PTEN permits acute increases in D3-phosphoinositide levels following TCR stimulation but inhibits distal signaling events by reducing the basal activity of Akt.
Phosphoinositide 3-kinase (PI3K) is important in TCR signaling. PI3K generates phosphatidylinositol 3, 4, 5-trisphosphate (PI-3,4,5-P3), which regulates membrane localization and/or activity of multiple signaling proteins. PTEN (phosphatase and tensin homologue deleted on chromosome 10) opposes PI3K, reversing this reaction. Maintaining the balance between these two enzymes is important for normal T cell function. Here we use the PTEN-null Jurkat T cell line to address the role of PTEN in modulating proximal and distal TCR-signaling events. PTEN expression at levels that restored low basal Akt phosphorylation (an indicator of PI-3,4,5-P3 levels), but which were not themselves cytotoxic, had minimal effect on TCR-stimulated activation of phospholipase Cgamma1 and Ca2+ flux, but reduced the duration of extracellular signal-regulated kinase (Erk) activation. Distal signaling events, including nuclear factor of activated T cells (NFAT) activation, CD69 expression and IL-2 production, were all inhibited by PTEN expression. Notably, PTEN did not block TCR-stimulated PI-3,4,5-P3 accumulation. The effect of PTEN on distal TCR signaling events was strongly correlated with the loss of the constitutive Akt activation and glycogen synthase kinase-3 (GSK3) inhibition that is typical of Jurkat cells, and could be reversed by expression of activated Akt or pharmacologic inhibition of GSK3. These results suggest that PTEN acts in T cells primarily to control basal PI-3,4,5-P3 levels, rather than opposing PI3K acutely during TCR stimulation.
Seminario
Maria-Cristina
MC
Laboratory of Cellular and Molecular Biology, National Institute on Aging, Baltimore, MD 21224, USA.
Precht
Patricia
P
Bunnell
Stephen C
SC
Warren
Sarah E
SE
Morris
Christa M
CM
Taub
Dennis
D
Wange
Ronald L
RL
D000730:Androstadienes / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D002118:Calcium / Q000276:immunology; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology; D019169:Jurkat Cells; D037181:Lectins, C-Type; D018613:Microscopy, Confocal; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000276:immunology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D018129:Phosphatidylinositol Phosphates / Q000276:immunology*; D051966:Phospholipase C gamma; D010744:Phosphoric Monoester Hydrolases / Q000276:immunology* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000276:immunology* / Q000378:metabolism; D010738:Type C Phospholipases / Q000276:immunology; D000077191:Wortmannin; D000099192:CD69 Antigens
D000730:Androstadienes; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002118:Calcium; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D007376:Interleukin-2; D037181:Lectins, C-Type; D019950:Mitogen-Activated Protein Kinase 1; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D018129:Phosphatidylinositol Phosphates; D051966:Phospholipase C gamma; D010744:Phosphoric Monoester Hydrolases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D010738:Type C Phospholipases; D000077191:Wortmannin; D000099192:CD69 Antigens; C060974:phosphatidylinositol 3,4,5-triphosphate; C494918:AKT1 protein, human; C494929:PTEN protein, human