Phosphorylated STAT3 physically interacts with NPM and transcriptionally enhances its expression in cancer

Zhuo Ren, Joeri Aerts, Joeri Pen, Carlo Heirman, Karine Breckpot, Jacques De Greve

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

The signal transducer and activator of transcription 3 (STAT3) can be activated by the tyrosine kinase domain of the chimeric protein nucleophosmin/anaplastic lymphoma kinase (NPM/ALK), and has a pivotal role in mediating NPM/ALK-related malignant cell transformation. Although the role of STAT3 and wild-type NPM in oncogenesis has been extensively investigated, the relationship between both molecules in cancer remains poorly understood. In the present study, we first demonstrate that STAT3 phosphorylation at tyrosine 705 is accompanied by a concomitant increase in the expression level of NPM. Nuclear co-translocation of phosphorylated STAT3 with NPM can be triggered by interferon-alpha (IFN-a) stimulation of Jurkat cells and phosphorylated STAT3 co-localizes with NPM in cancer cells showing constitutive STAT3 activation. We further demonstrate that STAT3 phosphorylation can transcriptionally mediate NPM upregulation in IFN-a-stimulated Jurkat cells and is responsible for maintaining its expression in cancer cells showing constitutive STAT3 activation. Inhibition of STAT3 phosphorylation or knockdown of NPM expression abrogates their simultaneous transnuclear movements. Finally, we found evidence for a physical interaction between NPM and STAT3 in conditions of STAT3 activation. In conclusion, NPM is a downstream effector of the STAT3 signaling, and can facilitate the nuclear entry of phosphorylated STAT3. These observations might open novel opportunities for targeting the STAT3 pathway in cancer.
Original languageEnglish
Pages (from-to)1650-1657
Number of pages7
JournalONCOGENE
Volume34
Issue number13
Early online date5 May 2014
DOIs
Publication statusPublished - 26 Mar 2015

Keywords

  • STAT3
  • phosphorylated
  • NPM
  • cancer

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