The Journal of Experimental Medicine
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Published 18 March 2002. doi:10.1084/jem.20011583
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© Rockefeller University Press, 0022-1007/2002/3/705/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 6, March 18, 2002 705-717

Original Article

 Differential Requirement for LAT and SLP-76 in GPVI versus T Cell Receptor Signaling

Barbi A. Judd1,2, Peggy S. Myung2,3, Achim Obergfell6, Erin E. Myers2, Alec M. Cheng7, Stephen P. Watson8, Warren S. Pear4,5, David Allman4, Sanford J. Shattil6 and Gary A. Koretzky2,4

1 University of Iowa Program in Molecular Biology, Iowa City, IA 52242
2 The Signal Transduction Program, Abramson Family Cancer Research Institute
3 Graduate Program in Immunology, University of Pennsylvania, Philadelphia, PA 19104
4 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
5 Institute of Medicine & Engineering, University of Pennsylvania, Philadelphia, PA 19104
6 Departments of Vascular Biology and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
7 Departments of Medicine and Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
8 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom

Address correspondence to Gary Koretzky, 415 BRBII/III, 421 Curie Blvd., University of Pennsylvania, Philadelphia, PA 19104. Phone: 215-746-5522; Fax: 215-746-5525; E-mail: koretzky{at}mail.med.upenn.edu

Mice deficient in the adaptor Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) exhibit a bleeding disorder and lack T cells. Linker for activation of T cells (LAT)-deficient mice exhibit a similar T cell phenotype, but show no signs of hemorrhage. Both SLP-76 and LAT are important for optimal platelet activation downstream of the collagen receptor, GPVI. In addition, SLP-76 is involved in signaling mediated by integrin {alpha}IIbß3. Because SLP-76 and LAT function coordinately in T cell signal transduction, yet their roles appear to differ in hemostasis, we investigated in detail the functional consequences of SLP-76 and LAT deficiencies in platelets. Previously we have shown that LAT-/- platelets exhibit defective responses to the GPVI-specific agonist, collagen-related peptide (CRP). Consistent with this, we find that surface expression of P-selectin in response to high concentrations of GPVI ligands is reduced in both LAT- and SLP-76–deficient platelets. However, platelets from LAT-/- mice, but not SLP-76-/- mice, aggregate normally in response to high concentrations of collagen and convulxin. Additionally, unlike SLP-76, LAT is not tyrosine phosphorylated after fibrinogen binding to integrin {alpha}IIbß3, and collagen-stimulated platelets deficient in LAT spread normally on fibrinogen-coated surfaces. Together, these findings indicate that while LAT and SLP-76 are equally required for signaling via the T cell antigen receptor (TCR) and pre-TCR, platelet activation downstream of GPVI and {alpha}IIbß3 shows a much greater dependency on SLP-76 than LAT.

Key Words: SLP-76 • LAT • GPVI • integrin {alpha}IIbß3 • T cell receptor


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