PMID- 16636147
OWN - NLM
STAT- MEDLINE
DCOM- 20060609
LR  - 20211020
IS  - 0021-9525 (Print)
IS  - 1540-8140 (Electronic)
IS  - 0021-9525 (Linking)
VI  - 173
IP  - 2
DP  - 2006 Apr 24
TI  - Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane 
      partitioning.
PG  - 279-89
AB  - Loss of tuberin, the product of TSC2 gene, increases mammalian target of 
      rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, 
      in cells expressing tuberin, it is not known how repression of mTOR signaling is 
      relieved to activate this pathway in response to growth factors and how hamartin 
      participates in this process. We show that hamartin colocalizes with 
      hypophosphorylated tuberin at the membrane, where tuberin exerts its 
      GTPase-activating protein (GAP) activity to repress Rheb signaling. In response 
      to growth signals, tuberin is phosphorylated by AKT and translocates to the 
      cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 
      981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin 
      to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 
      14-3-3 in response to AKT phosphorylation is sequestered away from its 
      membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to 
      relieve the growth inhibitory effects of this tumor suppressor.
FAU - Cai, Sheng-Li
AU  - Cai SL
AD  - Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, 
      Smithville, 78957, USA.
FAU - Tee, Andrew R
AU  - Tee AR
FAU - Short, John D
AU  - Short JD
FAU - Bergeron, Judith M
AU  - Bergeron JM
FAU - Kim, Jinhee
AU  - Kim J
FAU - Shen, Jianjun
AU  - Shen J
FAU - Guo, Ruifeng
AU  - Guo R
FAU - Johnson, Charles L
AU  - Johnson CL
FAU - Kiguchi, Kaoru
AU  - Kiguchi K
FAU - Walker, Cheryl Lyn
AU  - Walker CL
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - HD46282/HD/NICHD NIH HHS/United States
GR  - ES08263-06S1/ES/NIEHS NIH HHS/United States
GR  - R01 HD046282/HD/NICHD NIH HHS/United States
GR  - R01 CA063613/CA/NCI NIH HHS/United States
GR  - R01 ES008263/ES/NIEHS NIH HHS/United States
GR  - P30 ES007784/ES/NIEHS NIH HHS/United States
GR  - ES07784/ES/NIEHS NIH HHS/United States
GR  - CA16672/CA/NCI NIH HHS/United States
GR  - CA63613/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (Growth Substances)
RN  - 0 (RHEBL1 protein, human)
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 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Cell Line
MH  - Cell Membrane/*chemistry
MH  - Growth Substances/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Microscopy, Confocal
MH  - Models, Biological
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-akt/*metabolism/pharmacology
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/analysis/antagonists & inhibitors/*metabolism
MH  - ras Proteins/metabolism
PMC - PMC2063818
EDAT- 2006/04/26 09:00
MHDA- 2006/06/10 09:00
PMCR- 2006/10/24
CRDT- 2006/04/26 09:00
PHST- 2006/04/26 09:00 [pubmed]
PHST- 2006/06/10 09:00 [medline]
PHST- 2006/04/26 09:00 [entrez]
PHST- 2006/10/24 00:00 [pmc-release]
AID - jcb.200507119 [pii]
AID - 200507119 [pii]
AID - 10.1083/jcb.200507119 [doi]
PST - ppublish
SO  - J Cell Biol. 2006 Apr 24;173(2):279-89. doi: 10.1083/jcb.200507119.