Phosphatidylinositol 3-Kinase Links the Interleukin-2 Receptor to Protein Kinase B and p70 S6 Kinase

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. 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. The high affinity interleukin-2 receptor (IL-2R), 1The abbreviations used areIL-2Rinterleukin-2 receptor;Erkextracellular-signal regulated kinase;PIphosphatidylinositol;ILinterleukin;MAPmitogen-activated protein;p70S6kp70 S6 kinase;FrapFKBP12-rapamycin-associated protein;PKBprotein kinase B;PdBuphorbol 12,13-dibutyrate;Abantibody;mAbmonoclonal antibody;CATchloramphenicol acetyltransferase;PKCprotein kinase C;MekErk kinase;HAhemagglutinin;rIL-2recombinant IL-2;Mops4-morpholinepropanesulfonic acid;PAGEpolyacrylamide gel electrophoresis;H2Bhistone 2B;rCD2rat CD2. which comprises α-, β-, and γ-subunits controls G1 to S progression, T cell clonal expansion, and functional differentiation (1Nelson B. Lord J. Greenberg P. Nature. 1994; 369: 333-336Crossref PubMed Scopus (282) Google Scholar, 2Nakamura Y. Russell S. Mess S. Friedmann M. Erdos M. Francois C. Jacques Y. Adelstein S. Leonard W. Nature. 1994; 369: 330-333Crossref PubMed Scopus (285) Google Scholar, 3Smith K.A. 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Immunol. 1993; 5: 337-344Crossref PubMed Scopus (12) Google Scholar). interleukin-2 receptor; extracellular-signal regulated kinase; phosphatidylinositol; interleukin; mitogen-activated protein; p70 S6 kinase; FKBP12-rapamycin-associated protein; protein kinase B; phorbol 12,13-dibutyrate; antibody; monoclonal antibody; chloramphenicol acetyltransferase; protein kinase C; Erk kinase; hemagglutinin; recombinant IL-2; 4-morpholinepropanesulfonic acid; polyacrylamide gel electrophoresis; histone 2B; rat CD2. PI 3-kinase is a ubiquitously expressed enzyme that catalyzes the phosphorylation of phosphoinositides at the D-3 hydroxyl of themyo-inositol ring generating PI 3-phosphate, PI 3,4-bisphosphate, and PI 3,4,5-trisphosphate (13Panayotou G. Waterfield M.D. Trends Cell Biol. 1992; 2: 358-360Abstract Full Text PDF PubMed Scopus (87) Google Scholar, 14Kapeller R. Cantley L. BioEssays. 1994; 16: 565-576Crossref PubMed Scopus (553) Google Scholar). The form of PI 3-kinase involved in protein-tyrosine kinase-dependent receptor signal transduction comprises a regulatory 85-kDa subunit that contains two Src homology 2 domains and at its N terminus one Src homology 3 domain and a catalytic 110-kDa subunit. Following IL-2R stimulation, several mechanisms have been proposed to recruit PI 3-kinase to the plasma membrane, where its cellular substrate PI 4,5-bisphosphate is located: engagement of the IL-2R leads to binding of the p85 regulatory subunit of PI 3-kinase to tyrosine 392 in the IL-2R β-chain (15Truitt K.E. Mills G.B. Turck C.W. Imboden J.B. J. Biol. Chem. 1994; 269: 5937-5943Abstract Full Text PDF PubMed Google Scholar); in addition, interleukin-2 (IL-2) in the of PI 3-kinase the Src family kinases Fyn L. Sutor S. Abraham R. J. 1994; PubMed Scopus Google Scholar) and Lck R. Merida I. T. Gaulton J. Biol. Chem. 1993; 268: Full Text PDF PubMed Google Scholar). 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We demonstrate that the serine/threonine kinase can activated by the cytokine IL-2 a PI 3-kinase-dependent Importantly, PI 3-kinase signals are sufficient to PKB in T cells, that PI 3-kinase as regulator of this serine/threonine kinase in lymphoid cells. PKB contains homology domain that can directly D-3 phosphoinositides S. K. A. Cell. 1995; Full Text PDF PubMed Scopus Google Scholar, R. Biochem. J. PubMed Scopus Google Scholar, A. D. Mol. Cell. Biol. PubMed Scopus Google Scholar), which contribute to the regulation of the PI 3-kinase signals are sufficient to for IL-2 in PKB PKB a target for PI 3-kinase signals IL-2 signal is expressed in the A. 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The also to serine/threonine kinase pathways regulated by that PI 3-kinase in T cells. and the of two kinases that are to PKB The of at one of these is regulated by binding D-3 phosphoinositides D. S. C. A. P. R. C. and P. Biol. We and for