Identification of FcgammaRIIa as the ITAM-bearing receptor mediating alphaIIbbeta3 outside-in integrin signaling in human platelets. Blood 2008 Oct 01;112(7):2780-6
Date
07/22/2008Pubmed ID
18641368Pubmed Central ID
PMC2556613DOI
10.1182/blood-2008-02-142125Scopus ID
2-s2.0-53449089830 (requires institutional sign-in at Scopus site) 154 CitationsAbstract
Immunoreceptor tyrosine-based activation motif (ITAM)-containing proteins have recently been demonstrated in macrophages and neutrophils to be required for cell surface integrins to transmit activation signals into the cell. To identify ITAM-bearing proteins that mediate signaling via the platelet-specific integrin alphaIIbbeta3, fibrinogen binding was induced by (1) allowing platelets to spread directly on immobilized fibrinogen, or (2) activating the PAR1 thrombin receptor on platelets in suspension. Both initiated strong, ligand binding-dependent tyrosine phosphorylation of the ITAM-bearing platelet Fc receptor, FcgammaRIIa, as well as downstream phosphorylation of the protein tyrosine kinase Syk and activation of phospholipase Cgamma2 (PLCgamma2). Addition of Fab fragments of an FcgammaRIIa-specific monoclonal antibody strongly inhibited platelet spreading on immobilized fibrinogen, as well as downstream tyrosine phosphorylation of FcgammaRIIa, Syk, and PLCgamma2, and platelets from a patient whose platelets express reduced levels of FcgammaRIIa exhibited markedly reduced spreading on immobilized fibrinogen. Finally, fibrinogen binding-induced FcgammaRIIa phosphorylation did not occur in human platelets expressing a truncated beta3 cytoplasmic domain. Taken together, these data suggest that ligand binding to platelet alphaIIbbeta3 induces integrin cytoplasmic domain-dependent phosphorylation of FcgammaRIIa, which then enlists selected components of the immunoreceptor signaling cascade to transmit amplification signals into the cell.
Author List
Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJAuthors
Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of WisconsinDebra 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
Amino Acid MotifsBlood Platelets
Cell Line
Cell Movement
Child
Fibrinogen
Humans
Intracellular Signaling Peptides and Proteins
Ligands
Phospholipase C gamma
Phosphorylation
Platelet Activation
Platelet Glycoprotein GPIIb-IIIa Complex
Protein Structure, Tertiary
Protein-Tyrosine Kinases
Receptors, IgG
Signal Transduction
Solubility
Syk Kinase