title: Signaling-mediated cooperativity between glycoprotein Ib-IX and protease-activated receptors in thrombin-induced platelet activation.
abstract: Thrombin-induced cellular response in platelets not only requires protease-activated receptors (PARs), but also involves another thrombin receptor, the glycoprotein Ib-IX complex (GPIb-IX). It remains controversial how thrombin binding to GPIb-IX stimulates platelet responses. It was proposed that GPIb-IX serves as a dock that facilitates thrombin cleavage of protease-activated receptors, but there are also reports suggesting that thrombin binding to GPIb-IX induces platelet activation independent of PARs. Here we show that GPIb is neither a passive thrombin dock nor a PAR-independent signaling receptor. We demonstrate a novel signaling-mediated cooperativity between PARs and GPIb-IX. Low-dose thrombin-induced PAR-dependent cell responses require the cooperativity of GPIb-IX signaling, and conversely, thrombin-induced GPIb-IX signaling requires cooperativity of PARs. This mutually dependent cooperativity requires a GPIb-IX-specific 14-3-3-Rac1-LIMK1 signaling pathway, and activation of this pathway also requires PAR signaling. The cooperativity between GPIb-IX signaling and PAR signaling thus drives platelet activation at low concentrations of thrombin, which are important for in vivo thrombosis.
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL;
authors.forename: Brian
authors.initials: B
authors.lastname: Estevez
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL;
authors.forename: Kyungho
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL;
authors.forename: M Keegan
authors.initials: MK
authors.lastname: Delaney
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL;
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Stojanovic-Terpo
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL;
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; and.
authors.forename: Changgeng
authors.initials: C
authors.lastname: Ruan
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL;
authors.forename: Jaehyung
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: Zaverio M
authors.initials: ZM
authors.lastname: Ruggeri
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago College of Medicine, Chicago, IL;
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Du
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D051379:Mice; D015539:Platelet Activation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D044462:Receptors, Proteinase-Activated / Q000378:metabolism*; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D044462:Receptors, Proteinase-Activated; C094990:adhesion receptor; D000255:Adenosine Triphosphate; D013917:Thrombin