PMID- 22460559
OWN - NLM
STAT- MEDLINE
DCOM- 20120713
LR  - 20220316
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Linking)
VI  - 32
IP  - 6
DP  - 2012 Jun
TI  - Divergent effects of p47(phox) phosphorylation at S303-4 or S379 on tumor 
      necrosis factor-alpha signaling via TRAF4 and MAPK in endothelial cells.
PG  - 1488-96
LID - 10.1161/ATVBAHA.112.247775 [doi]
AB  - OBJECTIVE: To define the mechanism of p47(phox) phosphorylation in regulating 
      endothelial cell response to tumor necrosis factor-alpha (TNFalpha) stimulation. METHODS 
      AND RESULTS: We replaced 11 serines (303-4, 310, 315, 320, 328, 345, 348, 359, 
      370, and 379) with alanines and investigated their effects on TNFalpha (100 U/mL, 30 
      minutes)-induced acute O(2)(.-) production and mitogen-activated protein kinase 
      phosphorylation in endothelial cells. Seven constructs, S303-4A (double), S310A, 
      S315A, S328A, S345A, S370A, and S379A, significantly reduced the O(2)(.-) 
      production, and 4 of them (S328A, S345A, S370A, and S379A) also inhibited 
      TNFalpha-induced extracellular-signal-regulated kinase (ERK) 1/2 phosphorylation. 
      Blocking the phosphorylation of S303-4 and S379 inhibited most effectively 
      TNFalpha-induced O(2)(.-) production. However, phosphorylation of S303-4 was not 
      required for TNFalpha-induced p47(phox) membrane translocation and binding to TNF 
      receptor-associated factor 4, ERK1/2 activation, and subsequent vascular cell 
      adhesion molecule-1 expression. Knockout of p47(phox) or knockdown of TNF 
      receptor-associated factor 4 using siRNA abolished TNFalpha-induced ERK1/2 
      phosphorylation, and inhibition of ERK1/2 activation significantly reduced the 
      TNFalpha-induced vascular cell adhesion molecule-1 expression. CONCLUSIONS: 
      Phosphorylation of p47(phox) at different serine sites plays distinct roles in 
      endothelial cell response to TNFalpha stimulation. Double serine (S303-4) 
      phosphorylation is crucial for acute O(2)(.-) production, but is not involved in 
      TNFalpha signaling through TNF receptor-associated factor 4 and ERK1/2. p47(phox) 
      requires serine phosphorylation at distinct sites to support specific signaling 
      events in response to TNFalpha.
FAU - Teng, Lei
AU  - Teng L
AD  - Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey 
      GU2 7XH, UK.
FAU - Fan, Lampson M
AU  - Fan LM
FAU - Meijles, Daniel
AU  - Meijles D
FAU - Li, Jian-Mei
AU  - Li JM
LA  - eng
GR  - 07863/Z/05/Z/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120329
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (TNF Receptor-Associated Factor 4)
RN  - 0 (Traf4 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
RN  - 11062-77-4 (Superoxides)
RN  - 452VLY9402 (Serine)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.1 (neutrophil cytosolic factor 1)
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)
SB  - IM
MH  - Animals
MH  - COS Cells
MH  - Chlorocebus aethiops
MH  - Endothelial Cells/*enzymology
MH  - Enzyme Activation
MH  - Humans
MH  - *MAP Kinase Signaling System
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Mutagenesis, Site-Directed
MH  - NADPH Oxidases/deficiency/genetics/*metabolism
MH  - Phosphorylation
MH  - Protein Transport
MH  - RNA Interference
MH  - Serine
MH  - Superoxides/metabolism
MH  - TNF Receptor-Associated Factor 4/*metabolism
MH  - Time Factors
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism
MH  - Vascular Cell Adhesion Molecule-1/metabolism
EDAT- 2012/03/31 06:00
MHDA- 2012/07/14 06:00
CRDT- 2012/03/31 06:00
PHST- 2012/03/31 06:00 [entrez]
PHST- 2012/03/31 06:00 [pubmed]
PHST- 2012/07/14 06:00 [medline]
AID - ATVBAHA.112.247775 [pii]
AID - 10.1161/ATVBAHA.112.247775 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1488-96. doi: 
      10.1161/ATVBAHA.112.247775. Epub 2012 Mar 29.