Brian G. Petrich, Per Fogelstrand, Anthony W. Partridge, Nima Yousefi, Ararat J. Ablooglu, Sanford J. Shattil, Mark H. Ginsberg
J Clin Invest.
2007;
117(8):2250–2259
doi:10.1172/JCI31024
This article Copyright © 2007, The American Society for Clinical Investigation
Abstract
|
Full text
|
PDF
I
n vitro studies indicate that binding of talin to the β3 integrin cytoplasmic domain (tail) results in integrin αIIbβ3 (GPIIb–IIIa) activation. Here we tested the importance of talin binding for integrin activation in vivo and its biological significance by generating mice harboring point mutations in the β3 tail. We introduced a β3(Y747A) substitution that disrupts the binding of talin, filamin, and other cytoplasmic proteins and a β3(L746A) substitution that selectively disrupts interactions only with talin. Platelets from animals homozygous for each mutation showed impaired agonist-induced fibrinogen binding and platelet aggregation, providing proof that inside-out signals that activate αIIbβ3 require binding of talin to the β3 tail. β3(L746A) mice were resistant to both pulmonary thromboembolism and to ferric chloride–induced thrombosis of the carotid artery. Pathological bleeding, measured by the presence of fecal blood and development of anemia, occurred in 53% of β3(Y747A) and virtually all β3-null animals examined. Remarkably, less than 5% of β3(L746A) animals exhibited this form of bleeding. These results establish that αIIbβ3 activation in vivo is dependent on the interaction of talin with the β3 integrin cytoplasmic domain. Furthermore, they suggest that modulation of β3 integrin–talin interactions may provide an attractive target for antithrombotics and result in a reduced risk of pathological bleeding.
This file is in Adobe Acrobat (PDF) format.
If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not
allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users:
Right-click on the Download link and choose the option that says something like "Save Link As...".
Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you
configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can
usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.