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© The Rockefeller University Press, 0021-9525/1998//1371 $5.00
The Journal of Cell Biology, Volume 142, Number 5, , 1998 1371-1379

Articles

ZAP-70 Tyrosine Kinase Is Required for LFA-1–dependent T Cell Migration



Ron D.M. Soede, Yvonne M. Wijnands, Ioana Van Kouteren-Cobzaru, and Ed Roos

Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

The ZAP-70 tyrosine kinase is essential for T cell activation by the T cell receptor. We show that ZAP-70 is also required for migration of T cells that is dependent on the integrin LFA-1. Invasion of TAM2D2 T cell hybridoma cells into fibroblast monolayers, which is LFA-1–dependent, was blocked by overexpression of dominant-negative ZAP-70 and by piceatannol but not by herbimycin A. The Syk inhibitor piceatannol blocks the Syk homologue ZAP-70, which is expressed by TAM2D2 cells, with the same dose dependence as the inhibition of invasion. Dominant-negative ZAP-70 completely inhibited the extensive metastasis formation of TAM2D2 cells to multiple organs upon i.v. injection into mice. Migration of TAM2D2 cells through filters coated with the LFA-1 ligand ICAM-1, induced by 1 ng/ml of the chemokine SDF-1, was blocked by anti–LFA-1 mAb and also abrogated by dominant-negative ZAP-70 and piceatannol. In contrast, migration induced by 100 ng/ml SDF-1 was independent of both LFA-1 and ZAP-70. LFA-1 cross-linking induced tyrosine phosphorylation, which was blocked by dominant-negative ZAP-70 and piceatannol. We conclude that LFA-1 engagement triggers ZAP-70 activity that is essential for LFA-1–dependent migration.

Key Words: integrin • activation • chemotaxis • SDF-1 • metastasis

Abbreviations used in this paper: CD3, cluster of differentiation 3; GST, glutathione-S-transferase; ICAM-1, intercellular adhesion molecule-1; IRES, internal ribosome entry site; LFA, leukocyte function-associated antigen-1; SDF-1, stromal cell-derived factor-1; TCR, T cell receptor; WT, wild-type; ZAP-70, zeta-associated protein-70.

This research was supported by a grant from the Dutch Cancer Society (NKI 95-969).

Address all correspondence to E. Roos, Division of Cell Biology, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands. Tel.: (31) 20-5121931. Fax: (31) 20-5121944. E-mail: eroos{at}nki.nl


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