Monfar M, Lemon K P, Grammer T C, Cheatham L, Chung J, Vlahos C J, Blenis J
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
Mol Cell Biol. 1995 Jan;15(1):326-37. doi: 10.1128/MCB.15.1.326.
Activation of phosphatidylinositol 3-kinase (PI3K) and activation of the 70/85-kDa S6 protein kinases (alpha II and alpha I isoforms, referred to collectively as pp70S6k) have been independently linked to the regulation of cell proliferation. We demonstrate that these kinases lie on the same signalling pathway and that PI3K mediates the activation of pp70 by the cytokine interleukin-2 (IL-2). We also show that the activation of pp70S6k can be blocked at different points along the signalling pathway by using specific inhibitors of T-cell proliferation. Inhibition of PI3K activity with structurally unrelated but highly specific PI3K inhibitors (wortmannin or LY294002) results in inhibition of IL-2-dependent but not phorbol ester (conventional protein kinase C [cPKC])-dependent pp70S6k activation. The T-cell immunosuppressant rapamycin potently antagonizes IL-2-(PI3K)- and phorbol ester (cPKC)-mediated activation of pp70S6k. Thus, wortmannin and rapamycin antagonize IL-2-mediated activation of pp70S6k at distinct points along the PI3K-regulated signalling pathway, or rapamycin antagonizes another pathway required for pp70S6k activity. Agents that raise the concentration of intracellular cyclic AMP (cAMP) and activate cAMP-dependent protein kinase (PKA) also inhibit IL-2-dependent activation of pp70S6k. In this case, inhibition appears to occur at least two points in this signalling path. Like rapamycin, PKA appears to act downstream of cPKC-mediated pp70S6k activation, and like wortmannin, PKA antagonizes IL-2-dependent activation of PI3K. The results with rapamycin and wortmannin are of added interest since the yeast and mammalian rapamycin targets resemble PI3K in the catalytic domain.
磷脂酰肌醇3激酶（PI3K）的激活以及70/85-kDa S6蛋白激酶（αII和αI亚型，统称为pp70S6k）的激活已分别与细胞增殖的调控相关联。我们证明这些激酶位于同一信号通路，且PI3K介导细胞因子白细胞介素-2（IL-2）对pp70的激活。我们还表明，通过使用T细胞增殖的特异性抑制剂，可在信号通路的不同点阻断pp70S6k的激活。用结构不相关但高度特异性的PI3K抑制剂（渥曼青霉素或LY294002）抑制PI3K活性，会导致抑制IL-2依赖性而非佛波酯（传统蛋白激酶C [cPKC]）依赖性的pp70S6k激活。T细胞免疫抑制剂雷帕霉素有力地拮抗IL-2-（PI3K）-和佛波酯（cPKC）介导的pp70S6k激活。因此，渥曼青霉素和雷帕霉素在PI3K调节的信号通路的不同点拮抗IL-2介导的pp70S6k激活，或者雷帕霉素拮抗pp70S6k活性所需的另一条通路。提高细胞内环状AMP（cAMP）浓度并激活cAMP依赖性蛋白激酶（PKA）的试剂也抑制IL-2依赖性的pp70S6k激活。在这种情况下，抑制似乎发生在该信号通路的至少两个点。与雷帕霉素一样，PKA似乎作用于cPKC介导的pp70S6k激活的下游，与渥曼青霉素一样，PKA拮抗IL-2依赖性的PI3K激活。雷帕霉素和渥曼青霉素的结果更具意义，因为酵母和哺乳动物的雷帕霉素靶点在催化结构域与PI3K相似。
