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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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GTPase-Activating Proteins / genetics
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GTPase-Activating Proteins / metabolism
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HEK293 Cells
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HeLa Cells
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Humans
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Intracellular Signaling Peptides and Proteins
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Lysosomes / genetics
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Lysosomes / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Molecular Sequence Data
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Monomeric GTP-Binding Proteins / genetics
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Monomeric GTP-Binding Proteins / metabolism
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Multiprotein Complexes
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Neuropeptides / genetics
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Neuropeptides / metabolism
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Protein Binding
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Proteins / genetics
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Proteins / metabolism*
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Ras Homolog Enriched in Brain Protein
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Signal Transduction
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TOR Serine-Threonine Kinases
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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Carrier Proteins
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GTPase-Activating Proteins
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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Neuropeptides
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Proteins
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RHEB protein, human
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Ras Homolog Enriched in Brain Protein
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TBC1D7 protein, human
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TSC1 protein, human
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TSC2 protein, human
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Monomeric GTP-Binding Proteins