Integrin-dependent Cell Adhesion Is Regulated by a Low Affinity Receptor Pool That Is Conformationally Responsive to Ligand
(*)
- Ted A. Yednock(§),
- Catherine Cannon,
- Christopher Vandevert,
- Erich G. Goldbach,
- Gray Shaw(1),
- Debra K. Ellis(1),
- Chen Liaw,
- Lawrence C. Fritz and
- Laura I. Tanner
- From the From Athena Neurosciences, Inc., South San Francisco, California 94080
- Genetics Institute, Cambridge, Massachusetts 02140
- § To whom correspondence should be addressed: 800 Gateway Blvd., South San Francisco, CA 94080. Tel.: 415-877-7622; Fax: 415-877-8370.
Abstract
α
β
integrin (VLA-4) appears to be unique among the leukocyte integrins in that it can initiate the adhesion of circulating lymphocytes
without cellular activation. It is not known how lymphocytes or other cell types maintain constitutive levels of α
β
integrin activity. The current report describes a monoclonal antibody, 15/7, that recognizes a high affinity or ligand-occupied
conformation of β
integrin. Studies with 15/7 revealed that α
β
integrin-dependent adhesion of leukocytic cell lines is mediated by a population of low affinity receptors that is conformationally
responsive to ligand; the 15/7 epitope could be induced by nanomolar concentrations of soluble VCAM-1 or by micromolar concentrations
of a peptide derived from the type III connecting segment domain of fibronectin (as ligands for α
β
integrin). The same receptors were also responsive to adhesion activating reagents, such as Mn
, activating anti-β
integrin antibodies, and phorbol myristate acetate, which induced the 15/7 epitope directly and/or decreased the concentration
of ligand required for epitope induction. In addition to the responsive receptor pool, cells expressed a second population
of α
β
integrin that was conformationally restrained, failing to respond to ligand or to any of the activating reagents. The relative
size of the responsive and inactive receptor pools, as well as the affinity of the responsive receptors, represented a stable
phenotype of different cell types and played important roles in defining the cells' adhesive capacity and ligand specificity.
Similar receptor populations were measured on lymphocyte subsets in whole blood. These studies provide insight into how cells
maintain different constitutive levels of α
β
integrin activity, and how the activity of β
integrin can be modulated by activators of cell adhesion.
Footnotes
-
↵(*) This work was funded, in part, by Wyeth-Ayerst Research, Princeton, NJ. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- CS1
-
type III connecting segment region 1
- EC
-
excitatory concentration for half-maximal expression
- FN
-
fibronectin
- FITC
-
fluorescein isothiocyanate
- PE
-
phycoerythrin
- PMA
-
phorbol myristate acetate
- PAGE
-
polyacrylamide gel electrophoresis
- FACS
-
fluorescence-activated cell sorter.
-
↵2 L. I. Tanner and T. A. Yednock, unpublished observations.
-
↵3 W. Puzon, T. A. Yednock, and Y. Takada, manuscript submitted for publication.
-
- Received August 9, 1995.
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
