Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity

Oncogene volume 26, pages 7656–7664 (2007)Cite this article

Abstract

Signal transducer and activator of transcription 3 (Stat3) belongs to a family of latent cytoplasmic transcription factors important for cytokine signaling. Stat3 is constitutively activated in various tumors, and activated Stat3 itself also acts as an oncogene. Transcriptional activity of Stat3 is controlled by Tyr-phosphorylation, followed by dimerization and nuclear translocation. However, phosphorylation on Ser727 is indispensable for its maximal transcriptional activity with unclear mechanism. Here, we report that peptidyl-prolyl cis/trans isomerase 1 (Pin1), which specifically recognizes the pSer/Thr-Pro motifs on its target proteins, interacts with Stat3 upon cytokine/growth factor stimulation. Overexpression of Pin1 promotes Stat3 transcriptional activity and target gene expression, as well as recruitment of transcription coactivator, p300. These effects, however, were compromised in the Pin1-deficient cells, and were totally dependent on the Ser727 phosphorylation site. Finally, we showed that Pin1 enhances Stat3-mediated epithelial–mesenchymal transition in breast cancer cells induced by oncostatin M. Our data reveal a novel, Ser727 phosphorylation-dependent, post-translational regulation mechanism for Stat3.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Bao L, Kimzey A, Sauter G, Sowadski JM, Lu KP, Wang DG . (2004). Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am J Pathol 164: 1727–1737.

    Article  CAS  Google Scholar 

  • Bowman T, Garcia R, Turkson J, Jove R . (2000). STATs in oncogenesis. Oncogene 19: 2474–2488.

    Article  CAS  Google Scholar 

  • Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C et al. (1999). Stat3 as an oncogene. Cell 98: 295–303.

    Article  CAS  Google Scholar 

  • Cao X, Tay A, Guy GR, Tan YH . (1996). Activation and association of Stat3 with Src in v-Src-transformed cell lines. Mol Cell Biol 16: 1595–1603.

    Article  CAS  Google Scholar 

  • Clevenger CV . (2004). Roles and regulation of stat family transcription factors in human breast cancer. Am J Pathol 165: 1449–1460.

    Article  CAS  Google Scholar 

  • Crenshaw DG, Yang J, Means AR, Kornbluth S . (1998). The mitotic peptidyl-prolyl isomerase, Pin1, interacts with Cdc25 and Plx1. EMBO J 17: 1315–1327.

    Article  CAS  Google Scholar 

  • Danial NN, Pernis A, Rothman PB . (1995). Jak–STAT signaling induced by the v-abl oncogene. Science 269: 1875–1877.

    Article  CAS  Google Scholar 

  • Darnell Jr JE, Kerr IM, Stark GR . (1994). Jak–STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264: 1415–1421.

    Article  CAS  Google Scholar 

  • Darnell Jr JE . (1997). STATs and gene regulation. Science 277: 1630–1635.

    Article  CAS  Google Scholar 

  • Decker T, Kovarik P . (2000). Serine phosphorylation of STATs. Oncogene 19: 2628–2637.

    Article  CAS  Google Scholar 

  • Fujimori F, Takahashi K, Uchida C, Uchida T . (1999). Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G(0) arrest. Biochem Biophys Res Commun 265: 658–663.

    Article  CAS  Google Scholar 

  • Holzer RG, Ryan RE, Tommack M, Schlekeway E, Jorcyk CL . (2004). Oncostatin M stimulates the detachment of a reservoir of invasive mammary carcinoma cells: role of cyclooxygenase-2. Clin Exp Metastasis 21: 167–176.

    Article  CAS  Google Scholar 

  • Jorcyk CL, Holzer RG, Ryan RE . (2006). Oncostatin M induces cell detachment and enhances the metastatic capacity of T-47D human breast carcinoma cells. Cytokine 33: 323–336.

    Article  CAS  Google Scholar 

  • Levy DE, Lee CK . (2002). What does Stat3 do? J Clin Invest 109: 1143–1148.

