PMID- 16362038
OWN - NLM
STAT- MEDLINE
DCOM- 20060307
LR  - 20211203
IS  - 0261-4189 (Print)
IS  - 1460-2075 (Electronic)
IS  - 0261-4189 (Linking)
VI  - 25
IP  - 1
DP  - 2006 Jan 11
TI  - Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 
      activation.
PG  - 58-69
AB  - Insulin-like growth factor-I inhibits transforming growth factor-beta (TGF-beta) 
      signaling by blocking activation of Smad3 (S3), via a phosphatidylinositol 
      3-kinase (PI3K)/Akt-dependent pathway. Here we provide the first report that the 
      kinase activity of Akt is necessary for its ability to suppress many TGF-beta 
      responses, including S3 activation and induction of apoptosis. Wild-type and 
      myristoylated Akts (Akt(WT) and Akt(Myr)) suppress TGF-beta-induced 
      phospho-activation of S3 but not Smad2 (S2), whereas kinase-dead Akt1 (Akt1K179M) 
      or dominant-negative PI3K enhances TGF-beta-induced phospho-activation of both S2 
      and S3. Using siRNA, rapamycin (Rap), and adenoviral expression for 
      FKBP12-resistant and constitutively active TGF-beta type I receptor (ALK5), we 
      demonstrate that mammalian target of Rap (mTOR) mediates Akt1 suppression of 
      phospho-activation of S3. These and further data on Akt1-S3 binding do not 
      support a recently proposed model that Akt blocks S3 activation through physical 
      interaction and sequestration of S3 from TGF-beta receptors. We propose a novel 
      model whereby Akt suppresses activation of S3 in an Akt kinase-dependent manner 
      through mTOR, a likely route for loss of tumor suppression by TGF-beta in 
      cancers.
FAU - Song, Kyung
AU  - Song K
AD  - Case Comprehensive Cancer Center Research Laboratories and Department of 
      Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA.
FAU - Wang, Hui
AU  - Wang H
FAU - Krebs, Tracy L
AU  - Krebs TL
FAU - Danielpour, David
AU  - Danielpour D
LA  - eng
GR  - R01 CA092102/CA/NCI NIH HHS/United States
GR  - R01 CA102074/CA/NCI NIH HHS/United States
GR  - R01CA092102/CA/NCI NIH HHS/United States
GR  - R01CA102074/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20051215
PL  - England
TA  - EMBO J
JT  - The EMBO journal
JID - 8208664
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Smad2 Protein)
RN  - 0 (Smad3 Protein)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR 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 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.30 (Activin Receptors, Type I)
RN  - EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type I)
RN  - EC 2.7.11.30 (TGFBR1 protein, human)
RN  - EC 2.7.11.30 (Tgfbr1 protein, rat)
RN  - EC 5.2.1.- (Tacrolimus Binding Protein 1A)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Activin Receptors, Type I/*antagonists & inhibitors/genetics/metabolism
MH  - Animals
MH  - Apoptosis
MH  - Cells, Cultured
MH  - Humans
MH  - Mutation
MH  - Phosphorylation
MH  - Protein Kinases/genetics/metabolism/*physiology
MH  - Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism/*physiology
MH  - RNA, Small Interfering/genetics/pharmacology
MH  - Rats
MH  - Receptor, Transforming Growth Factor-beta Type I
MH  - Receptors, Transforming Growth Factor beta/*antagonists & 
      inhibitors/genetics/metabolism
MH  - Sirolimus/pharmacology
MH  - Smad2 Protein/metabolism
MH  - Smad3 Protein/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Tacrolimus Binding Protein 1A/metabolism
MH  - Transforming Growth Factor beta/*antagonists & inhibitors/metabolism
PMC - PMC1356360
EDAT- 2005/12/20 09:00
MHDA- 2006/03/08 09:00
PMCR- 2007/01/11
CRDT- 2005/12/20 09:00
PHST- 2005/05/25 00:00 [received]
PHST- 2005/11/24 00:00 [accepted]
PHST- 2005/12/20 09:00 [pubmed]
PHST- 2006/03/08 09:00 [medline]
PHST- 2005/12/20 09:00 [entrez]
PHST- 2007/01/11 00:00 [pmc-release]
AID - 7600917 [pii]
AID - 10.1038/sj.emboj.7600917 [doi]
PST - ppublish
SO  - EMBO J. 2006 Jan 11;25(1):58-69. doi: 10.1038/sj.emboj.7600917. Epub 2005 Dec 15.