| First Author | Teng L | Year | 2012 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 32 |
| Issue | 6 | Pages | 1488-96 |
| PubMed ID | 22460559 | Mgi Jnum | J:346503 |
| Mgi Id | MGI:7616541 | Doi | 10.1161/ATVBAHA.112.247775 |
| Citation | Teng L, et al. (2012) Divergent effects of p47(phox) phosphorylation at S303-4 or S379 on tumor necrosis factor-alpha signaling via TRAF4 and MAPK in endothelial cells. Arterioscler Thromb Vasc Biol 32(6):1488-96 |
| abstractText | 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. |
