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Published 15 April 2002. doi:10.1083/jcb.200201097
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© The Rockefeller University Press, 0021-9525/2002/4/253 $5.00
The Journal of Cell Biology, Volume 157, Number 2, April 15, 2002 253-263

Article

Translocation of PKC{theta} in T cells is mediated by a nonconventional, PI3-K– and Vav-dependent pathway, but does not absolutely require phospholipase C



Martin Villalba1,2, Kun Bi1, Junru Hu1, Yoav Altman1, Paul Bushway1, Eric Reits3, Jacques Neefjes3, Gottfried Baier4, Robert T. Abraham5 and Amnon Altman1

1 Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
2 Laboratory of Intracellular Signaling and Gene Regulation, Institut de Génétique Moléculaire de Montpellier-CNRS, 34293 Montpellier, France
3 Department of Tumor Biology, Netherlands Cancer Center, 1066 CX Amsterdam, Netherlands
4 Institute for Medical Biology and Human Genetics, University of Innsbruck, A-6020 Innsbruck, Austria
5 Program in Signal Transduction Research, The Burnham Institute, La Jolla, CA 92037

Address correspondence to Amnon Altman or Martin Villalba, Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Tel.: (858) 558-3527. Fax: (858) 558-3526. E-mail: amnon{at}liai.org or Villalba{at}liai.org

PKC{theta} plays an essential role in activation of mature T cells via stimulation of AP-1 and NF-{kappa}B, and is known to selectively translocate to the immunological synapse in antigen-stimulated T cells. Recently, we reported that a Vav/Rac pathway which depends on actin cytoskeleton reorganization mediates selective recruitment of PKC{theta} to the membrane or cytoskeleton and its catalytic activation by anti-CD3/CD28 costimulation. Because this pathway acted selectively on PKC{theta}, we addressed here the question of whether the translocation and activation of PKC{theta} in T cells is regulated by a unique pathway distinct from the conventional mechanism for PKC activation, i.e., PLC-mediated production of DAG. Using three independent approaches, i.e., a selective PLC inhibitor, a PLC{gamma}1-deficient T cell line, or a dominant negative PLC{gamma}1 mutant, we demonstrate that CD3/CD28-induced membrane recruitment and COOH-terminal phosphorylation of PKC{theta} are largely independent of PLC. In contrast, the same inhibitory strategies blocked the membrane translocation of PKC{alpha}. Membrane or lipid raft recruitment of PKC{theta} (but not PKC{alpha}) was absent in T cells treated with phosphatidylinositol 3-kinase (PI3-K) inhibitors or in Vav-deficient T cells, and was enhanced by constitutively active PI3-K. 3-phosphoinositide-dependent kinase-1 (PDK1) also upregulated the membrane translocation of PKC{theta}, but did not associate with it. These results provide evidence that a nonconventional PI3-K– and Vav-dependent pathway mediates the selective membrane recruitment and, possibly, activation of PKC{theta} in T cells.

Key Words: protein kinase C-{theta}; phospholipase C; Vav; phosphatidylinositol 3-kinase; T cell


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