Portal de Periódicos da CAPES

Integrins Minireview Series

2000; Elsevier BV; Volume: 275; Issue: 29 Linguagem: Inglês

10.1074/jbc.r000007200

1083-351X

John A. McDonald,

Cell Adhesion Molecules Research

Integrins constitute a large family of αβ 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.Hynes R.O. Cell. 1987; 48: 549-554Abstract Full Text PDF PubMed Scopus (3079) Google Scholar). 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.Bornstein P. McPherson J. Sage H. Nossell H.L. Vogel H.J. Pathobiology of the Endothelial Cell. 6. Academic Press, Orlando, FL1982: 215-228Crossref Google Scholar). 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. Integrins constitute a large family of αβ 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.Hynes R.O. Cell. 1987; 48: 549-554Abstract Full Text PDF PubMed Scopus (3079) Google Scholar). 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.Bornstein P. McPherson J. Sage H. Nossell H.L. Vogel H.J. Pathobiology of the Endothelial Cell. 6. Academic Press, Orlando, FL1982: 215-228Crossref Google Scholar). 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.