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TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin

X F Zheng1, D Florentino, J Chen

  • 1Howard Hughes Medical Institute Department of Chemistry, Harvard University Cambridge, Massachusetts 02138, USA.

Cell
|July 14, 1995
PubMed

Insights

The rapamycin-sensitive pathway, involving TOR1 and TOR2 proteins, regulates cell cycle progression. Kinase activity is crucial for G1 function, with rapamycin selectively inhibiting this process.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The rapamycin-sensitive pathway is crucial for transmitting mitogenic signals to the cell cycle machinery, specifically for G1 phase progression.
  • Genetic studies in yeast identified TOR1 and TOR2 as key genes in this pathway, hypothesized to be novel phosphatidylinositol kinases.

Purpose of the Study:

  • To investigate the functional requirement of the kinase domain in TOR1 and TOR2 proteins for their roles in G1 cell cycle progression.
  • To elucidate the mechanism by which FKBP12-rapamycin affects TOR protein function, particularly concerning G1 phase and essential cellular processes.

Main Methods:

  • Genetic analysis of yeast strains with mutations in TOR1 and TOR2 genes.
  • Assessment of cell cycle progression (G1) and cell growth under various conditions, including rapamycin treatment.
  • Functional characterization of the kinase and FKBP12-rapamycin-binding domains of TOR proteins.

Main Results:

  • An intact kinase domain is essential for the G1 cell cycle functions of both TOR1 and TOR2 proteins.
  • Overexpression of a mutated TOR1 protein (affecting the FKBP12-rapamycin-binding domain) inhibited yeast cell growth.
  • The essential function of TOR2 requires an intact kinase domain, but this function is not sensitive to rapamycin.
  • While the G1 function of both TOR proteins is rapamycin-sensitive, the essential function of TOR2 is not.

Conclusions:

  • The kinase activity of TOR proteins is indispensable for their G1 cell cycle functions.
  • FKBP12-rapamycin does not broadly inhibit TOR kinase activity but likely interferes selectively with effector interactions or phosphorylation.
  • This selective interference suggests a nuanced regulatory mechanism of TOR proteins in cell cycle control and essential cellular processes.

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