Liao Y, Wei Y, Zhou X, Yang J-Y, Dai C, Chen Y-J, Agarwal N K, Sarbassov D, Shi D, Yu D, Hung M-C
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Oncogene. 2009 Jul 2;28(26):2436-45. doi: 10.1038/onc.2009.98. Epub 2009 May 18.
The serine/threonine protein kinase B (PKB, also known as Akt) plays a pivotal role in diverse cellular functions. Elevated expression of activated Akt has been detected in a wide variety of human cancers; however, the mechanism of Akt protein stability regulation remains unclear. In this study, we showed a strong correlation between the expression levels of an oncogenic peptidyl-prolyl cis/trans isomerase Pin1 and levels of Akt phosphorylation at S473 in multiple cancer types (P<0.0001). Akt-pS473 status combined with Pin1 expression levels predicted a poorer prognosis than did either one alone in patients with breast cancer (P=0.0052). We further showed that Pin1 regulated Akt stability and phosphorylation on S473 through the phosphorylated Thr-Pro motifs of Akt. These motifs are conserved evolutionary and are required for the maintenance of Akt stability and its interaction with Pin1. In addition, repressing Pin1 expression through either homologue Pin1 knockout or small interfering RNA-mediated knockingdown compromised its ability to protect Akt from degradation. Our results show how Akt protein stability is regulated by the peptidyl-prolyl cis/trans isomerase Pin1 and highlight the importance of this oncogenic network in human disease pathogenesis.
丝氨酸/苏氨酸蛋白激酶B（PKB，也称为Akt）在多种细胞功能中起关键作用。在多种人类癌症中均检测到活化型Akt的表达升高；然而，Akt蛋白稳定性调控的机制仍不清楚。在本研究中，我们发现在多种癌症类型中，致癌肽基脯氨酰顺/反异构酶Pin1的表达水平与Akt在S473位点的磷酸化水平之间存在强相关性（P<0.0001）。在乳腺癌患者中，Akt-pS473状态与Pin1表达水平相结合预测的预后比单独任何一项都差（P=0.0052）。我们进一步表明，Pin1通过Akt的磷酸化苏氨酸-脯氨酸基序调节Akt的稳定性及S473位点的磷酸化。这些基序在进化上是保守的，是维持Akt稳定性及其与Pin1相互作用所必需的。此外，通过同源Pin1基因敲除或小干扰RNA介导的敲低来抑制Pin1表达，会损害其保护Akt不被降解的能力。我们的结果显示了肽基脯氨酰顺/反异构酶Pin1如何调节Akt蛋白的稳定性，并突出了这一致癌网络在人类疾病发病机制中的重要性。
