PMID- 12234610
OWN - NLM
STAT- MEDLINE
DCOM- 20021007
LR  - 20211203
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 64
IP  - 7
DP  - 2002 Oct 1
TI  - A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling.
PG  - 1071-7
AB  - Originally discovered as an anti-fungal agent, the bacterial macrolide rapamycin 
      is a potent immunosuppressant and a promising anti-cancer drug. In complex with 
      its cellular receptor, the FK506-binding protein (FKBP12), rapamycin binds and 
      inhibits the function of the mammalian target of rapamycin (mTOR). By mediating 
      amino acid sufficiency, mTOR governs signaling to translational regulation and 
      other cellular functions by converging with the phosphatidylinositol 3-kinase 
      (PI3K) pathway on downstream effectors. Whether mTOR receives mitogenic signals 
      in addition to nutrient-sensing has been an unresolved issue, and the mechanism 
      of action of rapamycin remained unknown. Our recent findings have revealed a 
      novel link between mitogenic signals and mTOR via the lipid second messenger 
      phosphatidic acid (PA), and suggested a role for mTOR in the integration of 
      nutrient and mitogen signals. A molecular mechanism for rapamycin inhibition of 
      mTOR signaling is proposed, in which a putative interaction between PA and mTOR 
      is abolished by rapamycin binding. Collective evidence further implicates the 
      regulation of the rapamycin-sensitive signaling circuitry by phospholipase D, and 
      potentially by other upstream regulators such as the conventional protein kinase 
      C, the Rho and ARF families of small G proteins, and calcium ions. As the mTOR 
      pathway has been demonstrated to be an important anti-cancer target, the 
      identification of new components and novel regulatory modes in mTOR signaling 
      will facilitate the future development of diagnostic and therapeutic strategies.
FAU - Chen, Jie
AU  - Chen J
AD  - Department of Cell and Structural Biology, University of Illinois at 
      Urbana-Champaign, 601 South Goodwin Avenue, B107, Urbana, IL 61801, USA. 
      jiechen@uiuc.edu
FAU - Fang, Yimin
AU  - Fang Y
LA  - eng
GR  - GM58064/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Phosphatidic Acids)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Immunosuppressive Agents/*pharmacology
MH  - Phosphatidic Acids/metabolism
MH  - Protein Kinases/*metabolism
MH  - Protein Structure, Tertiary
MH  - Signal Transduction/drug effects/physiology
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
RF  - 67
EDAT- 2002/09/18 10:00
MHDA- 2002/10/09 04:00
CRDT- 2002/09/18 10:00
PHST- 2002/09/18 10:00 [pubmed]
PHST- 2002/10/09 04:00 [medline]
PHST- 2002/09/18 10:00 [entrez]
AID - S0006295202012637 [pii]
AID - 10.1016/s0006-2952(02)01263-7 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2002 Oct 1;64(7):1071-7. doi: 10.1016/s0006-2952(02)01263-7.