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Mitotic raptor promotes mTORC1 activity, G(2)/M cell cycle progression, and internal ribosome entry site-mediated

Francisco Ramírez-Valle1, Michelle L Badura, Steve Braunstein

  • 1Department of Microbiology, NYU School of Medicine, 550 First Avenue, New York, NY 10016, USA.

Molecular and Cellular Biology
|May 5, 2010
PubMed

Insights

The mechanistic target of rapamycin complex 1 (mTORC1) pathway is hyperactive during mitosis, promoting cell cycle progression. Mitotic phosphorylation of raptor, a key mTORC1 component, facilitates this process and enhances internal ribosome entry site-dependent translation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanistic target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation by integrating nutrient and growth factor signals.
  • Protein synthesis, crucial for cell growth, decreases significantly during the G2/M phase of the cell cycle.
  • The role of mTOR signaling during mitosis and its coordination with protein synthesis remain unclear.

Purpose of the Study:

  • To investigate the activity and function of the mTOR complex 1 (mTORC1) pathway during mitosis.
  • To identify novel regulatory mechanisms of mTORC1 during cell division.
  • To understand the role of mTORC1 in coordinating cell cycle progression and protein synthesis during mitosis.

Main Methods:

  • Phosphopeptide mapping and mutational analysis of raptor, a component of mTORC1.
  • Cell cycle analysis using phosphorylation-deficient mutants and raptor depletion.
  • Identification of kinases involved in raptor phosphorylation using cyclin-dependent kinase 1 (cdk1) and glycogen synthase kinase 3 (GSK3) pathways.
  • Analysis of internal ribosome entry site (IRES)-dependent translation during mitosis.

Main Results:

  • mTORC1 signaling is hyperactive during mitosis, despite reduced upstream activator activity and overall protein synthesis.
  • A novel G2/M-specific phosphorylation of raptor was identified, altering mTORC1 function during mitosis.
  • Mitotic raptor phosphorylation promotes cell cycle transit through G2/M, while its absence causes delays.
  • Mitotic raptor enhances IRES-dependent mRNA translation and is associated with rapamycin resistance.

Conclusions:

  • Mitotic raptor phosphorylation is a critical regulator of mTORC1 activity during cell division.
  • This phosphorylation event facilitates cell cycle progression through mitosis and enhances IRES-mediated translation.
  • The mTORC1 pathway's role in mitosis may contribute to rapamycin insensitivity and increased translation of specific mRNAs.

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