mTOR Tumor Suppressor Complex and Tuberous Sclerosis in Children
Tumor Suppressor Protein Complex and Normal State
Tumor suppressor protein complex formed by TSC1 and TSC2 binding: TSC may arise from a mutation in one of two genes, TSC1 (hamartin), with loci on 9q, or TSC2 (tuberin), with loci on 16p, which code for tumor suppressor protein complex.
Complex inactivates Rheb: This tumor suppressor complex drives the GTPase, the Ras homolog enriched in brain protein, into the inactive state (guanosine diphosphate-bound state) via tuberin’s GTPase activating function.
Decrease in mTOR stimulation lessens cell proliferation: The GTPase Ras homolog is enriched by a brain protein called Rheb, which in the (guanosine-triphosphate) active state acts to increase the mammalian target rapamycin (mTOR), a protein kinase that appears to be evolutionarily conserved. mTOR is a factor that serves to increase cell growth as opposed to cell proliferation (11).
mTOR tumor suppressor complex regulation
mTOR Pathway Disinhibition and TSC
Mutation of TSC1 or TSC2 inhibits tumor suppressor protein complex formation: In summary, if the tumor suppressor complex is fully functional, Rheb is driven into its inactive, guanosine diphosphate-bound state, lowering the mTOR signaling pathway’s effects.
Rheb activity no longer influenced by tumor suppressor protein complex: Mutations, such as those causing TSC, result in the active, guanosine triphosphate Rheb. This active Rheb causes mTOR pathway signaling.
Rheb stimulates mTOR activity and cell proliferation: mTOR acts through the protein Raptor,to increase cell growth and protein synthesis by phosphorylating protein s6 kinases (S6Ks) and effecting the eukaryotic initiation factor 4E binding protein 1 (4E-BP1) (11).
Summary of TSC1 and TSC2 function: Functional tumor suppressors hamartin and tuberin cause a down-regulation of the mTOR pathway S6K1 and 4E-BP1, while mutations increase, thus producing TSC. The mutations lead to benign tumors in multiple organs, including the brain and heart (20).