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Differential roles for the adapters Gads and LAT in platelet activation by GPVI and CLEC-2

Hughes, C.E and Auger, Jocelyn M. and McGlade, J and Eble, Johannes A. and Pearce, Andrew C and Watson, Steve P (2008) Differential roles for the adapters Gads and LAT in platelet activation by GPVI and CLEC-2. Journal Of Thrombosis And Haemostasis, 6 (12). pp. 2152-2159. ISSN 1538-7933

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URL of Published Version: http://www3.interscience.wiley.com/cgi-bin/fulltext/121425805/PDFSTART

Identification Number/DOI: 10.1111/j.1538-7836.2008.03166.x

Background: The adapter proteins SLP-76 and LAT have been shown to play critical roles in the activation of PLCc2 in platelets downstream of GPVI/FcRc and the C-type lectin receptor CLEC-2. SLP-76 is constitutively associated with the adapter Gads in platelets, which also binds to tyrosine phosphorylated LAT, thereby providing a potential pathway of regulation of SLP-76. Objective: In the present study, we have compared the role of Gads alongside that of LAT following activation of the major platelet glycoprotein receptors using mice deficient in the two adapter proteins.
Results: Gads was found to be required for the efficient onset of aggregation and secretion in response to submaximal stimulation of GPVI and CLEC-2, but to be dispensable for activation following stronger stimulation of the two receptors. Gads was also dispensable for spreading induced through integrin aIIbb3 or the GPIb–IX–V complex.Further, Gads plays a negligible role in aggregate formation on collagen at an arteriolar rate of shear. In stark contrast, platelets deficient in the adapter LAT exhibit a marked decrease in aggregation and secretion following activation of GPVI and CLEC-2, and are unable to form stable aggregates on collagen at arteriolar shear. Conclusions: The results demonstrate that Gads plays a key role in linking the adapter LAT to SLP-76 in response to weak activation of GPVI and CLEC-2 whereas LAT is required for full activation over a wider range of agonist concentrations. These results reveal the presence of a Gads-independent pathway of platelet activation downstream of LAT.

Type of Work:Article
Date:27 September 2008 (Publication)
School/Faculty:Schools (1998 to 2008) > School of Medicine
Department:Centre for Cardiovascular Sciences, Institute of Biomedical Research
Subjects:R Medicine (General)
Institution:University of Birmingham
Copyright Holders:John Wiley & Sons
ID Code:162
Refereed:YES
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