    Article  CAS  Google Scholar 

  • Lim CP, Cao X . (1999). Serine phosphorylation and negative regulation of Stat3 by JNK. J Biol Chem 274: 31055–31061.

    Article  CAS  Google Scholar 

  • Lu KP, Hanes SD, Hunter T . (1996). A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380: 544–547.

    Article  CAS  Google Scholar 

  • Lu PJ, Zhou XZ, Shen M, Lu KP . (1999). Function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science 283: 1325–1328.

    Article  CAS  Google Scholar 

  • Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT et al. (2003). GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. EMBO J 22: 1325–1335.

    Article  CAS  Google Scholar 

  • Ng DC, Lin BH, Lim CP, Huang G, Zhang T, Poli V et al. (2006). Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J Cell Biol 172: 245–257.

    Article  CAS  Google Scholar 

  • Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H et al. (1999). Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 18: 4657–4668.

    Article  CAS  Google Scholar 

  • Thiery JP . (2003). Epithelial–mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15: 740–746.

    Article  CAS  Google Scholar 

  • Wen Z, Zhong Z, Darnell Jr JE . (1995). Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82: 241–250.

    Article  CAS  Google Scholar 

  • Winkler KE, Swenson KI, Kornbluth S, Means AR . (2000). Requirement of the prolyl isomerase Pin1 for the replication checkpoint. Science 287: 1644–1647.

    Article  CAS  Google Scholar 

  • Wulf G, Finn G, Suizu F, Lu KP . (2005). Phosphorylation-specific prolyl isomerization: is there an underlying theme? Nat Cell Biol 7: 435–441.

    Article  CAS  Google Scholar 

  • Wulf G, Garg P, Liou YC, Iglehart D, Lu KP . (2004). Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J 23: 3397–3407.

    Article  CAS  Google Scholar 

  • Wulf G, Ryo A, Liou YC, Lu KP . (2003). The prolyl isomerase Pin1 in breast development and cancer. Breast Cancer Res 5: 76–82.

    Article  CAS  Google Scholar 

  • Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J et al. (1995). Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269: 81–83.

    Article  CAS  Google Scholar 

  • Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, Volinia S et al. (2002). The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419: 853–857.

    Article  CAS  Google Scholar 

  • Zhang F, Li C, Halfter H, Liu J . (2003). Delineating an oncostatin M-activated STAT3 signaling pathway that coordinates the expression of genes involved in cell cycle regulation and extracellular matrix deposition of MCF-7 cells. Oncogene 22: 894–905.

    Article  CAS  Google Scholar 

  • Zhang T, Seow KT, Ong CT, Cao X . (2002). Interdomain interaction of Stat3 regulates its Src homology 2 domain-mediated receptor binding activity. J Biol Chem 277: 17556–17563.

    Article  CAS  Google Scholar 

  • Zheng H, You H, Zhou XZ, Murray SA, Uchida T, Wulf G et al. (2002). The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419: 849–853.

    Article  CAS  Google Scholar 

  • Zhou XZ, Kops O, Werner A, Lu PJ, Shen M, Stoller G et al. (2000). Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Mol Cell 6: 873–883.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Agency for Science, Technology and Research of Singapore. T Uchida is supported by Grant-in-Aid for Scientific Research on Priority Areas of Japan. X Cao is an adjunct staff in the Department of Biochemistry, National University of Singapore.

Author information

Authors and Affiliations

  1. Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Singapore, Republic of Singapore

    C Lufei, T H Koh & X Cao

  2. Graduate School of Agricultural Science, Tohoku University, Sendai, Japan

    T Uchida

Authors
  1. C Lufei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T H Koh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to X Cao.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lufei, C., Koh, T., Uchida, T. et al. Pin1 is required for the Ser727 phosphorylation-dependent Stat3 activity. Oncogene 26, 7656–7664 (2007). https://doi.org/10.1038/sj.onc.1210567

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210567

Keywords

This article is cited by

Search

Advanced search

Quick links