TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1.
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.
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Christian C
CC
Dibble
Winfried
W
Elis
Suchithra
S
Menon
Wei
W
Qin
Justin
J
Klekota
John M
JM
Asara
Peter M
PM
Finan
David J
DJ
Kwiatkowski
Leon O
LO
Murphy
Brendan D
BD
Manning
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C522923:TBC1D7 protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins