Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips

Jing Huang, Heng Zhu, Stephen J. Haggarty, David R. Spring, Heejun Hwang, Fulai Jin, Michael Snyder, Stuart L. Schreiber

Research output: Contribution to journalArticle

Abstract

The TOR (target of rapamycin) proteins play important roles in nutrient signaling in eukaryotic cells. Rapamycin treatment induces a state reminiscent of the nutrient starvation response, often resulting in growth inhibition. Using a chemical genetic modifier screen, we identified two classes of small molecules, small-molecule inhibitors of rapamycin (SMIRs) and small-molecule enhancers of rapamycin (SMERs), that suppress and augment respectively, rapamycin's effect in the yeast Saccharomyces cerevisiae. Probing proteome chips with biotinylated SMIRs revealed putative intracellular target proteins, including Tep1p, a homolog of the mammalian PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor, and Ybr077cp (Nir1p), a protein of previously unknown function that we show to be a component of the TOR signaling network. Both SMIR target proteins are associated with PI(3,4)P 2, suggesting a mechanism of regulation of the TOR pathway involving phosphatidylinositides. Our results illustrate the combined use of chemical genetics and proteomics in biological discovery and map a path for creating useful therapeutics for treating human diseases involving the TOR pathway, such as diabetes and cancer.

Original languageEnglish (US)
Pages (from-to)16594-16599
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number47
DOIs
StatePublished - Nov 23 2004

Fingerprint

Sirolimus
Proteome
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase
Food
Chromosomes, Human, Pair 10
Eukaryotic Cells
Starvation
Proteomics
Saccharomyces cerevisiae
Neoplasms
Proteins
Yeasts
Growth

Keywords

  • Diabetes
  • Drug discovery
  • Drug target identification
  • Proteomics

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips. / Huang, Jing; Zhu, Heng; Haggarty, Stephen J.; Spring, David R.; Hwang, Heejun; Jin, Fulai; Snyder, Michael; Schreiber, Stuart L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 47, 23.11.2004, p. 16594-16599.

Research output: Contribution to journalArticle

Huang, Jing ; Zhu, Heng ; Haggarty, Stephen J. ; Spring, David R. ; Hwang, Heejun ; Jin, Fulai ; Snyder, Michael ; Schreiber, Stuart L. / Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 47. pp. 16594-16599.
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