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

  • Background:The adapter proteins SLP-76 and LAT have been shown to play critical roles in the activation of PLCgamma2 in platelets downstream of GPVI/FcRgamma 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 alphaIIbbeta3 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. Keywords: CLEC-2, Gads, GPVI, LAT, platelet, signalosome, SLP-76

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Author:Craig E. Hughes, Jocelyn M. Auger, Johannes A. EbleORCiDGND, Jane McGlade, Andrew C. Pearce, Steve P. Watson
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/18826392
Parent Title (English):Journal of thrombosis and haemostasis
Publisher:Blackwell Publishing
Place of publication:Oxford
Document Type:Article
Year of Completion:2008
Date of first Publication:2008/11/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2010/01/27
Tag:CLEC-2; GPVI; Gads; LAT; SLP-76; platelet; signalosome
Page Number:8
First Page:2152
Last Page:2159
Copyright © 2008 International Society on Thrombosis and Haemostasis ; Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
Source:Journal of Thrombosis and Haemostasis, 6, S. 2152–2159 ; doi: 10.1111/j.1538-7836.2008.03166.x.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell 3.0