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Rheb fills a GAP between TSC and TOR

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Abstract

There has been much interest in determining the molecular and cellular functions of hamartin and tuberin, which are encoded by the genes TSC1 and TSC2 that are mutated in the tuberous sclerosis complex disease. Recently, several laboratories have independently reported a major breakthrough in this field. Together, these genetic, biochemical and cell-biological studies have demonstrated that the tuberin–hamartin complex inhibits target of rapamycin (TOR) signaling by acting as a GTPase-activating protein for the Ras-related small G protein Rheb.

Section snippets

The tuberin–hamartin complex controls TOR proteins through inhibition of Rheb

The molecular function of the tuberin–hamartin complex has been elusive. Tuberin possesses a region of homology to the catalytic domain of Rap-family GTPase-activating proteins (GAPs) at its C terminus and has weak in vitro GAP activity towards both Rap1 and Rab5 9, 10, which are two very different small G proteins. However, there is no in vivo evidence to support tuberin being a GAP for either of these proteins. Genetic and biochemical data from several groups have now convincingly shown that

Unresolved questions: mechanisms of Rheb regulation and activation of TOR proteins

Whereas the identification of Rheb as a downstream target of the tuberin–hamartin complex and an upstream activator of TOR adds a crucial step to this emerging and highly conserved pathway, many important questions remain. For instance, the role of hamartin in the GAP activity of tuberin towards Rheb is still unclear, as the various in vitro and in vivo studies lead to conflicting results. Some groups found that, in the context of full-length tuberin, complex formation between tuberin and

Impact on the study and potential treatment of TSC

The placement of Rheb directly downstream of the tuberin–hamartin complex has many implications for TSC researchers. The most important question is whether or not constitutive activation of Rheb upon genetic loss of TSC1 or TSC2 can account for the entire phenotypic mosaic of the TSC disease. The fact that patient-derived mutations mapped to the GAP domain of tuberin are defective in GAP activity towards Rheb 18, 20, 22 suggests that Rheb is, at the very least, an important player in the

Acknowledgements

We thank the Tuberous Sclerosis Alliance Rothberg Courage Fund and the American Cancer Society for support, and Nicole Logsdon for discussion and critical comments on the manuscript.

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