PMID- 18235224
OWN - NLM
STAT- MEDLINE
DCOM- 20080417
LR  - 20211203
IS  - 1551-4005 (Electronic)
IS  - 1551-4005 (Linking)
VI  - 7
IP  - 3
DP  - 2008 Feb 1
TI  - mTORC1 signaling requires proteasomal function and the involvement of CUL4-DDB1 
      ubiquitin E3 ligase.
PG  - 373-81
AB  - The mammalian target-of-rapamycin (mTOR) signaling pathway serves as a major 
      regulator of cell growth, cell size and metabolism. In vivo, mTOR exists in two 
      complexes, both of which contain the catalytic subunit mTOR, the invariable 
      subunit mLST8, and a complex specific subunit Raptor or Rictor, forming either 
      the rapamycin-sensitive mTORC1 or rapamycin-insensitive mTORC2, respectively. The 
      exact functions of Raptor or Rictor in these complexes are still unclear. Here we 
      demonstrate that mTORC1-mediated signaling events require the function of the 26S 
      proteasome. Inhibition of the 26S proteasome by MG132 leads to the rapid 
      inhibition of phosphorylation of the mTORC1 substrates S6 kinase and 4E-BP1. We 
      have further discovered that the WD40 repeat proteins Raptor and mLST8 bind the 
      CUL4-DDB1 ubiquitin E3 ligase. Loss of CUL4B or DDB1 specifically blocks the 
      phosphorylation of S6 kinase at threonine 389 and 4E-BP1 at serine 65 and 
      threonines 37 and 46, while loss of CUL4B enhances the phosphorylation of AKT at 
      serine 473. These phosphorylation effects are identical to those resulting from 
      the inactivation of Raptor. Our data suggest that the CUL4-DDB1 ubiquitin ligase 
      interacts with Raptor and regulates the mTORC1- mediated signaling pathway 
      through ubiquitin-dependent proteolysis.
FAU - Ghosh, Papia
AU  - Ghosh P
AD  - Laboratory of Cancer Genomics, Division of Basic Science, Nevada Cancer 
      Institute, Las Vegas, Nevada 89135, USA.
FAU - Wu, Min
AU  - Wu M
FAU - Zhang, Hui
AU  - Zhang H
FAU - Sun, Hong
AU  - Sun H
LA  - eng
GR  - CA77695/CA/NCI NIH HHS/United States
GR  - CA98955/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071102
PL  - United States
TA  - Cell Cycle
JT  - Cell cycle (Georgetown, Tex.)
JID - 101137841
RN  - 0 (CUL4A protein, human)
RN  - 0 (CUL4B protein, human)
RN  - 0 (Cullin Proteins)
RN  - 0 (DDB1 protein, human)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 3.4.99.- (ATP dependent 26S protease)
SB  - IM
MH  - Amino Acid Sequence
MH  - Cell Line
MH  - Cells, Cultured
MH  - Cullin Proteins/genetics/*physiology
MH  - DNA-Binding Proteins/genetics/*physiology
MH  - Humans
MH  - Hydrolysis
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Molecular Sequence Data
MH  - Multiprotein Complexes
MH  - Peptide Hydrolases/metabolism
MH  - Proteasome Endopeptidase Complex/genetics/*physiology
MH  - Proteins
MH  - Signal Transduction/*physiology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/genetics/*physiology
MH  - Ubiquitin-Protein Ligases/genetics/*physiology
EDAT- 2008/02/01 09:00
MHDA- 2008/04/18 09:00
CRDT- 2008/02/01 09:00
PHST- 2008/02/01 09:00 [pubmed]
PHST- 2008/04/18 09:00 [medline]
PHST- 2008/02/01 09:00 [entrez]
AID - 5267 [pii]
AID - 10.4161/cc.7.3.5267 [doi]
PST - ppublish
SO  - Cell Cycle. 2008 Feb 1;7(3):373-81. doi: 10.4161/cc.7.3.5267. Epub 2007 Nov 2.