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A point mutation in the integrin beta 3 cytoplasmic domain (S752-->P)
impairs bidirectional signaling through alpha IIb beta 3 (platelet
glycoprotein IIb-IIIa)
YP Chen, TE O'Toole, J Ylanne, JP Rosa and MH Ginsberg
Department of Vascular Biology, Scripps Research Institute, La Jolla, CA
92037.
Agonist-induced inside-out signaling results in an increased affinity of
integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa) for soluble
ligands (fibrinogen [Fg] and PAC1). Ligand binding to integrins initiates
outside-in signaling that leads to cellular responses such as cell
spreading and focal adhesion formation. A point mutation in the beta 3
cytoplasmic domain (S752-->P) is associated with blocked inside- out
alpha IIb beta 3 signaling in a variant Glanzmann's thrombasthenia. This
mutation was introduced into beta 3 and cotransfected into Chinese hamster
ovary cells with a chimeric alpha subunit consisting of the alpha IIb
extracellular and transmembrane domains and the alpha 6B cytoplasmic
domain. The substitution of the alpha IIb cytoplasmic domain with that of
alpha 6 led to activation of alpha IIb beta 3 to bind PAC1, mimicking
inside-out signaling. This effect was reversed by the S752-->P mutation,
indicating a disruption of inside-out signaling by the mutation. In
addition, transfectants expressing this beta 3 variant showed reduced alpha
IIb beta 3-mediated cell spreading on immobilized Fg, focal adhesion, and
fibrin clot retraction, suggesting an impairment in outside-in alpha IIb
beta 3 signaling. Therefore, a single point mutation in the beta 3
cytoplasmic domain impaired bidirectional signaling through alpha IIb beta
3.
Volume 84,
Issue 6,
pp. 1857-1865,
09/15/1994
Copyright © 1994 by The American Society of Hematology
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