Cutting edge: gab2 mediates an inhibitory phosphatidylinositol 3'-kinase pathway in T cell antigen receptor signaling.
Phosphatidylinositol 3'-kinase (PI3K) is a key component of multiple signaling pathways, where it typically promotes survival, proliferation, and/or adhesion. Here, we show that in TCR signaling, the scaffolding adapter Gab2 delivers an inhibitory signal via PI3K. Overexpression of Gab2 in T cell lines inhibits TCR-evoked activation of the IL-2 promoter, blocking NF-AT- and NF-kappaB-directed transcription. Inhibition is abrogated by mutating the Gab2 p85-binding sites, by treatment with PI3K inhibitors or by cotransfection of phosphatase homolog of tensin. Our findings provide the first evidence of a negative function for a scaffolding adapter in T cells and identify Gab2/PI3K-containing complexes as novel regulators of TCR signaling.
Pratt
J C
JC
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Igras
V E
VE
Maeda
H
H
Baksh
S
S
Gelfand
E W
EW
Burakoff
S J
SJ
Neel
B G
BG
Gu
H
H
D048868:Adaptor Proteins, Signal Transducing; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000276:immunology; D006388:Hemagglutinins / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D006388:Hemagglutinins; D007376:Interleukin-2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C490895:GAB2 protein, human