A directional switch of integrin signalling and a new anti-thrombotic strategy

Nature. 2013 Nov 7;503(7474):131-5. doi: 10.1038/nature12613. Epub 2013 Oct 27.


Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin αIIbβ3 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 β3 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Antithrombins / adverse effects
  • Antithrombins / pharmacology*
  • Antithrombins / therapeutic use
  • Binding Sites
  • Bleeding Time
  • Cell Polarity*
  • Cytoplasm / metabolism
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • Hemorrhage / chemically induced
  • Humans
  • Integrin beta3 / chemistry
  • Integrin beta3 / genetics
  • Integrin beta3 / metabolism
  • Integrins / chemistry
  • Integrins / deficiency
  • Integrins / genetics
  • Integrins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Signal Transduction / drug effects*
  • Talin / metabolism
  • Thrombosis / drug therapy*
  • Thrombosis / metabolism
  • Thrombosis / pathology


  • Antithrombins
  • Integrin beta3
  • Integrins
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Talin
  • GTP-Binding Protein alpha Subunits, G12-G13