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Dysregulation of the TSC-mTOR pathway in human disease

Ken Inoki1, Michael N Corradetti, Kun-Liang Guan

  • 1Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.

Nature Genetics
|December 30, 2004
PubMed

Insights

Dysregulated mammalian target of rapamycin (mTOR) signaling is linked to hamartoma syndromes. This pathway may also underlie other cellular hypertrophic disorders, suggesting a common molecular basis.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Genetics

Background:

  • The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, integrating signals from nutrients and growth factors.
  • mTOR influences protein synthesis by phosphorylating critical translation regulators like S6 kinase and eukaryotic initiation factor 4E binding protein 1.

Purpose of the Study:

  • To explore the functional relationship between the mTOR signaling pathway and various genetic diseases.
  • To present evidence supporting a unified model for mTOR dysregulation in cellular hypertrophic disorders.

Main Methods:

  • Review of emerging evidence on mTOR signaling.
  • Analysis of genetic mutations in tumor-suppressor genes linked to hamartoma syndromes.
  • Development of a model for mTOR dysregulation in disease.

Main Results:

  • High levels of dysregulated mTOR activity are associated with hamartoma syndromes such as tuberous sclerosis complex, PTEN-related hamartoma syndromes, and Peutz-Jeghers syndrome.
  • These syndromes are often caused by mutations in tumor-suppressor genes that normally inhibit mTOR.
  • Emerging evidence suggests a functional link between mTOR signaling and multiple genetic diseases.

Conclusions:

  • Dysregulation of the mTOR pathway is implicated in hamartoma syndromes due to mutations in negative regulators.
  • The study proposes that mTOR dysregulation could be a common molecular basis for hamartoma syndromes and other cellular hypertrophic disorders.

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