PMID- 12393899
OWN - NLM
STAT- MEDLINE
DCOM- 20030212
LR  - 20220310
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 277
IP  - 51
DP  - 2002 Dec 20
TI  - ERK1/2 antagonizes glycogen synthase kinase-3beta-induced apoptosis in cortical 
      neurons.
PG  - 49577-84
AB  - Inhibition of glycogen synthase kinase-3beta (GSK3beta) is one of the mechanisms 
      by which phosphatidylinositol 3-kinase (PI3K) activation protects neurons from 
      apoptosis. Here, we report that inhibition of ERK1/2 increased the basal activity 
      of GSK3beta in cortical neurons and that both ERK1/2 and PI3K were required for 
      brain-derived neurotrophic factor (BDNF) suppression of GSK3beta activity. 
      Moreover, cortical neuron apoptosis induced by expression of recombinant GSK3beta 
      was inhibited by coexpression of constitutively active MKK1 or PI3K. Activation 
      of both endogenous ERK1/2 and PI3K signaling pathways was required for BDNF to 
      block apoptosis induced by expression of recombinant GSK3beta. Furthermore, 
      cortical neuron apoptosis induced by LY294002-mediated activation of endogenous 
      GSK3beta was blocked by expression of constitutively active MKK1 or by BDNF via 
      stimulation of the endogenous ERK1/2 pathway. Although both PI3K and ERK1/2 
      inhibited GSK3beta activity, neither had an effect on GSK3beta phosphorylation at 
      Tyr-216. Interestingly, PI3K (but not ERK1/2) induced the inhibitory 
      phosphorylation of GSK3beta at Ser-9. Significantly, coexpression of 
      constitutively active MKK1 (but not PI3K) still suppressed neuronal apoptosis 
      induced by expression of the GSK3beta(S9A) mutant. These data suggest that 
      activation of the ERK1/2 signaling pathway protects neurons from GSK3beta-induced 
      apoptosis and that inhibition of GSK3beta may be a common target by which ERK1/2 
      and PI3K protect neurons from apoptosis. Furthermore, ERK1/2 inhibits GSK3beta 
      activity via a novel mechanism that is independent of Ser-9 phosphorylation and 
      likely does not involve Tyr-216 phosphorylation.
FAU - Hetman, Michal
AU  - Hetman M
AD  - Departments of Environmental Health and Pharmacology, University of Washington, 
      Seattle, WA 98195-7234, USA.
FAU - Hsuan, Shih-Ling
AU  - Hsuan SL
FAU - Habas, Agata
AU  - Habas A
FAU - Higgins, Matthew J
AU  - Higgins MJ
FAU - Xia, Zhengui
AU  - Xia Z
LA  - eng
GR  - AG 19193/AG/NIA NIH HHS/United States
GR  - NS 37359/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20021021
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Culture Media, Serum-Free)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - 42HK56048U (Tyrosine)
RN  - 452VLY9402 (Serine)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.1 (Gsk3b protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Culture Media, Serum-Free/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/pharmacology
MH  - Glycogen Synthase Kinase 3/*metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - MAP Kinase Kinase 1
MH  - Mitogen-Activated Protein Kinase 1/*metabolism
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Mutagenesis, Site-Directed
MH  - Neurons/metabolism/*pathology
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - Plasmids/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Proteins/metabolism
MH  - Serine/chemistry/metabolism
MH  - Signal Transduction
MH  - Transfection
MH  - Tyrosine/chemistry/metabolism
EDAT- 2002/10/24 04:00
MHDA- 2003/02/14 04:00
CRDT- 2002/10/24 04:00
PHST- 2002/10/24 04:00 [pubmed]
PHST- 2003/02/14 04:00 [medline]
PHST- 2002/10/24 04:00 [entrez]
AID - S0021-9258(19)32931-X [pii]
AID - 10.1074/jbc.M111227200 [doi]
PST - ppublish
SO  - J Biol Chem. 2002 Dec 20;277(51):49577-84. doi: 10.1074/jbc.M111227200. Epub 2002 
      Oct 21.