J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/06/1639/11 $2.00
Volume 137, Number 7, June 30, 1997 1639-1649

ZAP-70 Protein Tyrosine Kinase Is Constitutively Targeted to the T Cell Cortex Independently of its SH2 Domains

Russell D.J. Huby,^* Makio Iwashima, Arthur Weiss,^§ and Steven C. Ley^*

^* Division of Cellular Immunology, National Institute for Medical Research, London NW7 1AA, United Kingdom;  Mitsubishi Chemical Corporation, Mitsubishi Kasei Institute of Life Sciences, Machida, Tokyo 194, Japan; and ^§ Howard Hughes Medical Institute, Department of Medicine, and Department of Microbiology and Immunology, University of California, San Francisco, California 94143

ZAP-70 is a nonreceptor protein tyrosine kinase that is essential for signaling via the T cell antigen receptor (TCR). ZAP-70 becomes phosphorylated and activated by LCK protein tyrosine kinase after interaction of its two NH₂-terminal SH2 domains with tyrosine-phosphorylated subunits of the activated TCR. In this study, the localization of ZAP-70 was investigated by immunofluorescence and confocal microscopy. ZAP-70 was found to be localized to the cell cortex in a diffuse band under the plasma membrane in unstimulated T cells, and this localization was not detectably altered by TCR stimulation. Analysis of mutants indicated that ZAP-70 targeting was independent of its SH2 domains but required its active kinase domain. The specific compartmentalization of ZAP-70 suggests that it may interact with an anchoring protein in the cell cortex via its hinge or kinase domains. It is likely that the maintenance of high concentrations of ZAP-70 at the cell cortex, that only has to move a short distance to interact with phophorylated TCR subunits, facilitates rapid initiation of signaling by the TCR. In addition, as the major increase in tyrosine phosphorylation induced by the TCR also occurs at the cell cortex (Ley, S.C., M. Marsh, C.R. Bebbington, K. Proudfoot, and P. Jordan. 1994. J. Cell. Biol. 125:639-649), ZAP-70 may be localized close to its downstream targets.

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