Breaking the Integrin Hinge
A DEFINED STRUCTURAL CONSTRAINT REGULATES INTEGRIN SIGNALING (*)
- Paul E. Hughes(§),
- Federico Diaz-Gonzalez(¶),
- Lilley Leong,
- Chuanyue Wu(1),
- John A. McDonald(1),
- Sanford J. Shattil and
- Mark H. Ginsberg(**)
- From the Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037 and the Samuel C. Johnson Medical Research Centre, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259
- ** To whom correspondence should be addressed. Tel.: 619-784-7118; Fax: 619-784-7343; ginsberg{at}scripps.edu.
Abstract
Integrins are heterodimeric (α, β) cell adhesion receptors. We demonstrate that point mutations in the cytoplasmic domains
of both the α and β subunits promote constitutive signaling by the integrin α
β
. By generating charge reversal mutations, we show these “activating” mutations may act by disrupting a potential salt bridge
between the membrane-proximal portions of the α and β subunit cytoplasmic domains. Thus, the modulation of specific interactions
between the α and β subunit cytoplasmic domains may regulate transmembrane signaling through integrins. In addition, these
activating mutations induce dominant alterations in cellular behavior, such as the assembly of the extracellular matrix. Consequently,
somatic mutations in integrin cytoplasmic domains could have profound effects in vivo on integrin-dependent functions such as matrix assembly, cell migration, and anchorage-dependent cell growth and survival.
Footnotes
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↵§ Postdoctoral fellow of the American Heart Association (California affiliate).
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↵* This was work was supported by grants from the National Institutes of Health (to M. H. G., J. A. McD., and S. J. S.). This is Paper 9604-VB from the Scripps Research Institute. 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.
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↵1 The abbreviations used are:
- PCR
-
polymerase chain reaction
- kb
-
kilobase(s)
- BSA
-
bovine serum albumin
- PBS
-
phosphate-buffered saline
- FITC
-
fluorescein isothiocyanate.
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↵2 M. H. Ginsberg, unpublished data.
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- Received January 22, 1996.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
