STAT5 is essential for Akt/p70S6 kinase activity during IL-2-induced lymphocyte proliferation.
IL-2R activates two distinct signaling pathways mediated by the adaptor protein Shc and the transcription factor STAT5. Prior mutagenesis studies of the IL-2R have indicated that the Shc and STAT5 pathways are redundant in the ability to induce lymphocyte proliferation. Yet paradoxically, T cells from STAT5-deficient mice fail to proliferate in response to IL-2, suggesting that the Shc pathway is unable to promote mitogenesis in the genetic absence of STAT5. Here we show in the murine lymphocyte cell line Ba/F3 that low levels of STAT5 activity are essential for Shc signaling. In the absence of STAT5 activity, Shc was unable to sustain activation of the Akt/p70S6 kinase pathway or promote lymphocyte proliferation and viability. Restoring STAT5 activity via a heterologous receptor rescued Shc-induced Akt/p70S6 kinase activity and cell proliferation with kinetics consistent with a transcriptional mechanism. Thus, STAT5 appears to regulate the expression of one or more unidentified components of the Akt pathway. Our results not only explain the severe proliferative defect in STAT5-deficient T cells but also provide mechanistic insight into the oncogenic properties of STAT5 in various leukemias and lymphomas.
Lockyer
Heather M
HM
British Columbia Cancer Agency, Trev and Joyce Deeley Research Centre, Victoria, Canada.
Tran
Eric
E
Nelson
Brad H
BH
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism / Q000502:physiology*; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000502:physiology; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D016296:Mutagenesis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000502:physiology; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism* / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D048868:Adaptor Proteins, Signal Transducing; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; C528024:SHC1 protein, human; D050799:STAT5 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa