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Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo. Blood 2013 Mar 07;121(10):1858-67

Date

12/25/2012

Pubmed ID

23264598

Pubmed Central ID

PMC3591804

DOI

10.1182/blood-2012-07-443325

Scopus ID

2-s2.0-84876238476 (requires institutional sign-in at Scopus site)   81 Citations

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.

Author List

Zhi H, Rauova L, Hayes V, Gao C, Boylan B, Newman DK, McKenzie SE, Cooley BC, Poncz M, Newman PJ

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Peter J. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Arterioles
Blood Platelets
Fibrin
Fibrinogen
Hemostasis
Humans
In Vitro Techniques
Mice
Mice, Inbred C57BL
Mice, Transgenic
Platelet Aggregation
Platelet Count
Platelet Glycoprotein GPIIb-IIIa Complex
Receptors, IgG
Receptors, Immunologic
Signal Transduction
Thrombosis
Tyrosine
Veins