PMID- 16715128
OWN - NLM
STAT- MEDLINE
DCOM- 20061213
LR  - 20211203
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 25
IP  - 53
DP  - 2006 Nov 9
TI  - Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 
      pathways.
PG  - 7029-40
AB  - Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), inhibits 
      tumor cell motility. However, the underlying mechanism is poorly understood. 
      Here, we show that rapamycin inhibited type I insulin-like growth factor 
      (IGF-I)-stimulated motility of a panel of cell lines. Expression of a 
      rapamycin-resistant mutant of mTOR (mTORrr) prevented rapamycin inhibition of 
      cell motility. However, cells expressing a kinase-dead mTORrr remained sensitive 
      to rapamycin. Downregulation of raptor or rictor by RNA interference (RNAi) 
      decreased cell motility. However, only downregulation of raptor mimicked the 
      effect of rapamycin, inhibiting phosphorylation of S6 kinase 1 (S6K1) and 4E-BP1. 
      Cells infected with an adenovirus expressing constitutively active and 
      rapamycin-resistant mutant of p70 S6K1, but not with an adenovirus expressing 
      wild-type S6K1, or a control virus, conferred to resistance to rapamycin. 
      Further, IGF-I failed to stimulate motility of the cells, in which S6K1 was 
      downregulated by RNAi. Moreover, downregulation of eukaryotic initiation factor 
      4E (eIF4E)-binding protein 1 (4E-BP1) by RNAi-attenuated rapamycin inhibition of 
      cell motility. In contrast, expression of constitutively active 4E-BP1 
      dramatically inhibited IGF-I-stimulated cell motility. The results indicate that 
      both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell 
      motility. Rapamycin inhibits IGF-I-stimulated cell motility, through suppression 
      of both S6K1 and 4E-BP1/eIF4E-signaling pathways, as a consequence of inhibition 
      of mTOR kinase activity.
FAU - Liu, L
AU  - Liu L
AD  - Department of Biochemistry and Molecular Biology, Louisiana State University 
      Health Sciences Center, Shreveport, LA 71130-3932, USA.
FAU - Li, F
AU  - Li F
FAU - Cardelli, J A
AU  - Cardelli JA
FAU - Martin, K A
AU  - Martin KA
FAU - Blenis, J
AU  - Blenis J
FAU - Huang, S
AU  - Huang S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060522
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CRTC1 protein, human)
RN  - 0 (CRTC2 protein, human)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Transcription Factors)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Animals
MH  - Cattle
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Cell Movement/*drug effects
MH  - Cytoprotection/drug effects
MH  - Down-Regulation
MH  - Enzyme Activation
MH  - Humans
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Mice
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Protein Kinases/genetics/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - Serum
MH  - Signal Transduction/*drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/metabolism
EDAT- 2006/05/23 09:00
MHDA- 2006/12/14 09:00
CRDT- 2006/05/23 09:00
PHST- 2006/05/23 09:00 [pubmed]
PHST- 2006/12/14 09:00 [medline]
PHST- 2006/05/23 09:00 [entrez]
AID - 1209691 [pii]
AID - 10.1038/sj.onc.1209691 [doi]
PST - ppublish
SO  - Oncogene. 2006 Nov 9;25(53):7029-40. doi: 10.1038/sj.onc.1209691. Epub 2006 May 
      22.