MINIREVIEW PROLOGUE
Integrins Minireview Series*
John A.
McDonald
From the Samuel C. Johnson Medical Research Center, Mayo Clinic
Scottsdale, Scottsdale, Arizona 85259
 |
ARTICLE |
Integrins constitute a large family of
heterodimeric cell surface, transmembrane proteins that
recognize a large number of extracellular ligands through a metal
ion-dependent interaction. The prescient term
"integrin" reflects their role in integrating cell adhesion and
migration with the cytoskeleton (1). Their biological and medical
importance is underscored by inherited diseases causing bleeding
(Glanzmann's thromasthenia) and infection (leukocyte adhesion
deficiency). Additional important roles for integrins in immune,
inflammatory and infectious disease have been revealed by in vitro and
gene ablation studies. The minireviews in this and following issues
update our understanding of integrins in four general areas: structure
and ligand binding (by Edward F. Plow, Thomas A. Haas, Li Zhang, Joseph
Loftus, and Jeffrey W. Smith), interactions with the actin cytoskeleton
and regulation of ligand binding (by David A. Calderwood, Sanford J. Shattil, and Mark H. Ginsberg), leukocyte integrins (by Estelle S. Harris, Thomas M. McIntyre, Stephen M. Prescott, and Guy A. Zimmerman), and modulation of integrin function by lateral associations with other
plasma membrane-spanning molecules (by Anne Woods and John R. Couchman).
Early on, it was noted that integrins isolated from cells solubilized
with detergents often bound poorly to immobilized ligands. Now, it is
clear that binding of integrins to ligands is regulated by
intracellular signaling, so-called "inside-out" signaling. This
provides a dynamic mechanism for regulating cell adhesion, e.g. during cell adhesion, migration, or platelet
aggregation. Ligand binding by integrins is modulated by changes in
avidity, e.g. by clustering integrins and increasing
interactions with multivalent ligands or by increasing binding affinity
by conformational changes as reviewed by Calderwood et al.
in the second minireview in this series. Calderwood et al.
also provide a comprehensive overview of known interactions between
integrin cytoplasmic domains and molecules associated with the actin
cytoskeleton. Ligand binding triggers intracellular signaling cascades.
Intriguingly, ligand engagement also regulates the response of attached
cells to growth factors, a relationship anticipated by Paul
Bornstein's concept of "dynamic reciprocity" between cells and the
extracellular matrix (2). In this context, integrins sample the
extracellular microenvironment, reporting via intracellular signaling
and regulating responses including growth, cellular differentiation,
and even death.
Integrins do not act alone; indeed, they lack catalytic activity and
depend upon an extensive array of extracellular and intracellular partners to localize to membrane microdomains, recruit signaling molecules, and trigger intracellular signaling. The fourth minireview in this series by Woods and Couchman focuses primarily on two classes
of membrane-spanning molecules implicated in modulation of integrins,
tetraspans, and syndecans, although many other molecules have been
implicated. The medical importance of leukocyte integrins and platelet
integrins has led to important insights into their chemistry and
biology. The development of pharmaceuticals targeting integrins is an
important part of many drug discovery portfolios aimed at allergy and
inflammatory disease, atherosclerosis, and clotting. In the third
minireview of this series Zimmerman and co-workers enlarge on the
general theme of integrin structure, ligand binding, and regulation
focusing on leukocyte integrins. Collectively, these reviews constitute
a good dictionary for the increasingly complex language of integrins.
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FOOTNOTES |
*
These minireviews will be reprinted in the 2000 Minireview
Compendium, which will be available in December, 2000.
To whom correspondence should be addressed: Samuel C. Johnson
Medical Research Center, Mayo Clinic Scottsdale, 13400 East Shea Blvd.,
Scottsdale, AZ 85259. Tel.: 480-301-8859; Fax: 480-301-7017; E-mail:
mcdonald@mayo.edu.
Published, JBC Papers in Press, May 11, 2000, DOI 10.1074/jbc.R000007200
| |
REFERENCES |
| 1.
|
Hynes, R. O.
(1987)
Cell
48,
549-554
|
| 2.
|
Bornstein, P.,
McPherson, J.,
and Sage, H.
(1982)
in
Pathobiology of the Endothelial Cell
(Nossell, H. L.
, and Vogel, H. J., eds), Vol. 6
, pp. 215-228, Academic Press, Orlando, FL
|
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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