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PMID:22795129

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Citation

Dibble, CC, Elis, W, Menon, S, Qin, W, Klekota, J, Asara, JM, Finan, PM, Kwiatkowski, DJ, Murphy, LO and Manning, BD (2012) TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 47:535-46

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.

Links

PubMed Online version:10.1016/j.molcel.2012.06.009

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TSC2

involved_in

GO:0032007: negative regulation of TOR signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSC2

located_in

GO:0033596: TSC1-TSC2 complex

ECO:0000353: physical interaction evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TSC1

involved_in

GO:0032007: negative regulation of TOR signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSC1

located_in

GO:0033596: TSC1-TSC2 complex

ECO:0000353: physical interaction evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TBCD7

involved_in

GO:0032007: negative regulation of TOR signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TBCD7

involved_in

GO:0090630: activation of GTPase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TBCD7

involved_in

GO:0032007: negative regulation of TOR signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TBCD7

involved_in

GO:0070848: response to growth factor

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TBCD7

involved_in

GO:0090630: activation of GTPase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TBCD7

involved_in

GO:0032007: negative regulation of TOR signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TBCD7

located_in

GO:0033596: TSC1-TSC2 complex

ECO:0000353: physical interaction evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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