title: A directional switch of integrin signalling and a new anti-thrombotic strategy.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Kelly A
authors.initials: KA
authors.lastname: O'Brien
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Stojanovic-Terpo
authors.forename: M Keegan
authors.initials: MK
authors.lastname: Delaney
authors.forename: Kyungho
authors.initials: K
authors.lastname: Kim
authors.forename: Jaehyung
authors.initials: J
authors.lastname: Cho
authors.forename: Stephen C-T
authors.initials: SC
authors.lastname: Lam
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Du
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000991:Antithrombins / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D001760:Bleeding Time; D016764:Cell Polarity; D003593:Cytoplasm / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D039661:Integrin beta3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects*; D016608:Talin / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000991:Antithrombins; D039661:Integrin beta3; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016608:Talin; D044365:GTP-Binding Protein alpha Subunits, G12-G13