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Published online 14 July 2003. doi:10.1083/jcb.200303120
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© The Rockefeller University Press, 0021-9525/2003/7/329 $5.00
The Journal of Cell Biology, Volume 162, Number 2, 329-339

Article

 Critical roles for the COOH-terminal NITY and RGT sequences of the integrin ß3 cytoplasmic domain in inside-out and outside-in signaling

Xiaodong Xi, Richard J. Bodnar, Zhenyu Li, Stephen C.-T. Lam and Xiaoping Du

Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612

Address correspondence to Xiaoping Du, Department of Pharmacology, College of Medicine, University of Illinois at Chicago, 835 South Wolcott Ave., Chicago, IL 60612. Tel.: (312) 355-0237. Fax: (312) 996-1225. E-mail: xdu{at}uic.edu

Bidirectional signaling of integrin {alpha}IIbß3 requires the ß3 cytoplasmic domain. To determine the sequence in the ß3 cytoplasmic domain that is critical to integrin signaling, cell lines were established that coexpress the platelet receptor for von Willebrand factor (vWF), glycoprotein Ib-IX, integrin {alpha}IIb, and mutants of ß3 with truncations at sites COOH terminal to T741, Y747, F754, and Y759. Truncation at Y759 did not affect integrin activation, as indicated by vWF-induced fibrinogen binding, but affected cell spreading and stable adhesion. Thus, the COOH-terminal RGT sequence of ß3 is important for outside-in signaling but not inside-out signaling. In contrast, truncation at F754, Y747, or T741 completely abolished integrin activation. A point mutation replacing Y759 with alanine also abolished integrin activation. Thus, the T755NITY759 sequence of ß3, containing an NXXY motif, is critical to inside-out signaling, whereas the intact COOH terminus is important for outside-in signaling. In addition, we found that the calcium-dependent protease calpain preferentially cleaves at Y759 in a population of ß3 during platelet aggregation and adhesion, suggesting that calpain may selectively regulate integrin outside-in signaling.

Key Words: integrin; platelet; calpain; signaling; platelet activation

* Abbreviation used in this paper: vWf, von Willebrand factor.


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