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Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylation

Oncogene volume 28, pages 2436–2445 (2009)Cite this article

Abstract

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.

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Acknowledgements

This project has been supported by funds from the Department of Defense Breast Cancer Research Program (DAMD17-01-1-0300), the Susan G Komen Foundation (BCTR0504146), a Research Development Award from the SPORE in Ovarian Cancer (P50-CA83639-A01) (to LY), and by the grant support from the NIH P01 099031, P20 CA101936 (MDACC Pancreatic Cancer SPORE), P50 CA116199 (MDACC Breast Cancer SPORE), P50 CA83639 (MDACC Ovarian Cancer SPORE), Marcus Foundation, National Breast Cancer Foundation, Inc., and Kadoorie Charitable Foundations (to M-C H). We acknowledge Dr Martin L Campbell at the Synthetic Antigen Laboratory, The University of Texas MD Anderson Cancer Center, for the synthesis of the phospho- and non-phospho-peptides as well as the NIH core grant to MD Anderson Cancer Center (CA16672). We thank Drs Xiangho He, Tiebang Kang, Bo Ping, Pingyu Zhang, Weiya Xia, and Mr William Spohn for their participation in the earlier development of this project. We also appreciate Dr Hay N (University of Illinois, Chicago, IL, USA), Dr Lu KP (Department of Medicine, Beth Deaconess Medical Center, Harvard Medical School, Boston, MA, USA), and Dr Xiao Z (Department of Biochemistry and Department of Medicine, Boston University School of Medicine, Boston, MA, USA) for their kindness in providing us the Akt1 MEF cells, Pin1 MEF cells, and Pin1 constructs. We are grateful for the technical assistance from Dr Jeng C Cheng and Dr Stephanie A Miller during the preparation of this paper. We also greatly appreciate the editing and language improvement of this paper by Ms Kristi Speights at the Department of Scientific Publication, The University of Texas MD Anderson Cancer Center.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Liao, Y Wei, X Zhou, J -Y Yang, Y -J Chen, N K Agarwal, D Sarbassov, D Yu & M -C Hung

  2. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Liao & C Dai

  3. Department of Pathology, Cancer Hospital, Fudan University, Shanghai, Shanghai, China

    X Zhou & D Shi

  4. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung, Taiwan

    Y -J Chen & M -C Hung

  5. Asia University, Taichung, Taiwan

    M -C Hung

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Correspondence to Y Liao or M -C Hung.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Liao, Y., Wei, Y., Zhou, X. et al. Peptidyl-prolyl cis/trans isomerase Pin1 is critical for the regulation of PKB/Akt stability and activation phosphorylation. Oncogene 28, 2436–2445 (2009). https://doi.org/10.1038/onc.2009.98

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