Biol. 32:171.

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Adhesion Molecules

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Takeichi, M. (1991) Science 251:1451.
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