The TSC1-TSC2 complex: a molecular switchboard controlling cell growth

Abstract

TSC1 and TSC2 are the tumour-suppressor genes mutated in the tumour syndrome TSC (tuberous sclerosis complex). Their gene products form a complex that has become the focus of many signal transduction researchers. The TSC1-TSC2 (hamartin-tuberin) complex, through its GAP (GTPase-activating protein) activity towards the small G-protein Rheb (Ras homologue enriched in brain), is a critical negative regulator of mTORC1 (mammalian target of rapamycin complex 1). As mTORC1 activity controls anabolic processes to promote cell growth, it is exquisitely sensitive to alterations in cell growth conditions. Through numerous phosphorylation events, the TSC1-TSC2 complex has emerged as the sensor and integrator of these growth conditions, relaying signals from diverse cellular pathways to properly modulate mTORC1 activity. In the present review we focus on the molecular details of TSC1-TSC2 complex regulation and function as it relates to the control of Rheb and mTORC1.

Figure 1. Schematic of the TSC1 and TSC2 proteins and the components and downstream targets of the two mTOR complexes

(A) The functional domains on TSC1 and TSC2 are depicted schematically with numbers representing amino acid residues on the full-length human proteins. Abbreviations: T2BD, TSC2-binding domain; T1BD, TSC1 -binding domain; Coil, predicted coiled-coil domain; GAP, GAP domain homologous with that in Rap1GAP. (B) mTOR is found in two functionally distinct complexes, mTORC1 and mTORC2, with distinct downstream substrates. mLST8, mammalian LST8; PH, pleckstrin homology domain.

Figure 2. Two models of the regulation of mTORC1 by TSC1–TSC2 and Rheb

(A) Model 1. Under poor growth conditions, the TSC1–TSC2 complex acts as a GAP for Rheb, thereby stimulating the conversion of Rheb–GTP into Rheb–GDP. Under optimal growth conditions, Rheb–GTP accumulates and binds directly to mTOR within mTORC1 to somehow activate it. Whether a GEF exists that counters the activity of the TSC1–TSC2 complex for Rheb regulation is not known. mLST8, mammalian LST8. (B) Model 2. The TSC1–TSC2 complex acts as described in (A) above, but Rheb–GTP activates mTORC1 through binding to FKBP38, thereby triggering its release from mTOR. In this model, FKBP38 inhibits mTORC1 under poor growth conditions in a manner analogous to the rapamycin–FKBP12 complex.

Figure 3. Direct phosphorylation sites on TSC1 and TSC2

(A) Phosphorylation of TSC1 at specific residues by different protein kinases. Among these, only the Thr⁴¹⁷ site is conserved between human and Drosophila TSC1. For the alignment, the phosphorylation site is indicated in yellow, identical residues in green, strongly similar residues in blue and semi-conserved residues in grey. (B) Same as above, but for TSC2. Among these sites, only the aligned sites are conserved between human and Drosophila TSC2. It should be noted that the AMPK/GSK3 sites in Drosophila (Ser¹¹⁰⁷/Ser¹¹⁰³) are not found in the same region of the primary sequence as in human TSC2.

Figure 4. Signal integration by the TSC1–TSC2 complex

The TSC1–TSC2 complex monitors growth conditions through multiple signalling pathways, which either inhibit or activate the complex to affect mTORC1 activity. See the text for details. Further abbreviations: Dvl, dishevelled; Frz, frizzled; MEK, MAPK/ERK kinase; TNFR, tumour-necrosis-factor receptor; VHL, von Hippel–Lindau tumour suppressor; VPS34, vacuolar protein sorting 34.