PMID- 19000755
OWN - NLM
STAT- MEDLINE
DCOM- 20090210
LR  - 20211203
IS  - 1873-3913 (Electronic)
IS  - 0898-6568 (Linking)
VI  - 21
IP  - 2
DP  - 2009 Feb
TI  - Sphingosine-1-phosphate induced mTOR-activation is mediated by the E3-ubiquitin 
      ligase PAM.
PG  - 293-300
LID - 10.1016/j.cellsig.2008.10.016 [doi]
AB  - The signaling pathways that are regulated by sphingosine-1-phosphate (S1P) and 
      mammalian target of rapamycin (mTOR) modulate cell growth, mitogenesis and 
      apoptosis in various cell types and are of major interest for the development of 
      new cancer therapeutics. Previous reports show that S1P can cross-activate the 
      mTOR pathway although the mechanisms that connect both pathways are still 
      unknown. We found that S1P-treatment activates mTOR in several cancer cell lines 
      and primary cells. The activation was independent of ERK, Akt and PI3-kinase, but 
      instead was mediated by the E3 ubiquitin ligase Protein Associated with Myc 
      (PAM). Increased intracellular PAM concentrations facilitated S1P- and 
      insulin-induced mTOR activation as well as p70S6K and 4EBP1 phosphorylation while 
      genetic deletion of PAM decreased S1P- and insulin-induced mTOR activation. PAM 
      activated by facilitating the GDP/GTP-exchange of Rheb which is an activator of 
      mTOR. In conclusion we show that PAM is a novel regulator of the mTOR pathway and 
      that PAM may directly activate Rheb as a guanosine exchange factor (GEF).
FAU - Maeurer, Christian
AU  - Maeurer C
AD  - Pharmazentrum Frankfurt, ZAFES, Institute of Clinical Pharmacology, Klinikum der 
      Johann Wolfgang Goethe-Universitat Frankfurt, Theodor-Stern-Kai 7, 60590 
      Frankfurt, Germany.
FAU - Holland, Sabrina
AU  - Holland S
FAU - Pierre, Sandra
AU  - Pierre S
FAU - Potstada, Wiebke
AU  - Potstada W
FAU - Scholich, Klaus
AU  - Scholich K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081030
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Lysophospholipids)
RN  - 0 (RHEBL1 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 26993-30-6 (sphingosine 1-phosphate)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 2.3.2.27 (MYCBP2 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
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  - EC 3.6.5.2 (ras Proteins)
RN  - NGZ37HRE42 (Sphingosine)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - HeLa Cells
MH  - Humans
MH  - Lysophospholipids/*pharmacology
MH  - Mice
MH  - Mixed Function Oxygenases/*metabolism
MH  - Phosphorylation
MH  - Protein Kinases/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/immunology/metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - Sphingosine/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Time Factors
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/immunology/metabolism
MH  - Ubiquitin-Protein Ligases/*metabolism
MH  - Ubiquitination
MH  - ras Proteins/metabolism
EDAT- 2008/11/13 09:00
MHDA- 2009/02/12 09:00
CRDT- 2008/11/13 09:00
PHST- 2008/07/16 00:00 [received]
PHST- 2008/10/10 00:00 [revised]
PHST- 2008/10/23 00:00 [accepted]
PHST- 2008/11/13 09:00 [pubmed]
PHST- 2009/02/12 09:00 [medline]
PHST- 2008/11/13 09:00 [entrez]
AID - S0898-6568(08)00327-6 [pii]
AID - 10.1016/j.cellsig.2008.10.016 [doi]
PST - ppublish
SO  - Cell Signal. 2009 Feb;21(2):293-300. doi: 10.1016/j.cellsig.2008.10.016. Epub 
      2008 Oct 30.