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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2466-2474. Prepublished online as a Blood First Edition Paper on June 19, 2007; DOI 10.1182/blood-2007-02-075432. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-02-075432v1 110/7/2466    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ragab, A. Articles by Payrastre, B. Search for Related Content PubMed PubMed Citation Articles by Ragab, A. Articles by Payrastre, B. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 20, 2007 Accepted June 11, 2007 Roles of the C-terminal tyrosine residues of LAT in GPVI-induced platelet activation; insights in the mechanism of PLC2 activation Ashraf Ragab, Sonia Severin, Marie-Pierre Gratacap, Enrique Aguado, Marie Malissen, Martine Jandrot-Perrus, Bernard Malissen, Jeannie Ragab-Thomas, and Bernard Payrastre* Dept Oncogenese, Signalisation et Innovatiion therapeutique, Inserm U564, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France Centre d'Immunologie de Marseille-Luminy, Inserm-CNRS-Universite de la Mediterrane, Marseille-Luminy, France Inserm U698, Hopital Bichat, Paris, France * Corresponding author; email: payrastr{at}toulouse.inserm.fr. Linker for activation of T cells (LAT) is an adaptor protein required for organisation of the signalling machinery downstream of the platelet collagen receptor, the glycoprotein VI (GPVI). Here, we investigated the effect of LAT mutations on specific signalling pathways and on platelet functions in response to GPVI triggering by convulxin (Cvx). Using mice containing tyrosine to phenylalanine mutations of the adaptor, we show the crucial role played by the tyrosine residues at position 175, 195 and 235 in the phosphorylation of LAT and in the whole pattern of protein tyrosine phosphorylation in response to Cvx. These three C-terminal tyrosine residues are important to recruit the tyrosine kinase Fyn which may be involved in LAT phosphorylation. Efficient phosphoinositide 3-kinase (PI3K) activation requires the three C-terminal tyrosine residues of LAT but not its tyrosine 136. Interestingly, single mutation of the tyrosine 136 results in the loss of phospholipase C2 (PLC2) activation without affecting its PI3K-dependent membrane association, and is sufficient to impair platelet responses to Cvx. Thus, activation of PLC2 via GPVI is dependent on two complementary events; its interaction with the tyrosine 136 of LAT and its membrane location which itself requires events mediated by the three C-terminal tyrosines of LAT. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M.-P. Gratacap, V. Martin, M.-C. Valera, S. Allart, C. Garcia, P. Sie, C. Recher, and B. Payrastre The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo Blood, August 27, 2009; 114(9): 1884 - 1892. [Abstract] [Full Text] [PDF]

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