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J. Biol. Chem., Vol. 279, Issue 24, 25646-25652, June 11, 2004

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Cross-talk with Ca²⁺ Influx Does Not Underlie the Role of Extracellular Signal-regulated Kinases in Cytotoxic T Lymphocyte Lytic Granule Exocytosis^*

Allan F. Fierro, Georjeana A. Wurth, and Adam Zweifach

From the Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262

One important mechanism cytotoxic T lymphocytes use to kill target cells is exocytosis of lytic granules that contain cytotoxic agents such as perforin and granzyme. Ca²⁺ influx and activation of protein kinase C have been known for many years to be key signals for granule exocytosis. Recent work has suggested that activation of extracellular signal-regulated kinases (ERK), members of the mitogen-activated protein kinase (MAP kinase) family, may be a third required signal. We surmised that the involvement of ERK in lytic granule exocytosis could be mediated through cross-talk with Ca²⁺ influx, rather than constituting an independent signal. We tested this idea using TALL-104 human leukemic CTLs as a model system and discovered the following. 1) ERK inhibition caused a modest decrease in the amplitude of increases in intracellular Ca²⁺ concentration, but this effect cannot account for the profound inhibition of granule exocytosis. 2) Ca²⁺ influx can activate ERK in TALL-104 cells, but this effect does not contribute to ERK activation stimulated by solid phase anti-CD3 monoclonal antibodies. We conclude that cross-talk between ERK signaling and Ca²⁺ does not mediate the role of ERK in CTL lytic granule exocytosis.

Received for publication, January 12, 2004 , and in revised form, March 18, 2004.

^* This work was supported by National Institutes of Health Grant AI054839. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Physiology and Biophysics, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262. Tel.: 303-315-5007; Fax: 303-315-8110; E-mail: adam.zweifach{at}UCHSC.edu.

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