TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1

Mol Cell. 2012 Aug 24;47(4):535-46. doi: 10.1016/j.molcel.2012.06.009. Epub 2012 Jul 12.

Abstract

The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysosomes / genetics
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism
  • Multiprotein Complexes
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Protein Binding
  • Proteins / genetics
  • Proteins / metabolism*
  • Ras Homolog Enriched in Brain Protein
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Carrier Proteins
  • GTPase-Activating Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Neuropeptides
  • Proteins
  • RHEB protein, human
  • Ras Homolog Enriched in Brain Protein
  • TBC7 protein, human
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins