Research: Colloquia Review

"TSC-mTOR signaling in cell growth control"

In this colloquium, I summarized the current understanding of the regulation of TSC-mTOR signaling and discussed its function in cell growth control, tumorigenesis and metabolic disease.

TOR (target of rapamycin) proteins are members of the phosphatidylinositol kinase related kinase (PIKK) family and are highly conserved from yeast to mammals. TOR kinase activity is regulated by multiple signals from growth factors, nutrients, stress, and cellular energy levels to control cell growth. The ribosomal S6 kinase 1 (S6K) and eukaryotic initiation factor 4E binding protein 1 (4EBP1) are two cellular targets of TOR kinase activity and are known to mediate TOR function in translational control in mammalian cells. However, the precise molecular mechanism of TOR regulation is not completely understood. One of the recent breakthroughs in the TOR signaling field is the identification of the Tuberous Sclerosis Complex gene products, TSC1 and TSC2, as negative regulators of TOR signaling. Furthermore, the discovery that the small GTPase Rheb as a direct downstream target of TSC1/2 and a positive regulator of the TOR function, has significantly advanced our understanding of the molecular mechanism of TOR activation.

TSC1 and TSC2 form a physical and a functional complex to inhibit Rheb-mTOR signaling. Furthermore, the activity of the TSC1/2 complex is regulated by growth factors, cellular energy levels, stress, and nutrients such as amino acids, indicating that the TSC1/2 complex acts as a signal integration point to regulate mTOR signaling.

Recent studies have established that high levels of dysregulated mTOR activity are associated with several hamartoma syndromes such as Tuberous Sclerosis Complex, the PTEN-related hamartoma syndromes (PTEN mutation), and Peutz-Jeghers syndrome (LKB1 mutation). These disorders are all caused by mutations in tumor suppressor genes that negatively regulate mTOR. Interestingly, loss of PTEN or LKB1 results in an inactivation of TSC2, indicating that TSC2 inactivation may be a common pathomechanism of these hamartoma syndromes.

Recent studies also suggest that TSC-mTOR signaling plays an important role for metabolic disorder such as diabetes. The high levels of dysregulated mTOR activity results in an insulin resistance in the TSC negative cell lines and obese animals. The dysregulation of the TSC-mTOR pathway might be responsible for diabetic complications.

By Ken Inoki, M.D., Ph.D., assistant research scientist, Guan Laboratory, January, 2005