Phosphatidylinositol 3-Kinase Links the Interleukin-2 Receptor to Protein Kinase B and p70 S6 Kinase*
- From the Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, 44 Lincoln’s Inn Fields, London WC2A 3PX, United Kingdom and the§Laboratory for Physiological Chemistry, Utrecht University, Universiteitsweg 100, Utrecht 3584 CG , The Netherlands
Abstract
Phosphatidylinositol 3-kinase (PI 3-kinase) is activated by the cytokine interleukin-2 (IL-2). We have used a constitutively active PI 3-kinase to identify IL-2-mediated signal transduction pathways directly regulated by PI 3-kinase in lymphoid cells. The serine/threonine protein kinase B (PKB)/Akt can act as a powerful oncogene in T cells, but its positioning in normal T cell responses has not been explored. Herein, we demonstrate that PKB is activated by IL-2 in a PI 3-kinase-dependent fashion. Importantly, PI 3-kinase signals are sufficient for PKB activation in IL-2-dependent T cells, and PKB is a target for PI 3-kinase signals in IL-2 activation pathways. The present study establishes also that PI 3-kinase signals or PKB signals are sufficient for activation of p70 S6 kinase in T cells. PI 3-kinase can contribute to, but is not sufficient for, activation of extracellular signal-regulated kinases (Erks) and Erk effector pathways. Therefore, PI 3-kinase is a selective regulator of serine/threonine kinase signal transduction pathways in T lymphocytes, and this enzyme provides a crucial link between the interleukin-2 receptor, the protooncogene PKB, and p70 S6 kinase.
Footnotes
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↵* This work was supported by the Imperial Cancer Research Fund and by Human Capital Mobility Program Grant ERB CHRX CT 94-0537.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Supported by a Boehringer Ingelheim Fellowship. To whom correspondence should be addressed. Tel.: 0171-269-3307; Fax: 0171-269-3479; E-mail: reif{at}icrf.icnet.uk.
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↵1 The abbreviations used are: IL-2R, interleukin-2 receptor; Erk, extracellular-signal regulated kinase; PI, phosphatidylinositol; IL, interleukin; MAP, mitogen-activated protein; p70S6k, p70 S6 kinase; Frap, FKBP12-rapamycin-associated protein; PKB, protein kinase B; PdBu, phorbol 12,13-dibutyrate; Ab, antibody; mAb, monoclonal antibody; CAT, chloramphenicol acetyltransferase; PKC, protein kinase C; Mek, Erk kinase; HA, hemagglutinin; rIL-2, recombinant IL-2; Mops, 4-morpholinepropanesulfonic acid; PAGE, polyacrylamide gel electrophoresis; H2B, histone 2B; rCD2, rat CD2.
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- Received February 18, 1997.
- Revision received March 24, 1997.
