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Molecular and Cellular Biology, December 1999, p. 8326-8334, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

LAT Is Required for Tyrosine Phosphorylation of Phospholipase Cgamma 2 and Platelet Activation by the Collagen Receptor GPVI

Jean-Max Pasquet,1,* Barbara Gross,1 Lynn Quek,1 Naoki Asazuma,1 Weiguo Zhang,2 Connie L. Sommers,3 Edina Schweighoffer,4 Victor Tybulewicz,4 Barbara Judd,5 Jong Ran Lee,5 Gary Koretzky,5 Paul E. Love,3 Lawrence E. Samelson,2 and Steve P. Watson1

Department of Pharmacology, University of Oxford, Oxford OX1 3QT,1 and Division of Cellular Immunology, National Institute for Medical Research, Mill Hill, London NW7 1AA,4 United Kingdom; Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 522425; and Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development,3 and Section on Lymphocyte Signaling, Cell Biology and Metabolism Branch,2 National Institutes of Health, Bethesda, Maryland 20892

Received 27 May 1999/Returned for modification 20 July 1999/Accepted 27 July 1999

In the present study, we have addressed the role of the linker for activation of T cells (LAT) in the regulation of phospholipase Cgamma 2 (PLCgamma 2) by the platelet collagen receptor glycoprotein VI (GPVI). LAT is tyrosine phosphorylated in human platelets heavily in response to collagen, collagen-related peptide (CRP), and Fcgamma RIIA cross-linking but only weakly in response to the G-protein-receptor-coupled agonist thrombin. LAT tyrosine phosphorylation is abolished in CRP-stimulated Syk-deficient mouse platelets, whereas it is not altered in SLP-76-deficient mice or Btk-deficient X-linked agammaglobulinemia (XLA) human platelets. Using mice engineered to lack the adapter LAT, we showed that tyrosine phosphorylation of Syk and Btk in response to CRP was maintained in LAT-deficient platelets whereas phosphorylation of SLP-76 was slightly impaired. In contrast, tyrosine phosphorylation of PLCgamma 2 was substantially reduced in LAT-deficient platelets but was not completely inhibited. The reduction in phosphorylation of PLCgamma 2 was associated with marked inhibition of formation of phosphatidic acid, a metabolite of 1,2-diacylglycerol, phosphorylation of pleckstrin, a substrate of protein kinase C, and expression of P-selectin in response to CRP, whereas these parameters were not altered in response to thrombin. Activation of the fibrinogen receptor integrin alpha IIbbeta 3 in response to CRP was also reduced in LAT-deficient platelets but was not completely inhibited. These results demonstrate that LAT tyrosine phosphorylation occurs downstream of Syk and is independent of the adapter SLP-76, and they establish a major role for LAT in the phosphorylation and activation of PLCgamma 2, leading to downstream responses such as alpha -granule secretion and activation of integrin alpha IIbbeta 3. The results further demonstrate that the major pathway of tyrosine phosphorylation of SLP-76 is independent of LAT and that there is a minor, LAT-independent pathway of tyrosine phosphorylation of PLCgamma 2. We propose a model in which LAT and SLP-76 are required for PLCgamma 2 phosphorylation but are regulated through independent pathways downstream of Syk.

* Corresponding author. Mailing address: Department of Pharmacology, University of Oxford, Mansfield Rd., Oxford OX1 3QT, United Kingdom. Phone: (44) 1865 271592. Fax: (44) 1865 271 853. E-mail: max.pasquet{at}pharm.ox.ac.uk.

Molecular and Cellular Biology, December 1999, p. 8326-8334, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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