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Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation

Science, 26 June 2009
Vol. 324, Issue 5935, p. 1713-1716
DOI: 10.1126/science.1171721

Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation

  1. Daniel J. Gough1,*,
  2. Alicia Corlett1,*,,
  3. Karni Schlessinger1,,
  4. Joanna Wegrzyn2,
  5. Andrew C. Larner2,
  6. David E. Levy1,§
  1. 1Department of Pathology and New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
  2. 2Department of Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
  1. §To whom correspondence should be addressed. E-mail: david.levy{at}med.nyu.edu

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor responsive to cytokine signaling and tyrosine kinase oncoproteins by nuclear translocation when it is tyrosine-phosphorylated. We report that malignant transformation by activated Ras is impaired without STAT3, in spite of the inability of Ras to drive STAT3 tyrosine phosphorylation or nuclear translocation. Moreover, STAT3 mutants that cannot be tyrosine-phosphorylated, that are retained in the cytoplasm, or that cannot bind DNA nonetheless supported Ras-mediated transformation. Unexpectedly, STAT3 was detected within mitochondria, and exclusive targeting of STAT3 to mitochondria without nuclear accumulation facilitated Ras transformation. Mitochondrial STAT3 sustained altered glycolytic and oxidative phosphorylation activities characteristic of cancer cells. Thus, in addition to its nuclear transcriptional role, STAT3 regulates a metabolic function in mitochondria, supporting Ras-dependent malignant transformation.

  • * These authors contributed equally to this work.

  • Present address: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeňská 1083, Prague 4, Czech Republic 14220.

  • Present address: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

  • Received for publication 2 February 2009.
  • Accepted for publication 11 May 2009.

Citation:

D. J. Gough, A. Corlett, K. Schlessinger, J. Wegrzyn, A. C. Larner, and D. E. Levy, Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation. Science 324, 1713-1716 (2009).

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