title: Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo.
abstract: The integrin family is composed of a series of 24 αβ heterodimer transmembrane adhesion receptors that mediate cell-cell and cell-extracellular matrix interactions. Adaptor molecules bearing immunoreceptor tyrosine-based activation motifs (ITAMs) have recently been shown to cooperate with specific integrins to increase the efficiency of transmitting ligand-binding-induced signals into cells. In human platelets, Fc receptor γ-chain IIa (FcγRIIa) has been identified as an ITAM-bearing transmembrane receptor responsible for mediating "outside-in" signaling through αIIbβ3, the major adhesion receptor on the platelet surface. To explore the importance of FcγRIIa in thrombosis and hemostasis, we subjected FcγRIIa-negative and FcγRIIa-positive murine platelets to a number of well-accepted models of platelet function. Compared with their FcγRIIa-negative counterparts, FcγRIIa-positive platelets exhibited increased tyrosine phosphorylation of Syk and phospholipase Cγ2 and increased spreading upon interaction with immobilized fibrinogen, retracted a fibrin clot faster, and showed markedly enhanced thrombus formation when perfused over a collagen-coated flow chamber under conditions of arterial and venous shear. They also displayed increased thrombus formation and fibrin deposition in in vivo models of vascular injury. Taken together, these data establish FcγRIIa as a physiologically important functional conduit for αIIbβ3-mediated outside-in signaling, and suggest that modulating the activity of this novel integrin/ITAM pair might be effective in controlling thrombosis.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201, USA.
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhi
authors.forename: Lubica
authors.initials: L
authors.lastname: Rauova
authors.forename: Vincent
authors.initials: V
authors.lastname: Hayes
authors.forename: Cunji
authors.initials: C
authors.lastname: Gao
authors.forename: Brian
authors.initials: B
authors.lastname: Boylan
authors.forename: Debra K
authors.initials: DK
authors.lastname: Newman
authors.forename: Steven E
authors.initials: SE
authors.lastname: McKenzie
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cooley
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Newman
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010974:Platelet Aggregation; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D017452:Receptors, IgG / Q000502:physiology*; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D013927:Thrombosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism*; D014680:Veins / Q000378:metabolism / Q000473:pathology
chemical_list: C080568:Fc gamma receptor IIA; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D014443:Tyrosine; D005337:Fibrin; D005340:Fibrinogen