PMID- 12172553
OWN - NLM
STAT- MEDLINE
DCOM- 20021011
LR  - 20221214
IS  - 1465-7392 (Print)
IS  - 1465-7392 (Linking)
VI  - 4
IP  - 9
DP  - 2002 Sep
TI  - TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.
PG  - 648-57
AB  - Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the 
      formation of hamartomas in a wide range of human tissues. Mutation in either the 
      TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and 
      sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and 
      functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 
      ribosomal protein S6 kinase 1 (an activator of translation) and activates the 
      eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of 
      translational initiation). These functions of TSC1-TSC2 are mediated by 
      inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is 
      directly phosphorylated by Akt, which is involved in stimulating cell growth and 
      is activated by growth stimulating signals, such as insulin. TSC2 is inactivated 
      by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its 
      interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in 
      insulin signalling, tumour suppressor functions and in the inhibition of cell 
      growth.
FAU - Inoki, Ken
AU  - Inoki K
AD  - Department of Biological Chemistry, University of Michigan Medical School, 1301 
      Catherine Road, Ann Arbor, MI 48109, USA. kunliang@umich.edu
FAU - Li, Yong
AU  - Li Y
FAU - Zhu, Tianquan
AU  - Zhu T
FAU - Wu, Jun
AU  - Wu J
FAU - Guan, Kun-Liang
AU  - Guan KL
LA  - eng
GR  - R01 DK124709/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Binding Sites/genetics
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Genes, Tumor Suppressor
MH  - Humans
MH  - Insulin/metabolism
MH  - Models, Biological
MH  - Mutation
MH  - Phosphoproteins/metabolism
MH  - Phosphorylation
MH  - *Protein Kinase Inhibitors
MH  - Protein Kinases/metabolism
MH  - *Protein Serine-Threonine Kinases
MH  - Proteins/genetics/metabolism
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Repressor Proteins/*antagonists & inhibitors/genetics/*metabolism
MH  - Ribosomal Protein S6 Kinases/antagonists & inhibitors
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases
MH  - Tuberous Sclerosis/genetics/metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins
EDAT- 2002/08/13 10:00
MHDA- 2002/10/12 04:00
CRDT- 2002/08/13 10:00
PHST- 2002/08/13 10:00 [pubmed]
PHST- 2002/10/12 04:00 [medline]
PHST- 2002/08/13 10:00 [entrez]
AID - ncb839 [pii]
AID - 10.1038/ncb839 [doi]
PST - ppublish
SO  - Nat Cell Biol. 2002 Sep;4(9):648-57. doi: 10.1038/ncb839.