Overcoming Amino-Nogo-induced Inhibition of Cell Spreading and Neurite Outgrowth by 12-O-Tetradecanoylphorbol-13-acetate-type TumorPromoters

TY - JOUR

T1 - Overcoming Amino-Nogo-induced Inhibition of Cell Spreading and Neurite Outgrowth by 12-O-Tetradecanoylphorbol-13-acetate-type TumorPromoters

AU - Deng, Kangwen

AU - Gao, Ying

AU - Cao, Zixuan

AU - Graziani, Edmund I.

AU - Wood, Andrew

AU - Doherty, Patrick

AU - Walsh, Frank S.

PY - 2010/2/26

Y1 - 2010/2/26

N2 - The N-terminal domain of NogoA, called amino-Nogo, inhibits axonal outgrowth and cell spreading via a largely unknown mechanism. In the present study, we show that amino-Nogo decreases Rac1 activity and inhibits fibroblast spreading. 12-O-Tetradecanoylphorbol-13-acetate-type tumor promoters, such as phorbol 12-myristate 13-acetate (PMA) and teleocidin, increase Rac1 activity and overcome the amino-Nogo-induced inhibition of cell spreading. The stimulating effect of tumor promoters on cell spreading requires activation of protein kinase D and the subsequent activation of Akt1. Furthermore, we identified Akt1 as a new signaling component of the amino-Nogo pathway. Akt1 phosphorylation is decreased by amino-Nogo. Activation of Akt1 with a cell-permeable peptide, TAT-TCL1, blocks the amino-Nogo inhibition. Finally, we provide evidence that these signaling pathways operate in neurons in addition to fibroblasts. Our results suggest that activation of protein kinase D and Akt1 are approaches to promote axonal regeneration after injury.

AB - The N-terminal domain of NogoA, called amino-Nogo, inhibits axonal outgrowth and cell spreading via a largely unknown mechanism. In the present study, we show that amino-Nogo decreases Rac1 activity and inhibits fibroblast spreading. 12-O-Tetradecanoylphorbol-13-acetate-type tumor promoters, such as phorbol 12-myristate 13-acetate (PMA) and teleocidin, increase Rac1 activity and overcome the amino-Nogo-induced inhibition of cell spreading. The stimulating effect of tumor promoters on cell spreading requires activation of protein kinase D and the subsequent activation of Akt1. Furthermore, we identified Akt1 as a new signaling component of the amino-Nogo pathway. Akt1 phosphorylation is decreased by amino-Nogo. Activation of Akt1 with a cell-permeable peptide, TAT-TCL1, blocks the amino-Nogo inhibition. Finally, we provide evidence that these signaling pathways operate in neurons in addition to fibroblasts. Our results suggest that activation of protein kinase D and Akt1 are approaches to promote axonal regeneration after injury.

U2 - 10.1074/jbc.M109.071548

DO - 10.1074/jbc.M109.071548

M3 - Article

SN - 1083-351X

VL - 285

SP - 6425

EP - 6433

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 9

ER -