Requirement for Abl kinases in T cell receptor signaling.
BACKGROUND
The c-Abl and Arg proteins comprise a unique family of nonreceptor tyrosine kinases that have been implicated in the regulation of cell proliferation and survival, cytoskeletal reorganization, cell migration, and the response to oxidative stress and DNA damage. Targeted deletion or mutation of c-Abl in mice results in a variety of immune system phenotypes, including splenic and thymic atrophy, lymphopenia, and an increased susceptibility to infection. However, despite the generation of these mice over a decade ago, little is known regarding the mechanisms responsible for these phenotypes or the immune-related consequences of ablation of both the c-Abl and Arg kinases, which are coexpressed in lymphoid tissues.


RESULTS
Here, we report that T cell receptor (TCR) stimulation results in activation of the endogenous Abl kinases. We demonstrate that Zap70 and the transmembrane adaptor linker for activation of T cells (LAT) are targets of the Abl kinases, and that loss of Abl kinase activity reduces TCR-induced Zap70 phosphorylation at tyrosine 319. This correlates with diminished LAT tyrosine phosphorylation, as well as reduced tyrosine phosphorylation and recruitment of phospholipase Cgamma1 to LAT. Significantly, we show that Abl kinase activity is required for maximal signaling leading to transcription of the IL-2 promoter, as well as TCR-induced IL-2 production and proliferation of primary T cells.


CONCLUSIONS
We conclude that the Abl kinases have a role in the regulation of TCR-mediated signal transduction leading to IL-2 production and cell proliferation.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Patricia A
PA
Zipfel
Weiguo
W
Zhang
Marisol
M
Quiroz
Ann Marie
AM
Pendergast
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001549:Benzamides; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D000068877:Imatinib Mesylate; D007376:Interleukin-2 / Q000378:metabolism; D008156:Luciferases; D008213:Lymphocyte Activation / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009841:Oligonucleotides; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D002352:Carrier Proteins; D007376:Interleukin-2; C491734:Lat protein, mouse; D008565:Membrane Proteins; D009841:Oligonucleotides; D010750:Phosphoproteins; D010879:Piperazines; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D000068877:Imatinib Mesylate; D008156:Luciferases; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse