Disruption of 3-Phosphoinositide-dependent Kinase 1 (PDK1) Signaling by the Anti-tumorigenic and Anti-proliferative AgentN-α-tosyl-l-phenylalanyl Chloromethyl Ketone*
Disruption of 3-Phosphoinositide-dependent Kinase 1 (PDK1) Signaling by the Anti-tumorigenic and Anti-proliferative AgentN-α-tosyl-l-phenylalanyl Chloromethyl Ketone*
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抗肿瘤和抗增殖剂 N-α-甲苯磺酰基-l-苯丙氨酰氯甲基酮* 会破坏 3-磷酸肌醇依赖性激酶 1 (PDK1) 信号传导*
DOI：
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发表时间：
2001
影响因子：
4.8
通讯作者：
J. Blenis
中科院分区：
文献类型：
--
作者：
B. Ballif;A. Shimamura;Eunice Pae;J. Blenis
N-α-甲苯磺酰基-1-苯丙氨酰氯甲基酮（TPCK）的抗肿瘤和抗增殖作用已被发现30多年。然而，对TPCK控制这些效应的离散细胞靶点知之甚少。我们实验室以前的工作表明，TPCK与免疫抑制剂雷帕霉素一样，是70千道尔顿核糖体S6激酶1（S6 K1）的有效抑制剂，S6 K1介导参与细胞生长和增殖的事件。我们在这里表明，雷帕霉素和TPCK显示不同的抑制机制对S6 K1的雷帕霉素抗性形式的S6 K1是TPCK敏感的。此外，我们发现TPCK抑制相关激酶和原癌基因Akt的激活。S6 K1和Akt的上游调节因子包括磷酸肌醇3-激酶（PI 3-K）和3-磷酸肌醇依赖性激酶1（PDK 1）。TPCK对有丝分裂原调节的PI 3-K活性或总细胞PDK 1活性没有影响，而TPCK阻止了S6 K1和Akt中PDK 1调节位点的磷酸化。此外，虽然PDK 1和促分裂原活化蛋白激酶（MAPK）都是90千道尔顿核糖体S6激酶（RSK）完全活化所需的，但TPCK抑制RSK活化而不抑制MAPK活化。与RSK和Akt部分通过促凋亡蛋白BAD的磷酸化介导细胞存活信号的能力一致，TPCK减少BAD磷酸化并导致白介素-3依赖性32 D细胞的细胞死亡。最后，与在缺乏PDK 1的胚胎干细胞中观察到的结果一致，蛋白激酶A活化不被TPCK抑制，显示TPCK对有丝分裂原调节的PDK 1信号传导具有特异性。因此，TPCK抑制PDK 1信号传导使控制包括增殖和存活在内的多种细胞过程的中央激酶级联失效，并为其显著的生物学效应提供了解释。
The anti-tumorigenic and anti-proliferative effects ofN-α-tosyl-l-phenylalanyl chloromethyl ketone (TPCK) have been known for more than three decades. Yet little is known about the discrete cellular targets of TPCK controlling these effects. Previous work from our laboratory showed TPCK, like the immunosuppressant rapamycin, to be a potent inhibitor of the 70-kilodalton ribosomal S6 kinase 1 (S6K1), which mediates events involved in cell growth and proliferation. We show here that rapamycin and TPCK display distinct inhibitory mechanisms on S6K1 as a rapamycin-resistant form of S6K1 was TPCK-sensitive. Additionally, we show that TPCK inhibited the activation of the related kinase and proto-oncogene Akt. Upstream regulators of S6K1 and Akt include phosphoinositide 3-kinase (PI 3-K) and 3-phosphoinositide-dependent kinase 1 (PDK1). Whereas TPCK had no effect on either mitogen-regulated PI 3-K activity or total cellular PDK1 activity, TPCK prevented phosphorylation of the PDK1 regulatory sites in S6K1 and Akt. Furthermore, whereas both PDK1 and the mitogen-activated protein kinase (MAPK) are required for full activation of the 90-kilodalton ribosomal S6 kinase (RSK), TPCK inhibited RSK activation without inhibiting MAPK activation. Consistent with the capacity of RSK and Akt to mediate a cell survival signal, in part through phosphorylation of the pro-apoptotic protein BAD, TPCK reduced BAD phosphorylation and led to cell death in interleukin-3-dependent 32D cells. Finally, in agreement with results seen in embryonic stem cells lacking PDK1, protein kinase A activation was not inhibited by TPCK showing TPCK specificity for mitogen-regulated PDK1 signaling. TPCK inhibition of PDK1 signaling thus disables central kinase cascades governing diverse cellular processes including proliferation and survival and provides an explanation for its striking biological effects.
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人纤溶酶原激活剂抑制剂-2基因的结构。
DOI：
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发表时间：
1989
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Ye,RD;Ahern,SM;LeBeau,MM;Lebo,RV;Sadler,JE
通讯作者：
Sadler,JE
DOI：
10.1073/pnas.96.8.4438
发表时间：
1999-04-13
影响因子：
11.1
作者：
Peterson, RT;Desai, BN;Schreiber, SL
通讯作者：
Schreiber, SL
影响因子：
4.4
作者：
C. Vlahos;W. Matter;R. F. Brown;A. Traynor-Kaplan;P. Heyworth;E. Prossnitz;R. Ye;P. Marder;J. Schelm;K. J. Rothfuss
通讯作者：
C. Vlahos;W. Matter;R. F. Brown;A. Traynor-Kaplan;P. Heyworth;E. Prossnitz;R. Ye;P. Marder;J. Schelm;K. J. Rothfuss
影响因子：
56.9
作者：
Montagne, J;Stewart, MJ;Thomas, G
通讯作者：
Thomas, G
一种逆转录病毒致癌基因 akt，编码含有 SH2 样区域的丝氨酸-苏氨酸激酶。
DOI：
10.1126/science.254.5029.274
发表时间：
1991
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bellacosa,A;Testa,JR;Staal,SP;Tsichlis,PN
通讯作者：
Tsichlis,PN