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Molecular and Cellular Biology, February 2000, p. 1426-1435, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Differential T-Cell Antigen Receptor Signaling Mediated by the Src Family Kinases Lck and Fyn

Michael F. Denny, Barbara Patai, and David B. Straus*

Departments of Medicine and Pathology, University of Chicago, Chicago, Illinois

Received 25 June 1999/Returned for modification 9 August 1999/Accepted 16 November 1999

Src family tyrosine kinases play a key role in T-cell antigen receptor (TCR) signaling. They are responsible for the initial tyrosine phosphorylation of the receptor, leading to the recruitment of the ZAP-70 tyrosine kinase, as well as the subsequent phosphorylation and activation of ZAP-70. Molecular and genetic evidence indicates that both the Fyn and Lck members of the Src family can participate in TCR signal transduction; however, it is unclear to what extent they utilize the same signal transduction pathways and activate the same downstream events. We have addressed this issue by examining the ability of Fyn to mediate TCR signal transduction in an Lck-deficient T-cell line (JCaM1). Fyn was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphorylation was altered and activation of ZAP-70 was defective. Despite this, the SLP-76 adapter protein was inducibly tyrosine phosphorylated, and both the Ras-mitogen-activated protein kinase and the phosphatidylinositol 4,5-biphosphate signaling pathways were activated. TCR stimulation of JCaM1/Fyn cells induced the expression of the CD69 activation marker and inhibited cell growth, but NFAT activation and the production of interleukin-2 were markedly reduced. These results indicate that Fyn mediates an alternative form of TCR signaling which is independent of ZAP-70 activation and generates a distinct cellular phenotype. Furthermore, these findings imply that the outcome of TCR signal transduction may be determined by which Src family kinase is used to initiate signaling.

* Corresponding author. Mailing address: University of Chicago, Department of Medicine/MC6084, 5841 S. Maryland Ave., Chicago, IL 60637. Phone: (773) 702-4708. Fax: (773) 702-2281. E-mail: dstraus{at}midway.uchicago.edu.

Molecular and Cellular Biology, February 2000, p. 1426-1435, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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