Controlling Signal Input to mTOR

Abstract

The proteins hamartin and tuberin form a heterodimer that inhibits cell growth and proliferation by blocking nutrient signaling through the mTOR pathway. Loss of function of either protein results in tumorigenesis associated with the human genetic syndrome tuberous sclerosis complex. Little is known about how this heterodimer functions--hamartin is predicted to have a transmembrane domain and tuberin bears a domain with guanosine triphosphatase (GTPase)-activating protein (GAP) activity. Tee et al. report that the heterodimer stimulates GTP hydrolysis of a small GTP-binding protein called Ras homolog enriched in brain (Rheb). Rheb-GTP appears to activate nutrient signaling input to mTOR. Overexpression of Rheb in cultured mammalian cells, in the absence of nutrients, induced activation of the 40 S ribosomal protein S6 kinase 1 (S6K1) and also the phosphorylation of the eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two targets of the mTOR-nutrient pathway. Rheb overexpression also enhanced S6K1 activation when cells were treated with amino acids, an effect that was blocked by the mTOR inhibitor rapamycin. However, additional overexpression of hamartin and tuberin blocked Rheb's ability to activate S6K1; this required an intact GAP domain in tuberin. Hamartin and tuberin enhanced the GTPase activity of Rheb in vitro, suggesting that the complex acts as a GAP. The requirement for farnesylation of Rheb for optimal activation of S6K1 suggests that membrane localization, perhaps in proximity to membrane-localized hamartin-tuberin, is important for modulating Rheb activity. The authors propose that Rheb becomes activated when nutrients are sufficient, thus promoting mTOR signaling when in the GTP-bound form. The hamartin-tuberin complex would then inhibit Rheb by stimulating GTP hydrolysis. A. R. Tee, B. D. Manning, P. P. Roux, L. C. Cantley, J. Blenis, Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13 , 1259-1268 (2003). [Online Journal]