Journal
JOURNAL OF CELL BIOLOGY
Volume 162, Issue 2, Pages 329-339Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200303120
Keywords
integrin; platelet; calpain; signaling; platelet activation
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Funding
- NHLBI NIH HHS [HL68819, R01 HL062350, HL62350, R01 HL041793, R01 HL068819, HL41793] Funding Source: Medline
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Bidirectional signaling of integrin alpha(IIb)beta(3) requires the beta(3) cytoplasmic domain. To determine the sequence in the beta(3) 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 beta(3) with truncations at sites COOH terminal to T-741, Y-754, F-754, and Y-759. Truncation at Y-759 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 33 is important for outside-in signaling but not inside-out signaling. In contrast, truncation at F-754, Y-747, or T-741 completely abolished integrin activation. A point mutation replacing Y-759 with alanine also abolished integrin activation. Thus, the (TNITY759)-N-755 sequence of beta(3), 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 Y-759 in a population of beta(3) during platelet aggregation and adhesion, suggesting that calpain may selectively regulate integrin outside-in signaling.
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