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Mol Cell Biol, May 1998, p. 2855-2866, Vol. 18, No. 5
Center for
Immunology,1
Divisions of
Nephrology2 and
Rheumatology,5
Department of
Medicine,3
Department of
Pathology,6 and
Howard Hughes Medical
Institute,7 Washington University School of
Medicine, St. Louis, Missouri 63110, and
Division of
Gastroenterology, Department of Internal Medicine, University of
Chicago, Chicago, Illinois 606374
Received 23 October 1997/Returned for modification 5 December
1997/Accepted 13 February 1998
T-cell antigen receptor (TCR) engagement results in sequential
activation of the Src protein tyrosine kinases (PTKs) Lck and Fyn and
the Syk PTKs, ZAP-70 and Syk. While the Src PTKs mediate the
phosphorylation of TCR-associated signaling subunits and the phosphorylation and activation of the Syk PTKs, the lack of a constitutively active Syk PTK has prohibited the analysis of Lck function downstream of these initiating signaling events. We describe here the generation of an activated Syk family PTK by substituting the
kinase domain of Syk for the homologous region in ZAP-70 (designated as
KS for kinase swap). Expression of the KS chimera resulted in its
autophosphorylation, the phosphorylation of cellular proteins, the
upregulation of T-cell activation markers, and the induction of
interleukin-2 gene synthesis in a TCR-independent fashion. The KS
chimera and downstream ZAP-70 or Syk substrates, such as SLP-76, were
still phosphorylated when expressed in Lck-deficient JCaM1.6 T cells.
However, expression of the KS chimera in JCaM1.6 cells failed to rescue
downstream signaling events, demonstrating a functional role for Lck
beyond the activation of the ZAP-70 and Syk PTKs. These results
indicate that downstream TCR signaling pathways may be differentially
regulated by ZAP-70 and Lck PTKs and provide a mechanism by which
effector functions may be selectively activated in response to TCR
stimulation.
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Genetic Evidence of a Role for Lck in T-Cell Receptor Function
Independent or Downstream of ZAP-70/Syk Protein Tyrosine
Kinases
*
Corresponding author. Mailing address: Box 8022, Washington University School of Medicine, 660 S. Euclid Ave., St.
Louis, MO 63110. Phone: (314) 362-9012. Fax: (314) 454-0175. E-mail: chan{at}im.wustl.edu.
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