Inorganic polyphosphate stimulates mammalian TOR, a kinase involved in the proliferation of mammary cancer cells.

Inorganic polyphosphate (poly P), chains of hundreds of phosphate residues linked by "high-energy" bonds as in ATP, has been conserved from prebiotic times in all cells. Poly P is essential for a wide variety of functions in bacteria, including virulence in pathogens. In this study, we observe the unique and many-fold stimulation by poly P in vitro of the protein kinase mTOR (mammalian target of rapamycin). To explore the role of poly P in mammalian cells, a yeast polyphosphatase, PPX1, was inserted into the chromosomes of MCF-7 mammary cancer cells. The transfected cells are markedly deficient in their response to mitogens, such as insulin and amino acids, as seen in their failure to activate mTOR to phosphorylate one of its substrates, PHAS-I (the initiation factor 4E-binding protein). In addition, the transfected cells are severely reduced in their growth in a serum-free medium. On the basis of these findings, we suggest that poly P (and/or PPX1) serves as a regulatory factor in the activation of mTOR in the proliferative signaling pathways of animal cells.
AuthorsLihong Wang, Cresson D Fraley, Jesika Faridi, Arthur Kornberg, Richard A Roth
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 20 Pg. 11249-54 (Sep 30 2003) ISSN: 0027-8424 [Print] United States
PMID12970465 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • DNA Primers
  • Phosphates
  • Protein Kinase Inhibitors
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Base Sequence
  • Breast Neoplasms (enzymology, pathology)
  • Cell Division (physiology)
  • DNA Primers
  • Enzyme Activation
  • Humans
  • Phosphates (pharmacology)
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Protein Kinases (metabolism, physiology)
  • TOR Serine-Threonine Kinases
  • Tumor Cells, Cultured

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