PMID- 16959881
OWN - NLM
STAT- MEDLINE
DCOM- 20061214
LR  - 20211203
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 103
IP  - 38
DP  - 2006 Sep 19
TI  - Human cytomegalovirus infection alters the substrate specificities and rapamycin 
      sensitivities of raptor- and rictor-containing complexes.
PG  - 14182-7
AB  - Signaling mediated by the mammalian target of rapamycin kinase (mTOR) is 
      activated during human cytomegalovirus (HCMV) infection. mTOR is found in two 
      complexes differing by the binding partner, rictor or raptor. Activated 
      mTOR-raptor promotes cap-dependent translation through the hyperphosphorylation 
      of the eIF4E-binding protein (4E-BP). This activity of the raptor complex is 
      normally inhibited by cell stress responses or the drug rapamycin. However, we 
      previously showed that this inhibition of mTOR signaling can be circumvented 
      during HCMV infection such that hyperphosphorylation of 4E-BP is maintained. Here 
      we show that HCMV infection also activates the rictor complex, as indicated by 
      increased phosphorylation of Akt S473; this phosphorylation is insensitive to 
      rapamycin but sensitive to caffeine in both uninfected and infected cells. By 
      using short-hairpin RNAs to deplete rictor and raptor, we find that rictor is 
      more significant than raptor for the viral infection. Surprisingly, the 
      inhibitory effects of rapamycin on viral growth are primarily due to the presence 
      of rictor, not raptor. Raptor and rictor depletion experiments show that in 
      HCMV-infected cells, both raptor- and rictor-containing complexes can mediate the 
      hyperphosphorylation of 4E-BP and the phosphorylation of p70S6 kinase. Under 
      these conditions, the rictor complex is rapamycin-sensitive for the 
      hyperphosphorylation of 4E-BP, but the raptor complex is not. These data suggest 
      that, during HCMV infection, the rictor- and raptor-containing complexes are 
      modified such that their substrate specificities and rapamycin sensitivities are 
      altered. Our data also suggest that the present understanding of rapamycin's 
      inhibitory effects is incomplete.
FAU - Kudchodkar, Sagar B
AU  - Kudchodkar SB
AD  - Department of Cancer Biology, Abramson Family Cancer Research Institute, School 
      of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6142, USA.
FAU - Yu, Yongjun
AU  - Yu Y
FAU - Maguire, Tobi G
AU  - Maguire TG
FAU - Alwine, James C
AU  - Alwine JC
LA  - eng
GR  - R01 CA028379/CA/NCI NIH HHS/United States
GR  - T32 AI007324/AI/NIAID NIH HHS/United States
GR  - CA28379/CA/NCI NIH HHS/United States
GR  - T32-AI-07324/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20060907
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (RICTOR protein, human)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/metabolism
MH  - Antibiotics, Antineoplastic/metabolism
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cell Cycle Proteins
MH  - Cells, Cultured
MH  - Cytomegalovirus/*physiology
MH  - Cytomegalovirus Infections/*metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Lentivirus/genetics/metabolism
MH  - Multiprotein Complexes
MH  - Nucleic Acid Conformation
MH  - Phosphoproteins/genetics/metabolism
MH  - Phosphorylation
MH  - Protein Kinases/genetics/metabolism
MH  - Proteins/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - RNA/chemistry/metabolism
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Regulatory-Associated Protein of mTOR
MH  - Signal Transduction/physiology
MH  - Sirolimus/*metabolism
MH  - Substrate Specificity
MH  - TOR Serine-Threonine Kinases
PMC - PMC1599931
COIS- The authors declare no conflict of interest.
EDAT- 2006/09/09 09:00
MHDA- 2006/12/15 09:00
PMCR- 2007/03/19
CRDT- 2006/09/09 09:00
PHST- 2006/09/09 09:00 [pubmed]
PHST- 2006/12/15 09:00 [medline]
PHST- 2006/09/09 09:00 [entrez]
PHST- 2007/03/19 00:00 [pmc-release]
AID - 0605825103 [pii]
AID - 3262 [pii]
AID - 10.1073/pnas.0605825103 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14182-7. doi: 
      10.1073/pnas.0605825103. Epub 2006 Sep 7.