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Molecular and Cellular Biology, November 2001, p. 7137-7149, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7137-7149.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

ZAP-70-Independent Ca2+ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation

Xiaochuan Shan,1,dagger Richard Balakir,1 Gabriel Criado,2 Jason S. Wood,1 Maria-Cristina Seminario,1 Joaquin Madrenas,2 and Ronald L. Wange1,*

Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825,1 and The John P. Robarts Research Institute and Departments of Microbiology and Immunology and of Medicine, The University of Western Ontario, London, Ontario, Canada N6A 5K82

Received 12 February 2001/Returned for modification 21 March 2001/Accepted 16 July 2001

The tyrosine kinase ZAP-70 has been implicated as a critical intermediary between T-cell antigen receptor (TCR) stimulation and Erk activation on the basis of the ability of dominant negative ZAP-70 to inhibit TCR-stimulated Erk activation, and the reported inability of anti-CD3 antibodies to activate Erk in ZAP-70-negative Jurkat cells. However, Erk is activated in T cells receiving a partial agonist signal, despite failing to activate ZAP-70. This discrepancy led us to reanalyze the ZAP-70-negative Jurkat T-cell line P116 for its ability to support Erk activation in response to TCR/CD3 stimulation. Erk was activated by CD3 cross-linking in P116 cells. However, this response required a higher concentration of anti-CD3 antibody and was delayed and transient compared to that in Jurkat T cells. Activation of Raf-1 and MEK-1 was coincident with Erk activation. Remarkably, the time course of Ras activation was comparable in the two cell lines, despite proceeding in the absence of LAT tyrosine phosphorylation in the P116 cells. CD3 stimulation of P116 cells also induced tyrosine phosphorylation of phospholipase C-gamma 1 (PLCgamma 1) and increased the intracellular Ca2+ concentration. Protein kinase C (PKC) inhibitors blocked CD3-stimulated Erk activation in P116 cells, while parental Jurkat cells were refractory to PKC inhibition. The physiologic relevance of these signaling events is further supported by the finding of PLCgamma 1 tyrosine phosphorylation, Erk activation, and CD69 upregulation in P116 cells on stimulation with superantigen and antigen-presenting cells. These results demonstrate the existence of two pathways leading to TCR-stimulated Erk activation in Jurkat T cells: a ZAP-70-independent pathway requiring PKC and a ZAP-70-dependent pathway that is PKC independent.

* Corresponding author. Mailing address: National Institute on Aging, 5600 Nathan Shock Dr., MSC-12, Baltimore, MD 21224-6825. Phone: (410) 558-8054. Fax: (410) 558-8107. E-mail: wanger{at}grc.nia.nih.gov.

dagger Present address: Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, MD 21287.

Molecular and Cellular Biology, November 2001, p. 7137-7149, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7137-7149.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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