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A GADS-INDEPENDENT PATHWAY OF PLCGAMMA2 REGULATION DOWNSTREAM OF THE COLLAGEN RECEPTOR, GPVI
Abstract number: P-T-255
Hughes1 C.E., Pedaries1 C., Auger1 J.M., McGlade2 J., Pearce1 A.C., Watson1 S.P.
11Centre for Cardiovascular Sciences, Insitute of Biomedical Research, The University of Birmingham, Birmingham, United Kingdom 22Department of Medical Biophysics, The University of Toronto, Toronto, Canada
How-to-cite Hughes CE, Pedaries C, Auger JM, McGlade J, Pearce AC, Watson SP. A GADS-INDEPENDENT PATHWAY OF PLCGAMMA2 REGULATION DOWNSTREAM OF THE COLLAGEN RECEPTOR, GPVI. J Thromb Haemost 2007; 5 Supplement 2: P-T-255
Abstract
Introduction: The adapter complex, LAT-Gads-SLP-76, plays a critical role in the regulation of Phospholipase Cgamma2 (PLCgamma2) by the T cell receptor and has been proposed to play a similar role in platelets downstream of the collagen receptor GPVI. This is supported by the partial and complete inhibition of platelet activation by the GPVI-specific CRP (collagen-related peptide) in LAT-/- and SLP-76-/- mice, respectively. In this study, we have evaluated the role of Gads in this pathway alongside that of LAT using mutant mice.
Methods: Platelet aggregation, secretion and tyrosine phosphorylation were measured in washed platelets. Thrombus formation at an intermediate shear rate was monitored in whole blood. Gads-/- mice were bred from heterozygotes on a Balb-c background. Results were compared to LAT-/- mice bred on a B6 background.
Results: Aggregation and secretion induced by low but not intermediate concentrations of CRP were weakly inhibited in the absence of Gads. Concurrently, there were no detectable effects on phosphorylation of PLCgamma2 and thrombus formation. In comparison, there was marked inhibition of aggregation, secretion and thrombus formation, along with partial blockade of PLCgamma2 phosphorylation, in LAT-/- platelets. The Gads-/- mice are being crossed onto a B6 background to investigate whether this accounts for the relative contributions of Gads and LAT to PLCgamma2 activation.
There is evidence that the Gads family member Grb2 is able to replace Gads in the LAT adapter complex. Strikingly, RNAi-induced knock-down Grb2 in primary murine megakaryocytes leads to inhibition of Ca2+ elevation in response to CRP but not to the G protein agonist thrombin.
Conclusions: These results provide evidence for a Gads-independent pathway of PLCgamma2 activation that is regulated through LAT and possibly Grb2.
This work was funded by the Wellcome Trust and the British Heart Foundation.
To cite this abstract use the following format:
Journal of Thrombosis and Haemostasis 2007; Volume 5, Supplement 2: abstract number
Session Details
| Date: |
01/08/2007
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| Time: |
00:00-00:00
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| Session name: |
XXIst ISTH Congress |
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| Location: |
Oxford, UK |
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