Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F.
Cell cycle progression initiated by interleukin-2 (IL-2) in T cells is critical for lymphoproliferation and an immune response. Phosphatidyl inositol 3-kinase (PI3K) is activated by IL-2. However, nuclear targets for PI3K are not known. Here we identify the cell cycle regulator E2F as an IL-2 target in T lymphocytes and PI3K as the critical signaling pathway. We eliminate both Stat5 and Raf/MEK pathways from E2F regulation. Protein kinase B (PKB) is activated by IL-2 via PI3K. The expression of an active PKB is sufficient to induce E2F activity. Inhibition of PI3K inhibits phosphorylation of Rb, induction of cyclin D3, and degradation of p27kip1. These results establish a crucial PI3K/PKB-mediated link between the IL-2 teceptor and the cell cycle machinery.
Brennan
P
P
Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London, United Kingdom. brennan@icrf.icnet.uk
Babbage
J W
JW
Burgering
B M
BM
Groner
B
B
Reif
K
K
Cantrell
D A
DA
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002352:Carrier Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000502:physiology; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D015534:Trans-Activators / Q000502:physiology; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002867:Chromones; D056743:Cyclin D3; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015375:Receptors, Interleukin-2; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D050717:Retinoblastoma-Like Protein p130; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D050680:Transcription Factor DP1; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C534696:CCND3 protein, human; C493837:RBL2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one