A directional switch of integrin signalling and a new anti-thrombotic strategy.
Nature
; 503(7474): 131-5, 2013 Nov 07.
Article
em En
| MEDLINE
| ID: mdl-24162846
ABSTRACT
Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin αIIbß3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Gα13 and greatly expands thrombi. Here we show that Gα13 and talin bind to mutually exclusive but distinct sites within the integrin ß3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Gα13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Gα13-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trombose
/
Transdução de Sinais
/
Integrinas
/
Antitrombinas
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Polaridade Celular
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Nature
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos