Inhibitor SourceBook™ Second Edition

Calbiochem • Inhibitor SourceBook
Cell Division/Cell Cycle/Cell Adhesion
Cell Division/Cell Cycle/Cell Adhesion
Cell Adhesion Inhibitors
Cell adhesion is crucial in the formation and maintenance
of coherent multi-cellular structures. Two
major types of cell adhesion processes are seen in multicellular
organisms: cell-cell adhesion where physical
bonds are formed between adjacent cells, and cell-matrix
adhesion where cells bind to adhesive proteins in the
extracellular matrix (ECM). A wide variety of adhesion
molecules have been identified that fall into four major
categories: cadherins, immunoglobulin (Ig)-like adhesion
molecules, integrins, and selectins. Cell adhesion
proteins are often transmembrane receptors that have
domains extending into both the extracellular space and
the intracellular space.
Cadherins are the main mediators of Ca 2+ -dependent cellcell
adhesion. Cadherin-mediated cell-cell adhesion is
accomplished by homophilic protein-protein interactions
between two cadherin molecules on cell surface. This
interaction is mediated by interactions between the
His-Ala-Val domains and between Trp residues and
hydrophobic pockets in amino-terminal cadherin
domains. Cadherins are critical in segregating embryonic
cells into tissues.
The Ig superfamily of cell adhesion molecules (CAM)
is expressed in a wide variety of cell types, including
neurons, leukocytes, epithelial, and endothelial cells.
Collectively, they function by both homophilic and
heterophilic binding. Their heterogeneous expression
pattern implicates them in diverse biological processes,
such as brain development, immune responses, tissue
sorting, morphogenesis, and development of the vascular
network. They are characterized by the presence of one
or more Ig-like domain in their extracellular region.
In addition, the ectodomain of Ig-CAMs may contain
various numbers of fibronectin type III (FNIII) repeats,
which possess the Arg-Gly-Asp (RGD) cell attachment
site. Neural cell adhesion molecules (N-CAMs) and the
intercellular cell adhesion molecules (ICAMs) are the beststudied
members of this family.
Integrins belong to a superfamily of non-covalently bound
heterodimeric membrane receptor glycoproteins. They are
composed of a variable a-subunit of 150-170 kDa and a
conserved 95 kDa b-subunit. Although both subunits are
required for adhesion, the binding specificity primarily
depends on the extracellular portion of the a-subunit.
While generally classified as adhesion molecules, integrins
also play an important role in signal transduction. Signal
transduction through integrins occurs in two directions:
from the extracellular microenvironment into the cell
(outside-in signaling), and from the cytoplasm to the
extracellular domain of the receptor (inside-out signaling).
Among the signaling molecules involved in integrinmediated
cell survival is focal adhesion kinase (FAK),
which is activated following integrin ligation. It activates
downstream survival pathways, such as PI 3-kinase, Akt,
and MAPK/ERK. In response to specific stimuli, integrins
that are generally diffused over the cell surface cluster in
focal contacts. Their combined affinities create a region
with sufficient adhesive capacity to adhere to the ECM. This
allows cells to bind to a large numbers of matrix molecules
simultaneously while still maintaining their ability to
explore their environment.
Selectins are expressed primarily on leukocytes and
endothelial cells. They play an important role in host
defense mechanisms. In contrast to other CAMs, selectins
bind to carbohydrate ligands. Hence, the resulting binding
forces are relatively weak. This allows selectin-mediated
interactions between leukocytes and endothelial cells and
promotes rolling of the leukocytes along the endothelium.
L-selectins are expressed on most leukocytes, E-selectins
are inducible on vascular endothelium upon stimulation
with cytokines, and P-selectins are found on activated
platelets and vascular endothelium.
Dysregulation of several CAMs, particularly the Ig-
CAMs, has been linked to tumor progression and
metastasis, making them a suitable target for therapeutic
intervention. Also, increased expression of CAMs
on the vascular endothelium is postulated to play an
important role in atherogenesis. CAMs also play critical
roles in the recruitment and migration of cells to sites
of inflammation. Hence, these molecules have become
targets for the development of drugs for treatment of
cancer, inflammation, and autoimmune diseases.
References:
Cavallaro, U., and Christofori, G. 2004. Nat. Rev. Cancer 4, 8.
Aplin, A.E., et al. 999. Curr. Opin. Cell Biol. 11, 737.
Meredith, J.E., et al. 997. Trends Cell Biol. 7, 46.
Ruoslahti, E., and Obrink, B. 996. Exp. Cell Res. 227, .
Law, D.A., et al. 996. J. Biol. Chem. 271, 08 .
Flores, M.E., et al. 996. Exp. Cell Res. 227, 40.
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