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Rheb fills a GAP between TSC and TOR.
Brendan D Manning1, Lewis C Cantley
1Department of Cell Biology, Harvard Medical School, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Rm 1028, 4 Blackfan Circle, Boston, MA 02115, USA.
Trends in Biochemical Sciences
|November 11, 2003
Summary
The tuberin-hamartin complex, encoded by TSC1 and TSC2 genes, inhibits target of rapamycin (TOR) signaling. This breakthrough clarifies the molecular function of tuberin and hamartin in tuberous sclerosis complex disease.
Area of Science:
- Molecular biology
- Cell biology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) disease is linked to mutations in TSC1 and TSC2 genes.
- The molecular and cellular functions of hamartin and tuberin, encoded by TSC1 and TSC2, are of significant interest.
- Previous understanding of hamartin and tuberin function was limited.
Purpose of the Study:
- To elucidate the molecular and cellular functions of hamartin and tuberin.
- To understand the mechanism by which TSC1 and TSC2 mutations lead to tuberous sclerosis complex.
- To identify the direct molecular targets and pathways regulated by the tuberin-hamartin complex.
Main Methods:
- Genetic studies
- Biochemical assays
- Cell-biological experiments
Main Results:
- The tuberin-hamartin complex was demonstrated to inhibit target of rapamycin (TOR) signaling.
- The tuberin-hamartin complex functions as a GTPase-activating protein (GAP).
- This GAP activity is directed towards the Ras-related small G protein Rheb.
Conclusions:
- The tuberin-hamartin complex directly inhibits TOR signaling through Rheb.
- This finding represents a major breakthrough in understanding TSC pathogenesis.
- The study clarifies a key molecular mechanism underlying tuberous sclerosis complex.