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Calcineurin preferentially synergizes with PKC‐θ to activate JNK and IL‐2 promoter in T lymphocytes
Author(s) -
Werlen Guy,
Jacinto Estela,
Xia Ying,
Karin Michael
Publication year - 1998
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/17.11.3101
Subject(s) - calcineurin , protein kinase c , biology , jurkat cells , microbiology and biotechnology , nfat , mapk/erk pathway , kinase , phosphatase , transcription factor , t cell , biochemistry , phosphorylation , immunology , transplantation , medicine , immune system , gene
Costimulation of the T cell receptor (TCR) and CD28 is required for optimal interleukin‐2 (IL‐2) induction. These signals, which can be replaced by the pharmacological agents phorbol ester (PMA) and Ca 2+ ionophore, synergistically activate the mitogen‐activated protein kinase (MAPK) JNK. Cyclosporin A, an inhibitor of the Ca 2+ ‐dependent phosphatase calcineurin which blocks IL‐2 induction, abrogates Ca 2+ ‐triggered synergistic JNK activation. As protein kinase C (PKC) downregulation inhibits PMA+ionophore‐induced JNK activation, we examined whether a particular PKC isoform is preferentially involved in this response. We found that PKC‐θ but neither PKC‐α nor PKC‐ϵ participates in JNK activation, whereas all three PKCs lead to ERK MAPK activation. PKC‐θ specifically cooperates with calcineurin, and together their signals converge on (or upstream of) Rac leading to potent JNK activation. Similarly, calcineurin and PKC‐θ specifically synergize to induce transcription of reporters driven by the c‐jun and IL‐2 promoters. PKC‐θ and calcineurin are also partially responsible for the synergistic activation of JNK following TCR and CD28 ligation. Preferential cooperation between PKC‐θ and calcineurin is observed in Jurkat T cells but not in HeLa cells. These results indicate that PKC isozymes have distinct biological functions and suggest that synergistic JNK activation is an important function for PKC‐θ in T‐cell activation.