Trends in Biochemical Sciences
Research FocusRheb fills a GAP between TSC and TOR
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.
References (25)
Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway
Mol. Cell
(2002)Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity
J. Biol. Chem.
(1995)The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis
J. Biol. Chem.
(1997)The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation
Cell
(2001)Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size
Cell
(2001)Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2
Mol. Cell
(2003)Rheb binds TSC2 and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner
J. Biol. Chem.
(2003)Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb
Curr. Biol.
(2003)Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway
Mol. Cell. Neurosci.
(2002)Tuberous Sclerosis
(1999)