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

• Published in: Nature (London) Vol. 503; no. 7474; pp. 131 - 135
• Main Authors: Shen, Bo, Zhao, Xiaojuan, O’Brien, Kelly A., Stojanovic-Terpo, Aleksandra, Delaney, M. Keegan, Kim, Kyungho, Cho, Jaehyung, Lam, Stephen C.-T., Du, Xiaoping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.11.2013; Nature Publishing Group
• Subjects: 631/80/79/1236; Amino Acid Motifs; Amino Acid Sequence; Animals; Antithrombins - adverse effects; Antithrombins - pharmacology; Antithrombins - therapeutic use; Binding Sites; Bleeding Time; Blood clot; Blood platelets; Bone marrow; Cell interaction; Cell Polarity; Cytoplasm - metabolism; Drug therapy; GTP-Binding Protein alpha Subunits, G12-G13 - metabolism; Health aspects; Hemorrhage - chemically induced; Hemostasis; Humanities and Social Sciences; Humans; Integrin beta3 - chemistry; Integrin beta3 - genetics; Integrin beta3 - metabolism; Integrins; Integrins - chemistry; Integrins - deficiency; Integrins - genetics; Integrins - metabolism; letter; Ligands; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; multidisciplinary; Physiological aspects; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Protein Binding; Protein Structure, Tertiary; Science; Signal Transduction - drug effects; Stem cells; Talin - metabolism; Thromboembolism; Thrombosis; Thrombosis - drug therapy; Thrombosis - metabolism; Thrombosis - pathology; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12613

The direction of integrin signalling is found to be determined by the coordinated and opposing binding waves of talin and Gα 13 to the same region of the integrin β 3 cytoplasmic domain at mutually exclusive but distinct sites, and a potent new anti-thrombotic drug that does not cause bleeding is designed on the basis of these findings. A novel inhibitor of thrombosis Integrins are cell adhesion molecules that transmit signals in a bidirectional manner to mediate both inside-out and outside-in signalling. The cytoplasmic domain interacts with intracellular molecules such as the cytoskeletal proteins talin and Gα 13 . In this study, Xiaoping Du and colleagues demonstrate that the direction of signalling can be switched and transmitted by the coordinated and opposing binding waves of talin and Gα 13 to the same region of the integrin cytoplasmic domain with distinct recognition motifs. The authors also designed an inhibitor that selectively targets outside-in signalling, and this molecule inhibits thrombosis in vivo without causing bleeding as a side effect. Integrins have a critical role in thrombosis and haemostasis 1 . Antagonists of the platelet integrin α IIb β 3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding 2 , 3 . It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally 4 , 5 . Inside-out signalling activates integrins through a talin-dependent mechanism 6 , 7 . Integrin ligation mediates thrombus formation and outside-in signalling 8 , 9 , which requires Gα 13 and greatly expands thrombi. Here we show that Gα 13 and talin bind to mutually exclusive but distinct sites within the integrin β 3 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 Gα 13 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 Gα 13 –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.