Phosphatidylinositol 3-kinase potentiates, but does not trigger, T cell proliferation mediated by the IL-2 receptor.
Proliferative signaling by the IL-2R can occur through two distinct pathways, one mediated by Stat5 and one by the adaptor protein Shc. Although Stat5 induces T cell proliferation by serving as a transcription factor, the mechanism of proliferative signaling by Shc is poorly defined. We examined the roles of two major signaling pathways downstream of Shc, the p44/p42 mitogen-activated protein kinase (extracellular signal-related kinase (Erk)) and phosphatidylinositol 3-kinase (PI3K) pathways, in promitogenic gene induction and proliferation in the IL-2-dependent T cell line CTLL-2. Using IL-2R mutants and specific pharmacologic inhibitors, we found that the PI3K, but not Erk, pathway is required for maximal induction of c-myc, cyclin D2, cyclin D3, cyclin E, and bcl-x(L) by Shc. To test whether the PI3K pathway is sufficient for proliferative signaling, a tamoxifen-regulated form of PI3K (mp110*ER) was expressed in CTLL-2 cells. Activation of the PI3K pathway through mp110*ER failed to up-regulate expression of the c-myc, cyclin D2, cyclin D3, cyclin E, bcl-2, or bcl-x(L) genes or down-regulate expression of p27(Kip1), even when coactivated with the Janus kinases (Jak) or the Raf/Erk pathway. Moreover, mp110*ER induced modest levels of thymidine incorporation without subsequent cell division. Although insufficient for mitogenesis, mp110*ER enhanced Stat5-mediated proliferative signaling through a mechanism independent of Stat5 transcriptional activity. Thus, in addition to serving a necessary, but insufficient role in Shc-mediated promitogenic gene expression, the PI3K pathway contributes to T cell proliferation by potentiating mitogenic signaling by Stat5.
Moon
J J
JJ
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Nelson
B H
BH
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011506:Proteins; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015534:Trans-Activators; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases