| First Author | Stefanini L | Year | 2014 |
| Journal | Blood | Volume | 123 |
| Issue | 17 | Pages | 2722-31 |
| PubMed ID | 24585775 | Mgi Jnum | J:210743 |
| Mgi Id | MGI:5571784 | Doi | 10.1182/blood-2013-12-543363 |
| Citation | Stefanini L, et al. (2014) A talin mutant that impairs talin-integrin binding in platelets decelerates alphaIIbbeta3 activation without pathological bleeding. Blood 123(17):2722-31 |
| abstractText | Tight regulation of integrin affinity is critical for hemostasis. A final step of integrin activation is talin binding to 2 sites within the integrin beta cytoplasmic domain. Binding of talin to a membrane-distal NPxY sequence facilitates a second, weaker interaction of talin with an integrin membrane-proximal region (MPR) that is critical for integrin activation. To test the functional significance of these distinct interactions on platelet function in vivo, we generated knock-in mice expressing talin1 mutants with impaired capacity to interact with the beta3 integrin MPR (L325R) or NPLY sequence (W359A). Both talin1(L325R) and talin1(W359A) mice were protected from experimental thrombosis. Talin1(L325R) mice, but not talin(W359A) mice, exhibited a severe bleeding phenotype. Activation of alphaIIbbeta3 was completely blocked in talin1(L325R) platelets, whereas activation was reduced by approximately 50% in talin1(W359A) platelets. Quantitative biochemical measurements detected talin1(W359A) binding to beta3 integrin, albeit with a 2.9-fold lower affinity than wild-type talin1. The rate of alphaIIbbeta3 activation was slower in talin1(W359A) platelets, which consequently delayed aggregation under static conditions and reduced thrombus formation under physiological flow conditions. Together our data indicate that reduction of talin-beta3 integrin binding affinity results in decelerated alphaIIbbeta3 integrin activation and protection from arterial thrombosis without pathological bleeding. |
