PMID- 17971449
OWN - NLM
STAT- MEDLINE
DCOM- 20080617
LR  - 20220225
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 1
DP  - 2008 Jan 4
TI  - Coupling of mammalian target of rapamycin with phosphoinositide 3-kinase 
      signaling pathway regulates protein phosphatase 2A- and glycogen synthase 
      kinase-3 -dependent phosphorylation of Tau.
PG  - 100-109
LID - S0021-9258(20)71367-0 [pii]
LID - 10.1074/jbc.M704292200 [doi]
AB  - Tau is an important microtubule-stabilizing protein in neurons. In its 
      hyperphosphorylated form, Tau protein loses its ability to bind to microtubules 
      and then accumulates and is part of pathological lesions characterizing 
      tauopathies, e.g. Alzheimer disease. Glycogen synthase kinase-3beta (GSK-3beta), 
      antagonized by protein phosphatase 2A (PP2A), regulates Tau phosphorylation at 
      many sites. Diabetes mellitus is linked to an increased risk of developing 
      Alzheimer disease. This could be partially caused by dysregulated GSK-3beta. In a 
      long term experiment (-16 h) using primary murine neuron cultures, we interfered 
      in the insulin/phosphoinositide 3-kinase (PI3K) (LY294002 treatment and insulin 
      boost) and mammalian target of rapamycin (mTor) (AICAR and rapamycin treatment) 
      signaling pathways and examined consequent changes in the activities of PP2A, 
      GSK-3beta, and Tau phosphorylation. We found that the coupling of PI3K with mTor 
      signaling, in conjunction with a regulatory interaction between PP2A and 
      GSK-3beta, changed activities of both enzymes always in the same direction. These 
      balanced responses seem to ensure the steady Tau phosphorylation at 
      GSK/PP2A-dependent sites observed over a long period of time (>/=6 h). This may 
      help in preventing severe changes in Tau phosphorylation under conditions when 
      neurons undergo transient fluctuations either in insulin or nutrient supply. On 
      the other hand, the investigation of Tau protein at Ser-262 showed that 
      interference in the insulin/PI3K and mTor signaling potentially influenced the 
      Tau phosphorylation status at sites where only one of two enzymes (in this case 
      PP2A) is involved in the regulation.
FAU - Meske, Volker
AU  - Meske V
AD  - Center of Anatomy, Institute of Integrative Neuroanatomy, Department of Clinical 
      Cell and Neurobiology, Charite, Charite-Platz 1, 10098 Berlin, Germany. 
      Electronic address: V.Meske@gmx.de.
FAU - Albert, Frank
AU  - Albert F
AD  - Center of Anatomy, Institute of Integrative Neuroanatomy, Department of Clinical 
      Cell and Neurobiology, Charite, Charite-Platz 1, 10098 Berlin, Germany.
FAU - Ohm, Thomas Georg
AU  - Ohm TG
AD  - Center of Anatomy, Institute of Integrative Neuroanatomy, Department of Clinical 
      Cell and Neurobiology, Charite, Charite-Platz 1, 10098 Berlin, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20071030
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Insulin)
RN  - 0 (tau Proteins)
RN  - 1W21G5Q4N2 (Okadaic Acid)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
RN  - G4962QA067 (Lithium Chloride)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Glycogen Synthase Kinase 3/*metabolism
MH  - Immunoblotting
MH  - Insulin/pharmacology
MH  - Lithium Chloride/pharmacology
MH  - Mice
MH  - Okadaic Acid/pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/*metabolism
MH  - Protein Phosphatase 2/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - *Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - tau Proteins/*metabolism
EDAT- 2007/11/01 09:00
MHDA- 2008/06/18 09:00
CRDT- 2007/11/01 09:00
PHST- 2007/11/01 09:00 [pubmed]
PHST- 2008/06/18 09:00 [medline]
PHST- 2007/11/01 09:00 [entrez]
AID - S0021-9258(20)71367-0 [pii]
AID - 10.1074/jbc.M704292200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Jan 4;283(1):100-109. doi: 10.1074/jbc.M704292200. Epub 2007 
      Oct 30.