Tec kinase signaling in T cells is regulated by phosphatidylinositol 3-kinase and the Tec pleckstrin homology domain.
Tec, the prototypical member of the Tec family of tyrosine kinases, is abundantly expressed in T cells and other hemopoietic cell types. Although the functions of Itk and Txk have recently been investigated, little is known about the role of Tec in T cells. Using antisense oligonucleotide treatment to deplete Tec protein from primary T cells, we demonstrate that Tec plays a role in TCR signaling leading to IL-2 gene induction. Interestingly, Tec kinases are the only known family of tyrosine kinases containing a pleckstrin homology (PH) domain. Using several PH domain mutants overexpressed in Jurkat T cells, we show that the Tec PH domain is required for Tec-mediated IL-2 gene induction and TCR-mediated Tec tyrosine phosphorylation. Furthermore, we show that Tec colocalizes with the TCR after TCR cross-linking, and that both the Tec PH and Src homology (SH) 2 domains play a role in this association. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, abolishes Tec-mediated IL-2 gene induction and Tec tyrosine phosphorylation, and partially suppresses Tec colocalization with the activated TCR. Thus, our data implicate the Tec kinase PH domain and phosphatidylinositol 3-kinase in Tec signaling downstream of the TCR.
Yang
W C
WC
Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester MA 01655, USA.
Ching
K A
KA
Tsoukas
C D
CD
Berg
L J
LJ
D019943:Amino Acid Substitution / Q000235:genetics; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics / Q000502:physiology*; D003545:Cysteine / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells; D008239:Lysine / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D000077191:Wortmannin
D000730:Androstadienes; D001120:Arginine; D001798:Blood Proteins; D003545:Cysteine; D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D007376:Interleukin-2; D008239:Lysine; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D000077191:Wortmannin; C060974:phosphatidylinositol 3,4,5-triphosphate; C039077:platelet protein P47; C089848:Tec protein-tyrosine kinase